bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–07–05
72 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.
  2. A Critical Role for Mitochondrial Dynamics in Cigarette Smoke Condensate-induced RPE Senescence.
  3. BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.
  4. Exercise and dietary interventions in the regulation of hepatic mitophagy and liver recovery (Review).
  5. Elucidating the NETs-BNIP3-pyroptosis axis in cerebral ischemia-reperfusion injury and the intervention of Bu Yang Huan Wu decoction.
  6. Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.
  7. Novel therapeutic strategies targeting mitochondrial quality control for metabolic dysfunction-associated steatotic liver disease.
  8. Mitochondrial Dysfunction and Diabetic Retinopathy: Research Progress from Pathogenic Mechanisms to Therapeutic Targets.
  9. Sirtuin 3 alleviates ovarian granulosa cell senescence through regulating mitochondrial quality control.
  10. AMPK orchestrates mitochondrial homeostasis via dynamics and mitophagy to combat hypoxia-induced energetic crisis in keratocytes.
  11. Restoration of macrophage mitochondrial dynamics and trafficking with enzymatic magnesium-manganese layered double hydroxide for osteoporotic therapy.
  12. [Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis].
  13. ClpP deficiency attenuates contrast-induced HK-2 cell injury through changes associated with mitochondrial dynamics and apoptosis.
  14. Traditional Chinese medicine-derived monomers improve bone metabolic imbalance and delay osteoporosis progression by regulating mitochondrial homeostasis.
  15. Systems modelling of mitochondrial dynamics in different exercise regimes.
  16. High glucose-induced mitochondrial fission promotes Müller cell activation via suppression of the Hippo pathway.
  17. IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.
  18. Tau protein as a regulator of mitochondrial function and dynamics.
  19. Cuminal-triggered mitophagy induces mitochondrial dysfunction, resulting in decreased vegetative growth and pathogenicity in Trichothecium roseum.
  20. [Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].
  21. Tanshinone IIA promotes mitophagy by inhibiting the MARCHF5-mediated ubiquitination and degradation of FUNDC1 to alleviate spinal cord injury.
  22. DRP1-mediated mitophagy facilitates oral squamous cell carcinoma tumor cell survival under glucose restriction.
  23. Exploring Sevoflurane promotes hippocampal neuron mitophagy in elderly postoperative cognitive dysfunction by HSP90AA1 based on network pharmacology.
  24. Impairments in mitochondrial dynamics and morphology in skeletal muscle of breast cancer patients after a single paclitaxel administration.
  25. Silibinin promotes hepatocyte proliferation through PINK1/Parkin-mediated mitophagy to alleviate acetaminophen-induced liver injury.
  26. Krüppel-like Factor 2 (KLF2) Regulates Autophagy, Mitophagy, Mitochondrial Health, and Function During Foam Cell Formation.
  27. EGR1 Mediates Ursodeoxycholic Acid-Promoted Mitophagy to Prevent Postovulatory Aging of Porcine Oocytes.
  28. Qiteng Xiaozhuo granules activate mitophagy to alleviate chronic glomerulonephritis.
  29. A thermosensitive TET-Parkin epigenetic axis couples mitochondrial quality control to adaptive thermogenesis in adipose tissue.
  30. miR-205-5p accelerates lung fibroblast senescence in IPF patients via mediation of mitochondrial dynamics.
  31. Laggera alata attenuates LPS‑induced systemic inflammation and hepatic‑pulmonary injury by regulating PINK1/Parkin-associated mitophagy and macrophage polarization.
  32. Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation.
  33. Syntabulin promotes heart failure by enhancing SR-mitochondria tethering and impairing mitofission.
  34. Fangchinoline alleviates hypertensive heart failure via PGC-1α/STAT6/PPARγ activation of mitophagy against ferroptosis.
  35. Jiedu Huoxue decoction inhibits cardiomyocyte apoptosis via PTEN/AKT/GSK3β-mediated mitochondrial dynamics in myocardial infarction: an integrative study of network pharmacology, transcriptomics and molecular docking.
  36. Endothelial mitochondrial homeostasis in the development and progression of atherosclerosis.
  37. A zinc-coordinated cascade-responsive therapeutic nanoassembly for remodeling the pathological microenvironment and restoring mitochondrial homeostasis in spinal cord injury.
  38. Arsenic Exposure Induces Hepatic Fibrosis and Triggers Early Inflammatory Responses by Inhibiting Hepatic Stellate Cell PINK1/Parkin-Mediated Mitophagy.
  39. Nrf2 Activators in Parkinson's Disease: Modulating Mitophagy and Regulating Cuproptosis.
  40. Activin A mitigates ferroptosis in cerebral ischemia/reperfusion injury via the PGC-1α/NRF1/TFAM axis.
  41. Mapk-driven remodeling of mitochondrial dynamics in melanoma: implications for metabolic plasticity and response to targeted therapy.
  42. The multifaceted roles of mitochondria and their therapeutic transformation: a new perspective on triple-negative breast cancer treatment.
  43. DHRS2 as a Novel Thalidomide Target Regulating Mitophagy and Inflammation in Head and Neck Squamous Cell Carcinoma.
  44. KLF15 activates PGC1α to rewire mitochondrial homeostasis and overcome cisplatin resistance in lung adenocarcinoma.
  45. Phenotyping of post-fertilization sperm mitophagy determinants discovered in a mammalian gamete-based cell-free system.
  46. A Forward Genetic Screen in Caenorhabditis elegans for Genes that Modulate α-synuclein-Induced Neurodegeneration through the Mitochondrial UPR.
  47. Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.
  48. Domain-Specific Genotype-Phenotype Correlations in DNM1L Disorders: Insights Into Mutation Hotspots and Clinical Severity.
  49. Tegument protein UL16 of herpes simplex virus 1 suppresses the innate immune response by downregulating MAVS abundance via mitophagy.
  50. A magnetic-acoustic dual-fesponsive nanoplatform for targeted PPARδ activation attenuates adolescent idiopathic scoliosis progression.
  51. Effects of Quercetagetin on Gut-Liver Axis Function and Cecal Microbial Diversity in Broilers via PINK1/Parkin-Mediated Mitophagy.
  52. When mitochondria lose their fold: matrix proteostasis and stress signaling.
  53. Cardiac extracellular vesicle proteomics identifies mitochondrial and contractile dysfunction in carbon monoxide poisoning and their reversal by hyperbaric oxygen therapy.
  54. 3D matrix stiffness drives energy metabolism to orchestrate stem cell osteogenesis via microtubule acetylation and mitochondrial dynamics.
  55. Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data.
  56. [Chrysophanol alleviates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and inhibiting M1 macrophage polarization].
  57. CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations.
  58. A multifunctional graphene oxide-based nanoplatform sensitizes ovarian cancer to cisplatin via ROS-PINK1/Parkin mitophagy under chemo-photothermal-photodynamic synergy.
  59. GPR4 promotes ferroptosis in nucleus pulposus cells via MAPK-dependent mitophagy suppression.
  60. Corrigendum to "Bushentongluo formula counteracts BMSCs senescence to alleviate postmenopausal osteoporosis by activating mitophagy via the SENP1-SIRT3 pathway" [Phytomedicine 152 (2026) 157827].
  61. Metabolic reprogramming, oxidative stress, and mitophagy in JSRV Env-transformed BEAS-2B cells: insights from integrated transcriptomics and metabolomics.
  62. Mitochondrial stress markers associate with phenotypic variability in Fabry disease.
  63. Correction: Mitophagy protects renal tubular epithelial cells from intermittent hypoxia-induced injury via the HIF-1α/BNIP3 pathway.
  64. Norepinephrine attenuates acute lung injury by protecting mitochondria via the β2-AR-AKAP1 axis and inhibiting alveolar epithelial pyroptosis.
  65. Hierarchical Studies in TRAP2 Mice Demonstrate that Neuronal Activation and Mitochondrial Networks Integration Constitute the Key Mechanism Underlying Painful Syncope.
  66. Mitochondrial quality control in human ageing and longevity.
  67. RyR1 Calcium Leak and Mitochondrial Ca2+ Homeostasis in Skeletal Muscle.
  68. NRF1 Activates the AMPK/SIRT1/PGC-1α/TFAM Axis to Suppress EMT and Tumor Progression in Lung Adenocarcinoma.
  69. Single-cell and pseudobulk analyses reveal hidden mitochondrial expression imbalance in gastric cancer.
  70. Zinc-polydopamine nanozyme promotes mitochondrial biogenesis and alleviates inflammation and muscle atrophy during the perioperative period of surgery.
  71. Bio-recruiting hydrogel targeting mitochondrial homeostasis under neutrophil extracellular traps for diabetic wound repair.
  72. DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
  1. iScience. 2026 Jul 17. 29(7): 116449
    Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.
    Enming Qiu, Guoqing Lv, Jianing Hou, Zhou Li, Gang Wang.
      Mitophagy is a selective autophagy that degrades dysfunctional mitochondria to maintain cellular homeostasis. Mitophagy is functionally coordinated with and regulated by mitochondrial biogenesis and mitochondrial dynamics, which include mitochondrial fusion, mitochondrial fission, and mitochondrial trafficking. Furthermore, researches have demonstrated that mitophagy plays a critical role in the occurrence and development of digestive cancer. Nonetheless, the mechanism of how mitophagy modulates digestive cancer and the mechanism of how mitochondrial biogenesis and dynamics influence mitophagy warrant more investigations. This review summarizes the current understanding of the regulatory mechanism of mitophagy and outlines recent advances from investigations that explore how mitochondrial biogenesis and dynamics coordinate with mitophagy. Additionally, this review provides a comprehensive view about how mitophagy could regulate the occurrence and development of digestive cancer. A deeper understanding about the role of mitophagy in regulation of digestive cancer benefits the development of more efficient therapeutic strategies for patients.
    Keywords:  Biological sciences
    DOI:  https://doi.org/10.1016/j.isci.2026.116449
  2. Free Radic Biol Med. 2026 Jul 01. pii: S0891-5849(26)00915-9. [Epub ahead of print]
    A Critical Role for Mitochondrial Dynamics in Cigarette Smoke Condensate-induced RPE Senescence.
    Qi Zhou, Zunyi Zhang, Yinga Wu, Chunmin Dong, Chen-Chuan Wu, James T Handa, Jing Ma, Shusheng Wang.
      Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Its pathogenesis remains incompletely understood, partly due to the complex interplay of genetic risk, aging, and environmental stressors. Cigarette smoking (CS) is a major modifiable risk factor for AMD, yet the mechanism linking CS to disease progression remains unclear. We hypothesize that CS accelerates AMD pathogenesis by exacerbating cellular senescence in the retinal pigment epithelium (RPE), thereby driving age-related RPE dysfunction and degeneration. In this study, differentiated ARPE-19 cells or mice were exposed to low-dose cigarette smoke condensate (CSC), and stress-induced senescence-like RPE phenotypes were induced, characterized by increased senescence markers, mitochondrial dysfunction, and retinal functional impairment. RPE senescence phenotypes were also confirmed in mice exposed to 6 months of CS in the smoking chamber. CSC-induced RPE senescence was associated with a biphasic alteration in mitochondrial morphology, progressing from early mitochondrial fragmentation to late mitochondrial hyperfusion, as well as impaired mitophagy flux, reduced mitochondrial turnover, and decreased mitochondrial biogenesis. Mechanistically, CSC increased dynamin-related protein 1 (DRP1) phosphorylation and promoted cleavage of the mitochondrial phosphatase PGAM5, mitochondrial remodeling associated with decreased DRP1 activities, elevated mitochondrial oxidative stress, and activation of mTOR signaling. Notably, overexpression of a DRP1 activity mutant (K38A) mimics the CSC-induced RPE senescence, while overexpression of the phosphodeficient DRP1-S637A mutant significantly attenuates both mTOR signaling and CSC-induced RPE senescence by restoring mitochondrial fission balance, improving mitochondrial quality-control responses, reducing mitochondrial oxidative stress. Collectively, these findings identify impaired DRP1-dependent mitochondrial remodeling as a key mechanism linking CSC exposure to RPE senescence. While we confirmed the RPE senescence phenotype in mice after 6 months of CS exposure, the specific mechanisms observed in this study require further validation in a chronic CS model. These findings encourage future research into mitochondrial dynamics and RPE senescence in AMD, suggesting that modulating RPE mitochondrial dynamics holds therapeutic potential for delaying AMD progression.
    Keywords:  Age-related macular degeneration; Cellular senescence; Cigarette smoke; DRP1; Mitochondrial ROS; Mitochondrial dynamics; Mitophagy; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.060
  3. J Biochem. 2026 Jun 30. pii: mvag048. [Epub ahead of print]
    BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.
    Tamara Ginevskaia, Takayuki Mito, Keiichi Inoue, Tomotake Kanki.
      Mitochondria are essential for cellular metabolism and homeostasis, and their quality and quantity must therefore be tightly controlled. Mitophagy, a selective form of autophagy targeting mitochondria, contributes to this control by eliminating damaged or superfluous mitochondria. Among the known mitophagy pathways, BNIP3/NIX-dependent mitophagy has emerged as a key mechanism, particularly under hypoxic and metabolic stress. Recent studies have provided important insights into how BNIP3 and NIX are transcriptionally induced, post-translationally regulated, and functionally coupled to the core autophagy machinery. These studies have also clarified their roles in isolation membrane tethering, membrane elongation, and mitophagosome formation. Beyond its molecular basis, accumulating evidence indicates that BNIP3/NIX-dependent mitophagy contributes to mitochondrial homeostasis, redox balance, and cellular stress adaptation. This review summarizes recent progress in understanding the molecular mechanisms and physiological significance of BNIP3/NIX-dependent mitophagy.
    DOI:  https://doi.org/10.1093/jb/mvag048
  4. Biomed Rep. 2026 Aug;25(2): 96
    Exercise and dietary interventions in the regulation of hepatic mitophagy and liver recovery (Review).
    Julia Windi Gunadi, Diana Krisanti Jasaputra, Faysal Kastella, Shanti Shanti, Ronny Lesmana.
      The high metabolic demand of the liver renders it dependent on mitophagy for mitochondrial quality control. While exercise and nutritional interventions are known to influence hepatic mitophagy, the precise regulatory mechanisms remain incompletely understood. Mitophagy in the liver is influenced by a combination of exercise-related parameters, dietary factors and sex-specific biological factors. Drawing from 19 animal studies published between 2016 and 2026, the present narrative review examines how different exercise modalities and dietary interventions regulate hepatic mitophagy. Among models of obesity and metabolic dysfunction, structured endurance training and higher-intensity exercise protocols yield better capacity to re-establish coordinated mitochondrial quality control than voluntary or low-intensity physical activity protocols. Notably, a single bout of exercise can produce a transient elevation in mitophagic flux, whereas sustained training over time expands mitophagy capacity without necessarily maintaining heightened flux at rest. Moderate-intensity continuous training more effectively restores canonical PTEN-induced kinase 1/Parkin-dependent flux, whereas high-intensity interval training favors structural mitochondrial recovery and upstream energetic signaling, although the relative efficacy depends on the model, disease severity and readout assessed. In high-fat or Western dietary settings, mitophagy is often compromised, with exercise producing incomplete recovery unless paired with improved diet or weight loss. These responses are also influenced by sex differences: Females tend to maintain higher intrinsic mitochondrial quality with less inducible mitophagy, whereas males exhibit a greater reliance on exercise-induced activation of mitophagy. Paternal and maternal developmental programming has also emerged as an important modulator of mitophagy induction. In conclusion, mitophagy in the liver is modified by different exercise and dietary interventions in a manner that is further conditioned by sex and developmental history.
    Keywords:  exercise; metabolic dysfunction-associated steatotic liver disease; mitophagy; paternal programming; sex differences
    DOI:  https://doi.org/10.3892/br.2026.2169
  5. Phytomedicine. 2026 Jun 12. pii: S0944-7113(26)00622-7. [Epub ahead of print]159 158390
    Elucidating the NETs-BNIP3-pyroptosis axis in cerebral ischemia-reperfusion injury and the intervention of Bu Yang Huan Wu decoction.
    Tianci Zhang, Shu Han Guo, Tiangang Zheng, Xiaohan Chen, Zhuorui Xu, Xiaohong Zhou, Weijuan Gao.
       BACKGROUND: Cerebral ischemia‑reperfusion injury (CIRI) leads to poor stroke outcomes, partly due to sustained endothelial damage triggered by neutrophil extracellular traps (NETs) during the subacute phase. However, the exact downstream pathways through which NETs drive endothelial cell death, and whether Buyang Huanwu Decoction (BHD) intervenes in this process, remain unclear.
    OBJECTIVE: To investigate how NETs induce endothelial injury in CIRI and to evaluate the protective effects of BHD.
    METHODS: Chemical profiling of BHD aqueous extract and BHD‑containing serum was performed by UHPLC‑HRMS. A rat transient middle cerebral artery occlusion (tMCAO) model and an in vitro model of primary brain microvascular endothelial cells (BMECs) subjected to oxygen‑glucose deprivation/reperfusion (OGD/R) together with isolated NETs were used. Network pharmacology and transcriptomics were applied to predict key targets. NET formation was dynamically monitored. Functional experiments included a pyroptosis inhibitor, mitophagy modulators, BHD, and lentivirus‑mediated BNIP3 knockdown/overexpression.
    RESULTS: Absorbable components of BHD included calycosin‑7‑O‑β‑D‑glucoside, hydroxysafflor yellow A, and paeoniflorin. BHD improved neurological deficits, reduced infarct volume, and preserved blood‑brain barrier integrity in tMCAO rats. NETs peaked on day 3 after reperfusion and were suppressed by BHD. Mechanistically, NETs synergized with OGD/R to overactivate BNIP3, leading to dysregulated mitophagic flux and subsequent NLRP3/caspase‑1/GSDMD‑mediated endothelial pyroptosis. BNIP3 knockdown attenuated this cascade, whereas BNIP3 overexpression mimicked the damaging effects. BHD inhibited this NETs‑BNIP3‑pyroptosis cascade. In parallel, BHD partially restored mitochondrial dynamics (p‑DRP1, FIS1, MFN1) and promoted mitochondrial biogenesis (PGC‑1α, SIRT1, TFAM), consistent with its multi‑target regulation of mitochondrial quality control. Furthermore, under BNIP3 overexpression, BHD still reduced mitophagy and pyroptosis markers, indicating BNIP3‑independent protective effects.
    CONCLUSION: These findings suggest that in CIRI, delayed NET formation overactivates BNIP3‑driven mitophagy and triggers endothelial pyroptosis. BHD exerts neurovascular protection by interfering with this NETs‑BNIP3‑pyroptosis axis while also improving mitochondrial dynamics and biogenesis as parallel protective mechanisms. This study provides experimental evidence for the pathogenic role of NETs and the multi‑target action of BHD in CIRI.
    Keywords:  Buyang huanwu decoction; Cerebral ischemia-reperfusion injury; Mitophagy; Neutrophil extracellular traps; Pyroptosis
    DOI:  https://doi.org/10.1016/j.phymed.2026.158390
  6. FASEB J. 2026 Jul 15. 40(13): e72089
    Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.
    Julien Goldstick, Diego Compte, Chun-Ling Sun, Alison E Ritter, C Michael Crowder.
      Hypoxia induces mitochondrial fragmentation. Whether this fragmentation promotes or prevents cell death and whether the mitochondrial dynamics machinery plays a role are unresolved. To address these questions, we measured the effect of hypoxia on mitochondrial morphology in a Caenorhabditis elegans Raptor mutant resistant to hypoxic death and in mutants with disrupted mitochondrial fission and fusion. The Raptor loss-of-function mutant reduced hypoxia-induced mitochondrial fragmentation and death. However, forcing mitochondrial fragmentation prior to hypoxia by combining the Raptor mutation with a loss-of-function mutation in mitofusin did not increase hypoxic death. A loss-of-function mutation in drp-1, which is required for mitochondrial fission, did not block hypoxia-induced mitochondrial fragmentation nor enhance Raptor hypoxia resistance; rather, drp-1(lf) was surprisingly mildly hypoxia resistant and partially suppressed the high-level hypoxia resistance of the Raptor mutant. Likewise, loss of DRP-1 function interacted synthetically with the Raptor(lf) mutant to produce tangled mitochondria, demonstrating a role of Raptor in maintenance of the mitochondrial network. Vitamin B12 supplementation and feeding with a bacterial strain replete in vitamin B12 mitigated hypoxia-induced mitochondrial fragmentation. Our results demonstrate that fragmented mitochondria do not necessarily promote hypoxic cell death, and hypoxia-induced mitochondrial fragmentation is mechanistically distinct from physiological mitochondrial fission.
    DOI:  https://doi.org/10.1096/fj.202601561R
  7. Front Physiol. 2026 ;17 1803228
    Novel therapeutic strategies targeting mitochondrial quality control for metabolic dysfunction-associated steatotic liver disease.
    Huiling Zuo, Jiaxin Chen, Yuhang Jiao, Xuan Ma, Xiangqiong Li, Yahui Xiao, Jiamei He, Zhuangzhuang Jia, Anhua Shi.
      Epidemiological evidence demonstrates that metabolic dysfunction-associated steatotic liver disease (MASLD) has evolved into one of the most widespread chronic liver disorders globally, posing a serious public health challenge. From a mechanistic perspective, the initiation of MASLD is predominantly fueled by multiple factors. Multiple pathological processes, including insulin resistance, oxidative stress, and inflammatory response, are all closely associated with the core issue of mitochondrial dysfunction. Mitochondria, serving as the hub for cellular energy metabolism, exhibit dysfunction that is widely recognized as the key nexus underlying the initiation and progression of MASLD. Maintaining mitochondrial homeostasis is the core mission of the mitochondrial quality control (MQC) system. The MQC system maintains mitochondrial homeostasis by the precise modulation of pathways including mitochondrial biogenesis (MB), mitochondrial dynamics (fusion and fission), and mitophagy. Hence, dysregulation of the MQC system may promote the pathological progression of MASLD. During the MASLD process, continuous metabolic stress disrupts the balance of MQC, and the dysregulation of MQC further exacerbates hepatocyte lipotoxicity damage, forming a vicious cycle. This review elucidates the mechanisms of MQC in MASLD as well as the latest findings. At the same time, we analyze in depth the regulatory mechanisms of each component of MQC and further explored therapeutic strategies of targeting mitochondria.
    Keywords:  metabolic dysfunction-associated steatotic liver disease (MASLD); mitochondrial; mitochondrial dysfunction; mitochondrial quality control (MQC); therapeutic strategies
    DOI:  https://doi.org/10.3389/fphys.2026.1803228
  8. Exp Eye Res. 2026 Jul 03. pii: S0014-4835(26)00313-1. [Epub ahead of print] 111157
    Mitochondrial Dysfunction and Diabetic Retinopathy: Research Progress from Pathogenic Mechanisms to Therapeutic Targets.
    Xiaoyan Zhu, Tao Jin, Yu Zhang, Lulu Lian, Wanli Du.
      Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus (DM) and remains a major cause of visual impairment and blindness in adults. Accumulating evidence indicates that DR is not merely a microvascular disorder, but a complex neurovascular disease driven by long-standing hyperglycemia, metabolic dysregulation, oxidative stress, chronic inflammation, neurodegeneration, and impaired neurovascular coupling. Mitochondria are central regulators of cellular energy metabolism and redox homeostasis, and mitochondrial dysfunction is increasingly recognized as a pivotal mechanism linking hyperglycemia-induced metabolic abnormalities to retinal neurovascular unit injury. Under persistent hyperglycemic conditions, excessive glucose flux and metabolic overload promote mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial DNA (mtDNA) damage, impaired oxidative phosphorylation, mitochondrial fusion-fission imbalance, defective mitochondrial biogenesis, dysregulated mitophagy, metabolic reprogramming, and epigenetic alterations. These abnormalities lead to ATP depletion, inflammatory amplification, and activation of multiple forms of programmed cell death, including apoptosis, ferroptosis, pyroptosis, necroptosis, and poly(ADP-ribose) polymerase 1 (PARP1)-dependent cell death. Mitochondrial injury affects retinal endothelial cells, pericytes, Muller cells, microglia, retinal ganglion cells, photoreceptors, and retinal pigment epithelial cells in a cell-type-specific manner, ultimately contributing to blood-retinal barrier disruption, capillary occlusion, neurovascular coupling impairment, retinal neurodegeneration, and progression from non-proliferative to proliferative DR. This review summarizes recent advances in mitochondrial dysfunction in DR, focusing on oxidative stress, mtDNA injury, mitochondrial metabolic reprogramming, mitochondrial dynamics, mitochondrial biogenesis, mitophagy, epigenetic regulation, mitochondria-associated cell death, and neurovascular unit dysfunction. Emerging mitochondria-targeted therapeutic strategies, including mitochondrial antioxidants, modulation of mitochondrial biogenesis and dynamics, mitophagy regulation, mtDNA protection, ferroptosis and inflammasome inhibition, epigenetic intervention, are also discussed. A deeper understanding of mitochondrial mechanisms may provide new therapeutic targets and translational opportunities for DR prevention and treatment.
    Keywords:  diabetic retinopathy; epigenetic modification; mitochondrial DNA; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neurovascular unit; oxidative stress; therapeutic targets
    DOI:  https://doi.org/10.1016/j.exer.2026.111157
  9. Theriogenology. 2026 Jun 25. pii: S0093-691X(26)00244-X. [Epub ahead of print]264 118054
    Sirtuin 3 alleviates ovarian granulosa cell senescence through regulating mitochondrial quality control.
    Jingmiao Shi, Ziling Zhao, Fuguo Wang, Yongju Zhao, Zhongquan Zhao, Dejun Xu.
      Cellular senescence-triggered irreversible proliferative arrest leads to follicular atresia and suppressed dominant follicle selection. Mitochondrial sirtuin 3 (SIRT3) contributes substantially to mitochondrial function, yet the exact molecular mechanisms underlying its regulation of granulosa cell senescence remain largely elusive.‌ Here, single-cell transcriptomic profiling in goats revealed that the downregulation of SIRT3, together with cellular senescence and mitochondrial dysfunction, are the hallmark features of granulosa cells in aged ovarian follicles. Knockdown of SIRT3 led to cellular senescence, which was characterized by proliferative arrest, cell cycle dysregulation and DNA damage accumulation. Importantly, SIRT3 knockdown aggravated mitochondrial dysfunction, as evidenced by impaired mitophagy, elevated reactive oxygen species (ROS) and increased mitochondrial fragmentation. SIRT3 overexpression alleviated etoposide-induced senescence by restoring mitophagy and mitochondrial function. Transcriptomic profiling further confirmed the predominant involvement of SIRT3 in mitochondrial regulatory pathways. Collectively, our results reveal that SIRT3 alleviates granulosa cell senescence through the regulation of mitochondrial quality control, which is critical for sustaining physiological follicular development.
    Keywords:  Goat; Mitochondrial dysfunction; Mitophagy; SIRT3
    DOI:  https://doi.org/10.1016/j.theriogenology.2026.118054
  10. Cell Biol Toxicol. 2026 Jul 01.
    AMPK orchestrates mitochondrial homeostasis via dynamics and mitophagy to combat hypoxia-induced energetic crisis in keratocytes.
    Xinlin Yan, Yi Guan, Guozhen Chen, Shumei Yang, Zhengyu Cao, Xuan Li.
       BACKGROUND: Hypoxia disrupts corneal stromal physiology and alters cellular energy metabolism. This study aimed to elucidate the molecular role of the cellular energy sensor AMP-activated protein kinase (AMPK) in modulating the energy metabolism of human keratocytes (HKs) under hypoxic conditions and to explore a potential therapeutic strategy.
    METHODS: In vitro, HKs were exposed to 1% O₂ for 2 h and 24 h to simulate hypoxia. In vivo, a mouse corneal alkali burn model was established, in which hypoxia is recognized as an important contributing factor to tissue injury. The expression of AMPK and its influence on downstream pathways related to mitochondrial metabolism were investigated. The AMPK agonist AICAR was administered in these models to assess its effects. Key molecular pathways, including AMPK/MFF/DRP1, AMPK/MTFR1L/OPA1 (mitochondrial dynamics), and AMPK/ULK1/PINK1/PARKIN (mitophagy), were analyzed to understand the mechanisms of action.
    RESULTS: In vitro, hypoxia shifted HKs energy production from oxidative phosphorylation to anaerobic glycolysis over time, accompanied by AMPK upregulation. AICAR restored mitochondrial function, increased OCR, reduced ECAR and ROS, and improved mitochondrial membrane potential. AMPK knockdown abolished these protective effects. In vivo, AICAR treatment of alkali-burned mouse corneas significantly reduced corneal opacity and fluorescein staining scores, restored mitochondrial respiration and glycolysis balance. Mechanistically, AICAR activated AMPK to regulate mitochondrial dynamics via the AMPK/MFF/DRP1 and AMPK/MTFR1L/OPA1 pathways and enhanced mitophagy through the AMPK/ULK1/PINK1/PARKIN axis. This coordinated action increased mitochondrial oxidative phosphorylation capacity.
    CONCLUSIONS: Activation of AMPK via AICAR ameliorates hypoxia‑induced energy imbalance in HKs in vitro and in mouse corneal alkali burn in vivo by restoring mitochondrial homeostasis. This mechanism represents a novel therapeutic target for hypoxia-related keratopathy and suggests a promising approach for energy replacement therapy.
    Keywords:  AMPK; Human keratocyte; Hypoxia; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1007/s10565-026-10222-y
  11. J Nanobiotechnology. 2026 Jul 01.
    Restoration of macrophage mitochondrial dynamics and trafficking with enzymatic magnesium-manganese layered double hydroxide for osteoporotic therapy.
    Wenwen Mao, Kehan Wang, Jingxian Mao, Zhuobin Xu, Chun Pan, Dandan Li, Tingting Liu, Hao Chen, Huihui Wang, Cheng Huang, Sihan Hu.
      Macrophages play pivotal roles at the interface of immune regulation and bone metabolism and frequently exhibit a proinflammatory phenotype that contributes to the osteoporotic microenvironment. We found that dysfunctional macrophages in the osteoporotic niche transferred injured mitochondria to osteoblasts, which was associated with increased cellular senescence and impaired osteogenic function. This detrimental mitochondrial transfer was associated with abnormal accumulation of succinate dehydrogenase (SDH), contributing to maintenance of the proinflammatory phenotype and mitochondrial injury. On the basis of this mechanism, a folate (FA)-modified magnesium-manganese layered double hydroxide (MgMn-LDH) loaded with the SDH inhibitor dimethyl malonate (DMM) was designed to modulate proinflammatory macrophages. This system promoted BNIP3-LC3B-associated mitophagy, which was accompanied by improved mitochondrial quality control, mitochondrial dynamics and mitochondrial transfer capacity. The functional mitochondrial transfer from treated macrophages to neighboring osteoblasts was associated with enhanced osteogenic activity under osteoporotic conditions. Furthermore, MgMn-LDH/DMM@FA treatment significantly ameliorated bone loss and improved bone microarchitecture in ovariectomized mice. Collectively, these findings suggest that mitigating mitochondrial injury and enhancing functional mitochondrial transfer in proinflammatory macrophages may represent a promising strategy for alleviating osteoporosis. An enzyme-active MgMn-LDH-based delivery system provides a potential therapeutic platform for osteoporosis intervention.
    Keywords:  Enzyme-active layered double hydroxide; Macrophage; Mitochondrial homeostasis; Osteoporotic microenvironment; Succinate dehydrogenase
    DOI:  https://doi.org/10.1186/s12951-026-04761-z
  12. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2026 Jun 29. 1-13
    [Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis].
    Yumin Zhang, Feiyu Zhu, Xiaotian Wu, Zhansong Li, Peng Huang, Yanpan Gao, Linghui Zeng.
       OBJECTIVES: To investigate the regulatory role of epigenetic regulator disruptor of telomeric silencing 1-like (DOT1L) and its mediated histone H3 lysine 79 (H3K79) methylation in modulating neuronal amyloid precursor protein (APP) expression, and to elucidate the underlying mechanisms involving mitochondrial homeostasis and the upstream p38 kinase.
    METHODS: Alzheimer's disease (AD) models were established using APP/presenilin-1 (APP/PS1) double-transgenic mice and N2a cells overexpressing the human Swedish mutant APP (N2a-APPswe). Immunofluorescence staining was employed to assess DOT1L expression and localization in mouse brain tissues. N2a-APPswe cells were treated with the DOT1L-specific inhibitor EPZ5676 and divided into four groups: blank control, solvent control, DOT1L inhibitor, and DOT1L inhibitor plus p38 agonist (Gynostemma pentaphyllum extract). Western blotting was performed to measure the phosphorylation levels of DRP1 at Ser616 and Ser637 (key mitochondrial fission regulators), the levels of autophagy-related proteins p62 and the LC3-Ⅱ/LC3-Ⅰ ratio, the phosphorylation level of p38, as well as the expression of APP and APP-processing proteins BACE1 and PS1. Real-time quantitative polymerase chain reaction was used to detect mRNA levels of APP and genes involved in mitochondrial fission and fusion. Proteomics data were systematically analyzed through Gene Ontology analysis, WikiPathways enrichment analysis, and STRING protein-protein interaction network analysis to identify key signaling pathways. Mitochondrial morphology was evaluated by Mito-Tracker fluore-scence staining to measure average branch length.
    RESULTS: DOT1L expression was signifi-cantly reduced in neurons of APP/PS1 mice compared to wild-type controls. DOT1L inhibition led to decreased H3K79me2 levels (P<0.01), accompanied by a marked increase in APP protein expression (P<0.01), although APP mRNA levels were reduced (P<0.01). Proteomics analysis revealed that differentially expressed proteins were highly enriched in the mitochondrial electron transport chain. Compared with the solvent control, the DOT1L inhibitor group showed inhibited mitochondrial fission, as evidenced by decreased p-DRP1 (Ser616), increased p-DRP1 (Ser637), downregulated MIEF1 mRNA, upregulated MFN1 mRNA (all P<0.05), and increased average mitochondrial branch length (P<0.05), along with reduced p-p38 levels (P<0.05). Co-administration of the p38 agonist significantly reversed these mitochondrial dynamics abnormalities (all P<0.05) and attenuated the abnormally elevated protein levels of APP, BACE1, and PS1 (P<0.05) compared to the DOT1L inhibitor group.
    CONCLUSIONS: DOT1L maintains normal mito-chondrial fission and functional homeostasis through regulation of the p38 signaling pathway, thereby modulating APP expression.
    Keywords:  Alzheimer’s disease; Amyloid precursor protein; Amyloid β-protein; Disruptor of telomeric silencing 1-like; Epigenetic regulation; Mitochondrial fission; Mitochondrial fusion; p38 mitogen-activated protein kinase
    DOI:  https://doi.org/10.3724/zdxbyxb-2025-0706
  13. PLoS One. 2026 ;21(7): e0352422
    ClpP deficiency attenuates contrast-induced HK-2 cell injury through changes associated with mitochondrial dynamics and apoptosis.
    Jing Wang, Lei Wang, Liang Xie, Chengchun Tang.
       BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) is a renal impairment that occurs after several days of intravascular administration of iodine-containing contrast media. ClpP is a key protease that plays an important role in cellular mitochondrial function. This study investigated the role of ClpP in mitochondrial dynamics and early injury in an in‑vitro CA‑AKI model.
    METHODS: mRNA sequencing was performed on HK-2 cells with or without iohexol exposure. Cell viability, mitochondrial dynamics-related protein expression, mitochondrial membrane potential (MMP), and cell apoptosis were assessed by cell counting kit-8, immunoblotting, JC‑1 staining and flow cytometry, respectively.
    RESULTS: Iohexol treatment at 80 mg I/mL reduced HK-2 cell viability to 63.44%, induced mitochondrial fission, inhibited mitochondrial fusion and promoted apoptosis. mRNA sequencing revealed significant upregulation of Opa1 and ClpP gene expression, as well as alterations in proteasome‑related signaling in iohexol-induced HK-2 cell. Western blot analysis further confirmed elevated ClpP protein expression after iohexol exposure. Importantly, ClpP knockdown partially restored MMP, increased Opa1 expression, improved mitochondrial morphology, and alleviated iohexol‑induced apoptosis.
    CONCLUSION: ClpP deficiency may exert cytoprotective effects against iohexol-induced HK-2 cell injury, at least partly through changes associated with mitochondrial dynamics, partial preservation of MMP, and attenuation of apoptosis. These findings suggest that ClpP may represent a potential molecular target for further investigation in CA-AKI.
    DOI:  https://doi.org/10.1371/journal.pone.0352422
  14. Front Cell Dev Biol. 2026 ;14 1846467
    Traditional Chinese medicine-derived monomers improve bone metabolic imbalance and delay osteoporosis progression by regulating mitochondrial homeostasis.
    Baohui Wang, Bo Dong.
      Osteoporosis is a systemic metabolic bone disease characterized by reduced bone mass, microarchitectural deterioration, and increased fracture risk. Its pathogenesis is driven by an imbalance between insufficient osteoblast-mediated bone formation and excessive osteoclast-mediated bone resorption. In recent years, mitochondrial homeostasis has emerged as an important pathological hub in this process. Beyond energy production, mitochondria regulate redox balance, mitophagy, apoptosis, senescence, and metabolic adaptation in bone cells. When mitochondrial homeostasis is disrupted, excessive reactive oxygen species accumulation, impaired membrane potential, defective quality control, and metabolic insufficiency collectively suppress osteogenic capacity while promoting osteoclastic activity, ultimately aggravating bone loss. A growing body of evidence suggests that monomers derived from traditional Chinese medicine can partially restore bone metabolic balance by improving mitochondrial function, reducing oxidative stress, and modulating mitochondrial quality control. These compounds have been reported to promote osteoblast survival and differentiation while suppressing osteoclastogenesis and bone resorption. However, the current evidence remains uneven in depth and quality. Most studies are still based on in vitro experiments and animal models, whereas direct evidence supporting mitochondria-specific targeting, long-term safety, bioavailability, and clinical applicability remains limited. This review summarizes the pathological role of mitochondrial homeostasis imbalance in osteoporosis and discusses how representative TCM-derived monomers regulate osteogenic and osteoclastic metabolism through mitochondrial mechanisms. It also critically evaluates current limitations and highlights future directions for improving mechanistic rigor and translational value.
    Keywords:  mitochondrial homeostasis; monomers derived from traditional Chinese medicine; osteoblasts; osteoclasts; osteoporosis
    DOI:  https://doi.org/10.3389/fcell.2026.1846467
  15. J Physiol. 2026 Jul 01.
    Systems modelling of mitochondrial dynamics in different exercise regimes.
    Ali Khalilimeybodi, Lingxia Qiao, Allen Leung, Andrew D McCulloch, Simon Schenk, Padmini Rangamani.
      Exercise stimulates skeletal muscle signalling and mitochondrial metabolism. Emerging evidence shows that mitochondrial dynamics (i.e. fission and fusion) could be regulated by exercise. Yet, key gaps remain in identifying (i) the signals that drive fission vs. fusion; (ii) how energy status and reactive oxygen species (ROS) shift control between dynamin-related protein 1 (DRP1) and mitofusin (MFN)/optic atrophy 1 (OPA1); and (iii) which intensity-duration combinations yield similar cytosolic signals but different mitochondrial remodelling. Therefore, we developed an integrative computational framework connecting exercise regimens to mitochondria fission-fusion machinery by linking blood-myofibre energetics in cytosol and mitochondria to signalling pathways. The influence of sprint, resistance and endurance exercise regimens on mitochondrial fission and fusion has been simulated. Classified qualitative validation of the signalling network model achieved 80% accuracy. The model predicts regimen-specific dynamics starting with an acute DRP1-driven fission during exercise followed by MFN1/2-OPA1-mediated re-fusion as energy stress declines, consistent with a cyclical triage-then-rebuild paradigm. Changes are most pronounced and sustained with endurance, sharp but brief with sprint, and minimal with resistance. Global sensitivity analysis identified AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator-1α→MFN1/2 as dominant fusion drivers, ROS and AMPK→mitochondrial fission factor/DRP1 as primary fission switches, and Ca2 +-calmodulin, extracellular-signal-regulated kinase and liver kinase B1/AMPK as shared regulators. The model predicts that an endurance base, augmented with one or two weekly high intensity interval training/sprint interval training sessions could maximize AMPK-ROS pulses and mitochondrial fission-fusion. This framework unifies muscle's signalling logic with energetic state to explain how intensity-volume combinations, bout spacing and kinase modulation tune mitochondrial remodelling, yielding testable predictions for optimizing training and adjuvant therapies to enhance mitochondrial quality and performance. KEY POINTS: Different exercise regimes such as sprint, resistance, and endurance can trigger different signalling pathways. Exercise also triggers mitochondrial remodelling in skeletal muscle. Using a systems biology model, we developed a systems biology model for skeletal muscle signalling and mitochondrial metabolism for exercise. Our model predicts the dynamics of mitochondrial fusion and fission in different exercise regimes and identifies which signalling pathways dominassste these remodelling mechanisms.
    Keywords:  ROS‐mediated signalling; exercise regime; metabolic signalling; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1113/JP290424
  16. Mol Cell Biochem. 2026 Jul 03.
    High glucose-induced mitochondrial fission promotes Müller cell activation via suppression of the Hippo pathway.
    Bo Li, Xing Wang, Xiao-Li Hao, Qin Wang, Bing Xu, Hui Peng, Peng Wang.
      Diabetic retinopathy (DR) is the leading cause of blindness in diabetic patients, in which high glucose (HG)-induced Müller cell activation constitutes a central pathological event. This study aimed to untangle the critical role and mechanism of mitochondrial fission in this process. We found that under HG conditions, the level of p-Drp1 was significantly elevated (P < 0.05), driving excessive mitochondrial fission. Functional experiments confirmed that artificially enhancing mitochondrial fission directly inhibited the Hippo signaling pathway (levels of core proteins p-MST1/2, p-LATS1, and p-YAP decreased, P < 0.05, and YAP translocated to the nucleus), thereby activating Müller cells (expression of marker proteins GS and Kir4.1 decreased, while expression of GFAP, AQP4, and inflammatory mediators IL-1β, IL-6, VEGF increased, P < 0.05). Key rescue experiments demonstrated that Drp1 silencing (reduced p-Drp1 level, P < 0.05) reversed the aforementioned activation; however, co-administration of the Hippo pathway inhibitor XMU-MP-1 re-induced cell activation, proving that the Hippo pathway is a necessary downstream mediator of mitochondrial fission. In a diabetic rat model, elevated p-Drp1, Hippo pathway inhibition, and cell activation were similarly observed; the mitochondrial fission inhibitor Mdivi-1 alleviated this pathological process, whereas XMU-MP-1 counteracted its protective effects. This study systematically elucidates, from ex vivo to in vivo, the causal regulatory axis of "HG- mitochondrial fission- Hippo pathway inhibition-Müller cell activation," providing experimental evidence and a potential target for developing DR-targeted therapeutic strategies centered on intervening in mitochondrial dynamics.
    Keywords:  Diabetic retinopathy; Hippo signaling pathway; Mitochondrial fission; Multiomics analysis; Müller cells; Neuroinflammation
    DOI:  https://doi.org/10.1007/s11010-026-05625-8
  17. Aging Dis. 2026 Jun 23.
    IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.
    Zeyu Zhang, Yanlin Chen, Weizhen Gao, Fengchen Zhang, Yichao Jin, Jie Li, Jiaqi Wang, Tao Lv, Feng Jia, Xiaohua Zhang.
      Aging is a potent risk factor for poor prognosis in subarachnoid hemorrhage (SAH), yet the molecular mechanisms underlying the age-related exacerbation of early brain injury remain incompletely understood. This study investigates the immunometabolic regulation of the microglial senescence-like transition following SAH, focusing on the immune-responsive gene 1 (IRG1)/itaconate axis. We observed that the endogenous upregulation of IRG1 and itaconate is a protective response to hemorrhagic stress that is significantly blunted in aged mice. Microglia-specific IRG1 deficiency exacerbated SAH-induced brain injury, characterized by an accelerated senescence-like transition and the secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, we demonstrate that IRG1 deficiency leads to excessive mitochondrial fission and dysfunction via the hyperactivity of Dynamin-related protein 1 (Drp1). Using click chemistry-based proteomics and site-directed mutagenesis, we identified that itaconate exerts its neuroprotective effects by directly alkylating the small GTPase RhoA at the cysteine 107 (C107) residue. This specific post-translational modification inhibits RhoA-GTP binding and downstream ROCK1 activation, thereby suppressing Drp1-mediated mitochondrial fragmentation. Importantly, treatment with the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) rescued mitochondrial dynamics and attenuated microglial senescence and neurological deficits, whereas the RhoA-C107S mutation abolished these protective effects. Collectively, our findings unveil a novel metabolic-mitochondrial checkpoint involving the IRG1/itaconate-RhoA-Drp1 axis. Restoring this pathway represents a promising therapeutic strategy to combat the age-related exacerbation of neuroinflammation and improve outcomes in SAH patients.
    DOI:  https://doi.org/10.14336/AD.2025.1527
  18. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2521642123
    Tau protein as a regulator of mitochondrial function and dynamics.
    Eleni Tsakiri, Carlos Campos-Marques, Christina Ploumi, Kalliopi Skourti, Antonis Roussos, Eirini Mytilinaiou, Anastasia Vamvaka Iakovou, Ildete Luísa Ferreira, Chrysoula Dioli, Despoina D Gianniou, Martina Samiotaki, Jonas Campos, Clarissa Waites, Nuno Sousa, Ioannis P Trougakos, Joana M Silva, A Cristina Rego, Ioannis Sotiropoulos, Konstantinos Palikaras.
      Mitochondrial damage is a shared hallmark of brain aging and neurodegeneration. While pathological Tau mutations disrupt mitochondrial dynamics and function, the physiological role of wild-type (WT) Tau in the maintenance of mitochondrial homeostasis remains poorly understood. Here, using Caenorhabditis elegans and mice lacking PTL-1, the nematode Tau-like homolog, and Tau respectively, we demonstrate that Tau deficiency promotes a shift toward a pro-fusion mitochondrial state associated with enhanced mitochondrial function and stress resistance. In both models, loss of Tau leads to increased mitochondrial activity and altered redox homeostasis, while it enhances resistance to heat and mitochondrial stress in C. elegans. Strikingly, loss of FZO-1, the mitofusin homolog, abolishes the beneficial phenotypes, whereas its overexpression phenocopies key aspects of Tau/PTL-1 deficiency. Together, our findings uncover a conserved role for WT Tau in restraining mitochondrial fusion and functional adaptation, highlighting its contribution to mitochondrial homeostasis and cellular stress responses.
    Keywords:  Tau; mitochondria; mitochondrial dynamics; neurodegeneration; neuron
    DOI:  https://doi.org/10.1073/pnas.2521642123
  19. Int J Food Microbiol. 2026 Jun 27. pii: S0168-1605(26)00306-5. [Epub ahead of print]459 111925
    Cuminal-triggered mitophagy induces mitochondrial dysfunction, resulting in decreased vegetative growth and pathogenicity in Trichothecium roseum.
    Rui Kang, Zhong Zhang, Pengfei Sun, Xiaobin Xu, Horchelle T Djomptchouang, Yang Bi, Dov Prusky, Kumsa Delessa Kuffi.
      Trichothecium roseum (T. roseum) is a significant postharvest pathogen that infects a wide range of fruits and vegetables. This study investigated the antifungal activity of cuminal (CA), the major active component of cumin essential oil, against T. roseum. The results showed that CA notably inhibited spore germination, germ tube elongation, mycelial growth, and pathogenicity in T. roseum. Mechanistic analyses revealed that CA induced excessive intracellular reactive oxygen species (ROS) accumulation in T. roseum, despite antioxidant elicitation, leading to oxidative stress. This stress triggered mitochondrial dysfunction, characterized by ultrastructural damage, membrane depolarization, cytochrome c release, and disturbance of Ca2+ homeostasis. Further examination showed that CA altered mitochondrial dynamics and activated TrAtg8-mediated mitophagy, as evidenced by upregulated autophagy-related genes and the definite colocalization of GFP-TrAtg8 with mitochondria and vacuoles. Excessive mitophagy impaired mitochondrial function, resulting in a 44.14% decrease in energy charge in CA-treated spores compared to the untreated control. This energy deficit led to the suppression of gene expression of cell wall-degrading enzymes, required for pathogenic attack, and to impaired environmental alkalization capability, which is crucial for successful host colonization. Consequently, this led to a significant reduction in T. roseum's pathogenicity. Taken together, this study establishes that CA disrupts T. roseum's energy metabolism via a cascade initiated by oxidative stress, which dysregulates mitochondria and traps the cell in a futile cycle of excessive mitophagy, ultimately decreasing its pathogenic capacity. This multi-target mechanism highlights CA's potential as a natural postharvest preservative for fruits and vegetables against T. roseum.
    Keywords:  Antifungal; Cuminal; Essential oil; Mitophagy; Pathogenicity; Reactive oxygen species; Trichothecium roseum
    DOI:  https://doi.org/10.1016/j.ijfoodmicro.2026.111925
  20. Zhongguo Zhong Yao Za Zhi. 2026 Apr;51(8): 2143-2152
    [Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].
    Jin-Yu Li, Xia-Xia Wang, Sheng-Fang Wan, Ting-Ting Feng, Ai-Jia Guo, Jing-Yi Liu, Kang Feng.
      Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.
    Keywords:  Alzheimer′s disease; PINK1/Parkin; TCM intervention; mitophagy
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20260113.701
  21. Pathol Res Pract. 2026 Jun 27. pii: S0344-0338(26)00258-X. [Epub ahead of print]286 156605
    Tanshinone IIA promotes mitophagy by inhibiting the MARCHF5-mediated ubiquitination and degradation of FUNDC1 to alleviate spinal cord injury.
    Zhipeng Pan, Yuanmou Li, Xiaona He, Heng Li, Yuhua Gui, Li Huang, Xiaodan Liu, Piao Li, Ling Li, Yan Qian, Li Deng, Yang Zhang.
       BACKGROUND: Spinal cord injury (SCI) has a poor prognosis and lacks effective treatment options. Dysfunction of mitophagy is involved in neuronal damage after SCI, and tanshinone IIA (TIIA) can regulate this process. This study aimed to investigate whether TIIA exerts neuroprotective effects by regulating mitophagy and the underlying mechanisms.
    METHODS: A modified Allen weight-drop method was used to strike the exposed T8-T10 thoracic spinal segments to establish a mouse model of SCI. PC12 cells were treated with nerve growth factor (NGF) to induce a neuronal phenotype, followed by oxygen-glucose deprivation (OGD) to establish an in vitro SCI model. The Basso Mouse Scale (BMS) was used to assess hindlimb motor function in mice; HE and Nissl staining were used to evaluate spinal cord tissue pathology; TUNEL and CCK-8 assays were used to assess cell damage; and Western blotting and immunofluorescence were performed to determine protein expression.
    RESULTS: TIIA inhibited neuronal cell damage in SCI models and improved hindlimb motor function in SCI mice. Additionally, TIIA reactivated autophagy in PC12 cells after OGD, whereas the inhibitory effect of TIIA on cell damage was weakened after treatment with the autophagy inhibitor Mdivi-1. Co-IP revealed that MARCHF5 binds to FUNDC1. TIIA activates mitophagy by inhibiting the MARCHF5-mediated ubiquitination and degradation of FUNDC1, and overexpression of MARCHF5 or knockdown of FUNDC1 can partially counteract the inhibitory effect of TIIA on the progression of SCI in mice.
    CONCLUSION: TIIA alleviates neuronal cell damage by inhibiting the MARCHF5-mediated ubiquitination and degradation of FUNDC1 to activate mitophagy, thereby ameliorating the progression of SCI.
    Keywords:  FUNDC1; MARCHF5; Mitophagy; Spinal cord injury; Tanshinone TIIA
    DOI:  https://doi.org/10.1016/j.prp.2026.156605
  22. Free Radic Biol Med. 2026 Jun 27. pii: S0891-5849(26)00906-8. [Epub ahead of print]254 391-404
    DRP1-mediated mitophagy facilitates oral squamous cell carcinoma tumor cell survival under glucose restriction.
    Qiuya Yu, Tao Xiao, Zixian Li, Yue Jing, Yuxian Song, Xiaoxin Zhang, Xiaofeng Huang, Yanhong Ni.
      Oral squamous cell carcinoma (OSCC) can progress within a nutrient-limited microenvironment, especially under low-glucose conditions. However, the mechanisms enabling tumor cells to cope with glucose limitation, particularly those that counteract reactive oxygen species (ROS) accumulation, remain largely unknown. Here, we showed that dynamin-related protein 1 (DRP1)-mediated mitophagy promoted OSCC cell survival under glucose restriction. High expression of DRP1 was observed in OSCC tumor cells and identified as an indicator of poor prognosis. Either expression knockdown or pharmacological inhibition of DRP1 significantly reduced tumor cell mitophagy, leading to increased ROS production and consequently accelerating OSCC tumor cell death. The promoting effect of DRP1 on OSCC tumor growth, alongside its inhibitory effect on ROS production, was also confirmed in vivo. Furthermore, as a key nutrient stress sensor, AMP-activated protein kinase (AMPK) was activated upon glucose restriction. Pharmacological inhibition of AMPK was associated with reduced DRP1 mitochondrial translocation and diminished mitophagy. These findings collectively uncover that DRP1 contributes to mitophagy and allows OSCC cells to adapt to glucose limitation and overcome associated ROS stress, providing potential mechanistic insights for enhancing the efficiency of targeted therapies strategies.
    Keywords:  Cell survival; DRP1; Glucose restriction; Mitophagy; OSCC; ROS
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.051
  23. Exp Brain Res. 2026 Jun 29. pii: 145. [Epub ahead of print]244(8):
    Exploring Sevoflurane promotes hippocampal neuron mitophagy in elderly postoperative cognitive dysfunction by HSP90AA1 based on network pharmacology.
    XiuFeng Liu, Chen Zhang, Juan Liu.
      As a common anesthetic, Sevoflurane may be involved in the development of postoperative cognitive dysfunction (POCD) in the elderly. This study aims to investigate whether Sevoflurane regulates mitophagy in hippocampal neurons in elderly POCD through HSP90AA1, using a network pharmacology-based approach. Multiple databases were used to screen the common targets of Sevoflurane, mitophagy and elderly POCD, and GO and KEGG pathway enrichment analyses were performed. The protein-protein interaction network was constructed using STRING database and Cytoscape software, and the binding characteristics of Sevoflurane to the core target HSP90AA1 were verified by molecular docking and dynamics simulation. For cellular experiments, mouse hippocampal neuronal cells (HT22) were treated with Sevoflurane, and rescue experiments were performed by knocking down HSP90AA1 (sh-HSP90AA1). Cell viability, oxidative stress, mitochondrial membrane potential (MMP), the expression of mitophagy markers and cell apoptosis were evaluated by CCK8 assay, LDH release detection, ROS detection, JC-1 staining, western blot and flow cytometry. A total of 42 common targets of Sevoflurane, mitophagy and elderly POCD were screened, among which HSP90AA1 was identified as one of the key hub targets. Molecular docking showed that Sevoflurane had a stable binding ability with HSP90AA1. Cell experiments showed that Sevoflurane treatment significantly inhibited HT22 cell viability and p63 protein expression, while increased LDH release, ROS level, MMP depolarization, LC3-II/LC3-I, PINK1, Parkin, HSP90AA1 protein expression, and cell apoptosis. However, knockdown of HSP90AA1 reversed the above cell injury effects induced by Sevoflurane. Sevoflurane may promote oxidative stress, mitophagy and apoptosis of hippocampal neurons by upregulating HSP90AA1, thereby aggravating the process of POCD in the elderly. These results suggest that HSP90AA1 is a potential key target for Sevoflurane-mediated neuronal injury.
    Keywords:  Hippocampal neurons; Mitophagy; Postoperative cognitive dysfunction; Sevoflurane
    DOI:  https://doi.org/10.1007/s00221-026-07307-9
  24. Exp Physiol. 2026 Jul 01.
    Impairments in mitochondrial dynamics and morphology in skeletal muscle of breast cancer patients after a single paclitaxel administration.
    Joris Mallard, Elyse Hucteau, Laura Somme, Hervé Bischoff, Valérie Demais, Pauline Silvestrin, Anne-Laure Charles, Roland Schott, Xavier Pivot, Thomas J Hureau, Allan F Pagano.
      Standard chemotherapy regimens for patients with breast cancer are based on epirubicin-cyclophosphamide (EC) and paclitaxel (TAX) administrations. While it has been shown that first EC administration impairs mitochondrial homeostasis, the isolated effects of TAX have not been studied without previous chemotherapy exposure. We conducted a prospective clinical study including five patients with breast cancer who underwent two vastus lateralis muscle biopsies before and 4 days after the first TAX administration, without any prior chemotherapy exposure. Mitochondrial respiratory capacity, reactive oxygen species production, mitochondrial dynamics and ultrastructure, and apoptosis were assessed using high-resolution respirometry, western blotting, transmission electron microscopy, and TUNEL assay, respectively. Post-TAX, the number of intermyofibrillar mitochondria decreased (-18%; P = 0.049), while the proportion of damaged mitochondria increased (+34%; P = 0.012). Mitochondrial area, perimeter and major/minor axis lengths increased (P < 0.05) while intermyofibrillar cristae area decreased (4.29% pre-TAX vs. 2.60% post-TAX; P = 0.044). Despite these morphological changes, oxidative phosphorylation capacity and respiratory control ratio remained unchanged, whereas complex I-linked substrate respiration decreased (-29%; P = 0.046). MFN2 (-43%; P = 0.040) and Fis1 (-46%; P = 0.046) protein levels decreased post-TAX while mitophagy markers were unchanged. Apoptosis was increased, as documented by increased Bax (+58%; P = 0.045) and TUNEL-positive nuclei (+395%; P = 0.041). In only 4 days, the first TAX administration induced severe skeletal muscle mitochondrial remodelling in patients with breast cancer, characterized by impaired mitochondrial dynamics that resulted in swollen and damaged organelles. These findings demonstrate that mitochondrial toxicity, classically documented at the end of treatment, occurs acutely and after only one chemotherapy administration.
    Keywords:  chemotherapy; mitochondrial dynamics; mitochondrial function; muscle biopsies; muscle homeostasis; skeletal muscle deconditioning
    DOI:  https://doi.org/10.1113/EP093922
  25. Clin Exp Med. 2026 Jul 03. pii: 247. [Epub ahead of print]26(1):
    Silibinin promotes hepatocyte proliferation through PINK1/Parkin-mediated mitophagy to alleviate acetaminophen-induced liver injury.
    Fengming Xu, Mohamed Albadry, Olaf Dirsch, Uta Dahmen.
      Acetaminophen (APAP) intoxication is a common cause of liver injury. Silibinin has demonstrated potent hepatoprotective properties. However, its underlying mechanisms in APAP-induced liver injury (AILI) remain unclear. Autophagy is a critical adaptive response in AILI, contributing to the clearance of damaged mitochondria and the attenuation of oxidative stress. Therefore, we focused primarily on investigating the role of autophagy in mediating the hepatoprotective effects of silibinin. The effects of silibinin were evaluated in both AML12 cells and a C57BL/6J mouse model of AILI. Both the in vitro and in vivo experiments comprised four groups: a control group, an AILI model group, a silibinin treatment group, and a silibinin plus autophagy inhibitor group using PINK1-siRNA in cell culture and 3-Methyladenine in the animal experiment. Following induction of the AILI model in mice with APAP at a dose of 300 mg/kg, the animals received the designated interventions for five consecutive days. Histopathological alterations were assessed using hematoxylin-eosin staining. Hepatocyte proliferation and apoptosis were evaluated using the CCK-8 assay and immunohistochemical staining for Ki-67 and cleaved caspase-3, respectively, as well as ELISA for Cyclin D1. Liver function was assessed by serum biochemical analysis of alanine aminotransferase, aspartate aminotransferase, total bilirubin, and albumin. Mitochondrial oxidative stress-related parameters, including superoxide dismutase and malondialdehyde, were measured using colorimetric assays. The expression of autophagy-related genes and proteins (PINK1, Parkin, AMPK, LC3 and p62) was analyzed by quantitative PCR, immunofluorescence, and Western blotting. Transmission electron microscopy was employed to examine mitochondrial ultrastructure and the formation of autolysosomes in mouse liver tissue. In AML12 cells, silibinin mitigated AILI by activating the PINK1/Parkin pathway, thereby promoting mitophagy and enhancing cell proliferation. Co-treatment with autophagy inhibitor PINK1-siRNA attenuated these protective effects of silibinin. In AILI mice, silibinin treatment markedly improved liver function, attenuated inflammatory responses, restored mitochondrial function, and enhanced hepatocyte proliferation. These improvements were associated with increased LC3-II expression and reduced p62 accumulation, indicating enhanced autophagic activity. Notably, the protective benefits of silibinin were significantly attenuated by the autophagy inhibitor 3-Methyladenine. Our findings suggest that silibinin protects against AILI by activating PINK1/Parkin-dependent mitophagy, which mitigates oxidative stress and inflammation while promoting hepatocyte regeneration.
    Keywords:  Acetaminophen-Induced Liver Injury; Autophagy; Hepatocyte Proliferation; Mitophagy; Silibinin
    DOI:  https://doi.org/10.1007/s10238-026-02218-z
  26. Dis Res. 2026 Jun;6(2): 53-64
    Krüppel-like Factor 2 (KLF2) Regulates Autophagy, Mitophagy, Mitochondrial Health, and Function During Foam Cell Formation.
    Md Sariful Islam Howlader, Manjusri Das, Surajit Hansda, Prathyusha Naidu, Hiranmoy Das.
       Backgrounds: Foam cell (FC) formation is a hallmark of early atherosclerosis, driven by dysregulated lipid uptake, impaired mitochondrial clearance, and metabolic reprogramming in myeloid cells. However, the precise role of KLF2 in modulating autophagy, mitophagy, and glycolysis during FC formation remains inadequately explored.
    Methods: This study uncovers the critical regulatory role of Krüppel-like factor 2 (KLF2) during foam cell formation of myeloid cells (RAW264.7) using quantitative real-time PCR, immunocytochemistry, confocal microscopy, and glycolysis stress test methods.
    Results: Exposure to oxidized low-density lipoprotein (ox-LDL) suppressed autophagy and mitophagy markers in myeloid cells. It also increased glycolytic activity in myeloid cells during FC formation. A well-known chemical suppressor of KLF2, GGPP, further amplified these changes, highlighting the importance of endogenous KLF2 in maintaining mitochondrial health and metabolic functions during formation. To confirm the role of KLF2 in this process, when a chemical inducer of KLF2, GGTI298, was added during FC formation, it restored autophagic and mitophagic machinery, including the expression of Beclin1, LC3B, Parkin, and Pink1, and reversed the abnormal increase in glycolysis during FC formation.
    Conclusion: These findings demonstrate that KLF2 is a key transcriptional regulator that limits FC formation by preserving mitochondrial health and reducing excessive glycolysis. Furthermore, these results suggest KLF2 could be a target for future development of therapeutics for preventing FC formation, which is an early event in atherosclerosis development.
    Keywords:  Autophagy; Foam cell; Glycolysis; Kruppel-like factor 2; Mitophagy
    DOI:  https://doi.org/10.54457/dr.202601003
  27. Aging Cell. 2026 Jul;25(7): e70612
    EGR1 Mediates Ursodeoxycholic Acid-Promoted Mitophagy to Prevent Postovulatory Aging of Porcine Oocytes.
    Ying Zhang, Qianru Han, Yongchao Liu, Wei Shen, Shunfeng Cheng, Xiaoya Li.
      Postovulatory oocyte aging (POA) is a key factor contributing to the decline in female fertility and the success rate of assisted reproductive technology. Currently, most studies on POA have focused on downstream phenotypes such as mitochondrial dysfunction and oxidative stress, while little is known about its key upstream regulatory factors. Here, we show that the downregulation of transcription factor Early Growth Response 1 (EGR1) is a key upstream event driving porcine oocyte aging. Microtranscriptome sequencing combined with experimental validation verified a notable reduction in EGR1 protein abundance in aged oocytes. We found that Ursodeoxycholic Acid (UDCA) upregulated EGR1, which in turn promoted the expression of the autophagy-related protein LC3B and the lysosomal protein LAMP1, while reducing P62 accumulation. Furthermore, UDCA enhanced the expression of mitophagy core proteins PINK1, VDAC1 and promoted mitochondrial-lysosomal colocalization, thereby improving mitophagy and restoring the quality of aged oocytes. Crucially, treatment with the EGR1 inhibitor plicamycin completely blocked UDCA's ability to enhance the developmental potential of aged oocytes, confirming that EGR1-mediated mitophagy was the core pathway underlying UDCA's effects. Collectively, this study innovatively identified EGR1 as a key bridge linking oocyte aging and decreased mitophagy, and clarified the novel mechanism by which UDCA exerts its protective effects through the "UDCA-EGR1-mitophagy" axis. Our findings advanced the research on oocyte aging from phenotypic observation to the upstream transcriptional regulation level, providing a novel theoretical target and experimental basis for fundamentally intervening in reproductive aging.
    Keywords:  EGR1; early embryonic development; mitophagy; porcine; postovulatory oocyte aging; ursodeoxycholic acid
    DOI:  https://doi.org/10.1111/acel.70612
  28. Phytomedicine. 2026 Jun 19. pii: S0944-7113(26)00700-2. [Epub ahead of print]159 158469
    Qiteng Xiaozhuo granules activate mitophagy to alleviate chronic glomerulonephritis.
    Tao Liu, Xing Xing Zhuang, Xiao Li Zhu, Yu Ting Zhang, Xi Wu, Xiu Juan Qin, Liang Bing Wei, Ya Chen Gao, Jia Rong Gao.
       BACKGROUND: Qiteng Xiaozhuo Granules (QTXZG), a traditional Chinese medicine formula, is widely recognized for its therapeutic effects. Previous studies have demonstrated that the Methyltransferase-like 3 (METTL3)/FOS Like Antigen 1 (FOSL1) N6-methyladenosine (m6A) axis plays a crucial role in the regulation of mitophagy in chronic glomerulonephritis (CGN) both in vitro and in vivo. However, it remains unclear whether QTXZG exerts its therapeutic effects in CGN through the METTL3/FOSL1 m6A axis to regulate mitophagy. This study aims to investigate the renal protective mechanisms of QTXZG by activating mitophagy in glomerular mesangial cells through the METTL3/FOSL1 m6A axis.
    METHODS: Adenine-induced CGN mice and lipopolysaccharide-stimulated mouse glomerular mesangial cells were employed as in vivo and in vitro models, respectively. The chemical characterization and quality control of QTXZG were performed using high-performance liquid chromatography fingerprinting, peak assignment, marker quantification, and analytical method validation. Renal function was evaluated via serum creatinine, blood urea nitrogen, immunoglobulin G, and immunoglobulin M quantification. Renal histopathology was analyzed using Hematoxylin and Eosin, Masson, and Periodic Acid-Schiff staining. QTXZG-containing serum concentration and treatment duration were optimized via cell counting kit-8 assays. Inflammation and oxidative stress were assessed by enzyme-linked immunosorbent assay and reactive oxygen species staining. Global m6A levels were quantified by colorimetric assays, and FOSL1 mRNA m6A modifications were validated via methylated RNA immunoprecipitation quantitative PCR. Actinomycin D experiments determined FOSL1 mRNA stability. METTL3/FOSL1 m6A axis and mitophagy were analyzed by western blot, transmission electron microscopy, MitoTracker Red staining, and microtubule-associated protein 1 light chain 3-mitochondria immunofluorescence co-localization.
    RESULTS: High-performance liquid chromatography fingerprinting of ten QTXZG batches identified sixteen common peaks, assigned them to corresponding herbal sources, and quantified five representative marker compounds. QTXZG improved renal function and suppressed mesangial cell proliferation in CGN mice, while reducing pro-inflammatory cytokines and reactive oxygen species levels and enhancing superoxide dismutase activity. Importantly, QTXZG promoted autophagosome formation and mitigated mitochondrial damage, with enhanced microtubule-associated protein 1 light chain 3-mitochondria/voltage-dependent anion channel 1 co-localization confirming mitophagy induction. Mechanistically, QTXZG inhibited METTL3/FOSL1 expression, reduced global m6A levels and FOSL1 mRNA m6A enrichment, and destabilized FOSL1 transcripts. Critically, METTL3 overexpression reversed QTXZG's effects on inflammation, oxidative stress, mitophagy, and METTL3/FOSL1 m6A axis in lipopolysaccharide-stimulated mouse glomerular mesangial cells.
    CONCLUSION: This study suggests that QTXZG induces mitophagy in glomerular mesangial cells in CGN by modulating the METTL3/FOSL1 m6A axis. Targeting FOSL1 m6A modification through the writer enzyme METTL3 may provide a potential therapeutic approach for the treatment of CGN.
    Keywords:  Chronic glomerulonephritis; Fos-like antigen 1; Glomerular mesangial cells; Methyltransferase-like 3; Mitophagy; N6-methyladenosine; Qiteng Xiaozhuo granules
    DOI:  https://doi.org/10.1016/j.phymed.2026.158469
  29. Metabolism. 2026 Jul 01. pii: S0026-0495(26)00196-4. [Epub ahead of print]183 156685
    A thermosensitive TET-Parkin epigenetic axis couples mitochondrial quality control to adaptive thermogenesis in adipose tissue.
    Seongjun Byun, Chan Hyeong Lee, Kyumin Jang, Minwoo Pak, Hyun-Ji Lee, Seongryeol Ryu, Inkyung Jung, Jungeun An, Myunggon Ko.
      Adipose tissue thermogenesis is a major determinant of energy homeostasis, and its dysregulation contributes to obesity and metabolic disease. Parkin-mediated mitophagy is required for thermogenic adaptation, but the upstream mechanisms linking thermal cues to this pathway remain poorly defined. Here, we identify the ten-eleven translocation (TET) family of DNA dioxygenases as thermosensitive epigenetic regulators of Prkn transcription in adipocytes. Cold exposure coordinately suppressed TET expression and reduced global 5-hydroxymethylcytosine (5hmC) levels in white and brown adipose tissue through β-adrenergic signaling. Adipose-specific TET triple-knockout mice exhibited enhanced white fat beiging, brown fat activation, increased energy expenditure, and improved cold tolerance. Transcriptomic network analysis identified Parkin as a key mitophagy node in TET-deficient adipose tissue. Consistent with this, loss of adipose TET reduced Parkin expression, impaired mitophagic flux, and promoted accumulation of metabolically active mitochondria with increased respiratory capacity. Mechanistically, TET proteins occupied the Prkn promoter and maintained a transcriptionally permissive state through catalytic conversion of 5-methylcytosine to 5hmC, whereas TET loss increased promoter methylation and suppressed Prkn expression. Re-expression of wild-type, but not catalytically inactive, Parkin largely normalized mitochondrial content and respiratory activity in TET-deficient adipocytes. Together, these findings define a thermosensitive TET-Parkin epigenetic axis that links environmental cold signals to mitochondrial quality control during adaptive thermogenesis.
    Keywords:  Adaptive thermogenesis; Adipose tissue browning; Epigenetic regulation; Mitophagy; Parkin; TET dioxygenase
    DOI:  https://doi.org/10.1016/j.metabol.2026.156685
  30. Mitochondrion. 2026 Jun 28. pii: S1567-7249(26)00079-6. [Epub ahead of print]91 102189
    miR-205-5p accelerates lung fibroblast senescence in IPF patients via mediation of mitochondrial dynamics.
    Rui Wei, Ying Shen, Bingpeng Guo, Shuchang Wang, Qian Han.
      Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that occurs primarily in the elderly. Although senescence of lung fibroblasts (LFs) contributes to IPF development, the potential mechanisms underlying LF senescence are not fully understood. This study aimed to delineate the role and underlying mechanisms of miR-205-5p in regulating LF senescence in patients with IPF. The LFs from IPF patients (IPF-LFs) and age-matched controls (Control-LFs) were isolated and cultured. Senescence of LFs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. Mitochondrial morphology of LFs was evaluated by MitoTracker staining and transmission electron microscope. The expression of miR-205-5p was examined by RT-PCR. Compared with Control-LFs, IPF-LFs exhibited increased cellular senescence with higher expression of SA-β-gal, p21 and p16 as well as decreased proliferative capacity. Importantly, IPF-LFs had decreased mitochondrial fission, evidenced by elongated mitochondria and downregulation of mitochondrial fission regulator 1-like protein (MTFR1L). The expression of miR-205-5p was much higher in IPF-LFs than Control-LFs. Notably, upregulation of miR-205-5p in Control-LFs led to increased cellular senescence, whereas downregulation rescued IPF-LF senescence. Mechanistically, miR-205-5p downregulated mitochondrial fission in LFs via MTFR1L, leading to mitochondrial dysfunction and cellular senescence. Taken together, our study illustrated that miR-205-5p serves as a critical regulator of cellular senescence of LFs isolated from IPF patients via mediation of mitochondrial dynamics.
    Keywords:  Fibroblast; Idiopathic pulmonary fibrosis; Mitochondria; Senescence; miR-205-5p
    DOI:  https://doi.org/10.1016/j.mito.2026.102189
  31. Mol Med Rep. 2026 Sep;pii: 246. [Epub ahead of print]34(3):
    Laggera alata attenuates LPS‑induced systemic inflammation and hepatic‑pulmonary injury by regulating PINK1/Parkin-associated mitophagy and macrophage polarization.
    Jiangcun Wei, Wen Zhong, Guangyun Zhou, Mingtao Huang, Xiaodong Huang, Jing Liang.
      Laggera alata is a traditional medicinal herb used for inflammatory and infectious diseases, but its mechanisms against endotoxin‑induced systemic inflammation remain unclear. The present study investigated the protective effects of total phenolics from Laggera alata (TPLA) on lipopolysaccharide (LPS)‑induced inflammatory injury and explored the involvement of PTEN‑induced putative kinase 1 (PINK1)/Parkin‑associated mitophagy and macrophage polarization. LPS‑induced inflammatory models were established in RAW264.7 macrophages and C57BL/6 mice. Cell viability, apoptosis, mitochondrial membrane potential (MMP), cytokine production, macrophage polarization and mitophagy‑related protein expression were evaluated. Mdivi‑1 was used to assess the involvement of mitophagy‑related signaling. In vivo, core body temperature, serum cytokines, and lung and liver histopathology were examined. TPLA improved the viability of LPS‑stimulated macrophages, reduced apoptosis, restored MMP, decreased p62 expression, and increased PINK1, Parkin and the LC3‑II/LC3‑I ratio. TPLA also suppressed M1‑associated indicators, including inducible nitric oxide synthase, IL‑12 and CD80/CD86, while enhancing M2‑associated indicators, including arginase 1, IL‑10 and CD206/CD163. In addition, TPLA reduced IL‑1β, IL‑6 and TNF‑α release. Mdivi‑1 partially reversed the effects of high‑dose TPLA on mitophagy‑related protein expression and macrophage polarization. In LPS‑challenged mice, TPLA alleviated hypothermia, reduced systemic cytokine levels, and attenuated hepatic and pulmonary injury. These findings suggest that TPLA protects against LPS‑induced systemic inflammation and hepatic‑pulmonary injury by modulating PINK1/Parkin‑associated mitophagy‑related signaling and macrophage polarization.
    Keywords:  LPS‑induced systemic inflammation; PINK1/Parkin; TPLA; macrophage polarization; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2026.13956
  32. Elife. 2026 Jul 01. pii: e82205. [Epub ahead of print]15
    Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation.
    Priyanka Gajwani, Li Wang, Koushik Debnath, Pierina Danos, Young-Mee Kim, Shubhi Srivastava, Zijing Ye, Sarah Krantz, Dongmei Wang, Chinnaswamy Tiruppathi, Peter T Toth, Sriram Ravindran, Jalees Rehman.
      Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.
    Keywords:  cell biology; human; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.82205
  33. Cardiovasc Res. 2026 Jun 29. pii: cvag139. [Epub ahead of print]
    Syntabulin promotes heart failure by enhancing SR-mitochondria tethering and impairing mitofission.
    Ying Li, Ziquan Sun, Haixia Duan, Mingyue Wu, Jing Yi, Gang Wang, Wenjuan Liu, Chenglin Zhang, Wanwen Cheng, Jicheng Li, Weixuan Chen, Kunfu Ouyang, Hui Tan, Yueheng Wu, Jie Liu.
       AIMS: Mitochondrial dysfunction is a critical driver of heart failure (HF). Syntabulin (SYBU), known for its role as a motor linker at the outer mitochondrial membrane in neuronal system, has recently been suggested as a heart failure-associated gene. However, the role of SYBU in regulating cardiac function remains unclear.
    METHODS AND RESULTS: Pressure overload-induced cardiac hypertrophy and HF was produced by transverse aortic constriction (TAC) in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes (NRVMs). SYBU expression was significantly increased in hypertrophic mouse hearts and patient hearts with dilated cardiomyopathy. The cardiac-specific upregulating SYBU expression, achieved via recombinant adeno-associated virus driven by cardiac troponin T promoter, led to increased cardiomyocyte death and worsened heart failure under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy (SIM) and analysis of mitochondria-associated endoplasmic reticulum membrane (MAM) fractions revealed that SYBU localizes to ER-mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)-mitochondria tethering through interactions with RyR2 and SERCA2, leading to mitochondrial Ca2+ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca2+ triggered ER stress and PKA activation, inducing phosphorylation of Drp1 at Ser637, and ultimately disrupting mitochondrial fission and mitophagy.
    CONCLUSION: Our findings established a critical role of SYBU in promoting HF by inducing cardiomyocyte injury via increasing SR-mitochondria tethering and impairing mitochondrial fission and mitophagy. Therefore, targeting SYBU and its downstream signaling pathways could be a promising therapeutic strategy to restrain HF in pressure overload - induced cardiac hypertrophy.
    Keywords:  SR–mitochondria tethering; heart failure; mitochondrial dynamic; syntabulin
    DOI:  https://doi.org/10.1093/cvr/cvag139
  34. Br J Pharmacol. 2026 Jun 30.
    Fangchinoline alleviates hypertensive heart failure via PGC-1α/STAT6/PPARγ activation of mitophagy against ferroptosis.
    Chang Liu, Zhuoqun Wang, Linxin Zhang, Di Yang, Zhihong Zhang, Xiaoli Cui, Ali H Eid, Mengyang Wang.
       BACKGROUND AND PURPOSE: Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra, shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro, neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis.
    KEY RESULTS: In vivo, FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro, FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers.
    CONCLUSIONS AND IMPLICATIONS: We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment.
    Keywords:  PGC‐1α; PPARγ; STAT6; fangchinoline; heart failure; mitophagy
    DOI:  https://doi.org/10.1111/bph.70552
  35. Chin Med. 2026 Jun 29. pii: 176. [Epub ahead of print]21(1):
    Jiedu Huoxue decoction inhibits cardiomyocyte apoptosis via PTEN/AKT/GSK3β-mediated mitochondrial dynamics in myocardial infarction: an integrative study of network pharmacology, transcriptomics and molecular docking.
    Mingjie Pang, Han Peng, Changlei Hu, Yutong Li, Yangzhen Pei, Bin Liu, Yuting Wu, Guanghong Chen, Haozhen Cui, Aihua Shen, Li Zheng, Lingpeng Xie, Yingchun Zhou, Guoyong Zhang, Xin Han.
       BACKGROUND: Myocardial infarction (MI) triggers oxidative stress, mitochondrial dysfunction, and cardiomyocyte apoptosis. At present, it remains urgently needed to develop novel therapies specifically suppressing cardiomyocyte apoptosis via improving mitochondrial dysfunction following MI. Jiedu Huoxue Decoction (JDHXD) may have the effect of ameliorating myocardial injury after MI.
    PURPOSE: This study examined the protection exerted by JDHXD against myocardial injury post-MI and investigated the underlying mechanisms of action.
    METHODS: UHPLC/Orbitrap-MS, network pharmacology and transcriptome analysis were used to study the effective components and potential targets of JDHXD for treating MI. In vivo: The MI mice received JDHXD (12.74/25.48 g/kg/day) or captopril treatment for 28 days. Later, cardiac function (tested by echocardiography and histopathology), apoptosis, oxidative stress, mitochondrial ultrastructure, mitochondrial fission/fusion and PTEN/AKT/GSK3β pathway protein levels were evaluated. In vitro: TBHP-induced cardiomyocytes (H9C2 cells and NCMs) were exposed to JDHXD treatment (50-200 μg/mL), with or without PTEN inhibitor Bpv (2 μM) or PTEN overexpression (through adenoviral transduction). Afterwards, cell apoptosis, oxidative stress, mitochondrial membrane potential, and relative proteins were assayed. Experiments such as molecular docking and surface plasmon resonance imaging (SPRi) were conducted to verify the effective components of JDHXD in preventing myocardial mitochondrial injury after MI.
    RESULTS: The results of network pharmacology and transcriptomics suggest that JDHXD may ameliorate myocardial injury after MI through modulating PTEN for activating the PI3K/AKT/GSK3β signaling pathway. In vivo: JDHXD dose-dependently improved left ventricular function, improved the oxidative stress-induced imbalance of mitochondrial fission/fusion, and inhibited cardiomyocyte apoptosis post-MI in association with suppressing the PTEN/AKT/GSK3β pathway. In vitro: JDHXD suppressed the TBHP-induced cardiomyocyte apoptosis, attenuated oxidative stress, preserved mitochondrial potential, and restored mitochondrial dynamics. PTEN inhibitor did not augment JDHXD's effects, whereas PTEN overexpression partially abolished JDHXD's protection against myocardial injury induced by oxidative stress. UHPLC/Orbitrap-MS, molecular docking, SPRi and experiments in vitro confirmed that puerarin is one of the main components of JDHXD in regulating the PTEN/AKT/GSK3β pathway to improve mitochondrial function after MI and inhibit cardiomyocyte apoptosis.
    CONCLUSIONS: JDHXD against oxidative stress-induced cardiomyocyte apoptosis post-MI through ameliorating mitochondrial dysfunction, which is partially mediated by suppressing the PTEN/AKT/GSK3β pathway to inhibit excessive mitochondrial fission and promote mitochondrial fusion.
    Keywords:  Cardiomyocyte apoptosis; JDHXD; Mitochondrial dynamics; Myocardial infarction; PTEN/AKT/GSK3β
    DOI:  https://doi.org/10.1186/s13020-026-01444-7
  36. Front Cardiovasc Med. 2026 ;13 1813122
    Endothelial mitochondrial homeostasis in the development and progression of atherosclerosis.
    Naznin Sultana Remex, Md Sakil Miah, Tamjid Islam, Richa Aishwarya, Md Hasif Sinha, Proma Dhar, Cyrine Ben Dhaou, A Wayne Orr, Md Shenuarin Bhuiyan.
      Vascular endothelial cells (ECs) play a critical role in vascular functional homeostasis, and endothelial dysfunction activates signaling pathways that drive the development and progression of atherosclerosis. Mitochondria in ECs play an essential signaling role in regulating redox balance, calcium signaling, metabolic signaling, and inflammatory responses. Disruption of mitochondrial functional homeostasis by atherogenic stimuli leads to excessive mitochondrial reactive oxygen species production, altered mitochondrial dynamics, defective mitophagy, and mitochondrial DNA damage. These mitochondrial defects in ECs reduce nitric oxide bioavailability through eNOS uncoupling, destabilize endothelial junctional complexes, and promote endothelial activation. Additionally, damaged mitochondria release mitochondrial danger-associated molecular patterns contributing to the activation of inflammation and redox-sensitive signaling pathways in ECs. In this review, we delineated the mechanistic links between endothelial mitochondrial dysfunction and the pathological features of atherosclerosis. We highlight the contribution of mitochondrial signaling to the regulation of oxidative stress, innate immune activation, and endothelial barrier disruption. We also discussed emerging therapeutic strategies targeting mitochondria-associated signaling pathways, including modulation of mitochondrial dynamics, mitophagy, redox signaling, and mitochondria-targeted drug delivery. Together, we provide insights into the role of endothelial mitochondria in atherosclerotic disease progression and compelling targets for mechanism-based therapeutic intervention.
    Keywords:  atherrosclerosis; endothelial cell; endothelial dysfunction; mitochondria; mitochondrial signaling pathway
    DOI:  https://doi.org/10.3389/fcvm.2026.1813122
  37. J Nanobiotechnology. 2026 Jun 29.
    A zinc-coordinated cascade-responsive therapeutic nanoassembly for remodeling the pathological microenvironment and restoring mitochondrial homeostasis in spinal cord injury.
    Chunyu Xiang, Xiaodong He, Fengshuo Guo, Haowen Luo, Liumin He, Wanguo Liu, Rui Gu.
      Secondary injury after spinal cord injury (SCI) is sustained by coupled oxidative stress and inflammation, which drives neuronal apoptosis and bioenergetic failure. Here, a cascade-responsive Zn2+-centered nanoassembly (Zn-PC/PA@Gel) is constructed through stepwise coordination among Zn2+, procyanidin (PC), and polyarginine (PA) to form a core-shell architecture with a Zn2+-procyanidin core (Zn-PC) and a Zn2+-polyarginine shell (Zn-PA). In a reactive oxygen species (ROS) rich injury microenvironment, oxidation of guanidino groups in the polyarginine shell enables in situ nitric oxide (NO) release and weakens Zn2+ coordination, triggering controlled shell disassembly for early modulation of local inflammation and tissue microenvironment. The subsequent release of PC and Zn2+ provides continuous antioxidant protection. Zn2+ further restores mitochondrial quality control by regulating the STAT3-FOXO3a-SOD2 axis, thus enhancing mitochondrial autophagy, enhancing endogenous antioxidant defense, and restoring mitochondrial homeostasis and energy metabolism. In a mouse spinal cord contusion model, Zn-PC/PA@Gel mitigated inflammation and oxidative stress, alleviated the burden of mitochondrial dysfunction, protected neurons, and promoted motor recovery, resulting in a Basso Mouse Scale (BMS) score of 7.0 on day 28. Overall, these results support Zn2+ coordinated cascade therapy nanoassembly, which combines microenvironmental regulation with mitochondrial homeostatic recovery to reduce secondary injury after SCI and promote locomotor improvement.
    Keywords:  Mitochondrial homeostasis; Polyarginine; Procyanidin; Spinal cord injury; Zinc-coordinated nanoassembly
    DOI:  https://doi.org/10.1186/s12951-026-04760-0
  38. Biol Trace Elem Res. 2026 Jul 02.
    Arsenic Exposure Induces Hepatic Fibrosis and Triggers Early Inflammatory Responses by Inhibiting Hepatic Stellate Cell PINK1/Parkin-Mediated Mitophagy.
    Feiyang Wu, Yan Wang, Sheng Li, Zhiyong Xu, Xiaohui Wang, Haijing Yin, Teng Ma, Li Wang.
      Arsenic contamination poses a significant environmental health risk, yet the mechanisms underlying its induction of hepatic fibrosis remain incompletely elucidated.Our previous clinical studies in arsenic poisoning areas found that serum inflammatory factors (such as IL-6, IL-1β, TNF-α) levels were significantly elevated, but there were no significant differences in liver function and fibrosis markers, suggesting that the inflammatory response precedes detectable typical pathological alterations. Established theories suggest that persistent inflammation is a key factor in the initiation of hepatic fibrosis. PINK1, a key initiator of mitophagy, was found to be downregulated in the livers of arsenic-exposed mice.Based on this, we propose a scientific hypothesis: arsenic exposure induces a persistent inflammatory response by inhibiting PINK1/Parkin-mediated mitophagy, thereby driving hepatic stellate cells (HSCs) activation and the fibrosis process. Experimental validation demonstrated that arsenic exposure significantly inhibited the PINK1/Parkin pathway, impaired mitophagy, and upregulated the expression of fibrosis markers and inflammatory factors in both liver tissues and cells. Conversely, PINK1 overexpression reversed these pathological phenotypes. In summary, dysregulation of the PINK1/Parkin pathway is a pivotal mechanism connecting arsenic exposure to chronic inflammation and the initiation of hepatic fibrosis, providing new insights for early recognition and targeted intervention of arsenic-related liver diseases.
    Keywords:  Arsenic; Hepatic fibrosis; Hepatic stellate cells; Mitophagy; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1007/s12011-026-05207-1
  39. Mol Neurobiol. 2026 Jul 02. pii: 738. [Epub ahead of print]63(1):
    Nrf2 Activators in Parkinson's Disease: Modulating Mitophagy and Regulating Cuproptosis.
    Junjing Xu, Jiawei Xiang, Yong Zhang, Xuehong Liu.
      Parkinson's disease (PD), one of the most prevalent age-related neurodegenerative disorders, is neuropathologically defined by the progressive degeneration and massive loss of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Multiple pathological cascades, which include excessive oxidative stress, persistent neuroinflammation, aberrant cuproptosis, and mitochondrial dysfunction, converge to drive PD pathogenesis and aggravate its progression. Nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal transcription factor governing antioxidant defense and cellular stress responses, is markedly downregulated and functionally compromised within the pathological microenvironment of PD-affected brain tissue. A growing body of evidence has demonstrated that Nrf2 activators represent promising and innovative therapeutic candidates for the treatment of PD. These compounds effectively trigger the activation of the downstream Nrf2 signaling cascade, thereby promoting the initiation and execution of mitophagy to eliminate dysfunctional and damaged mitochondria and restore intracellular metabolism homeostasis. Meanwhile, activation of the Nrf2 signaling pathway suppresses aberrant intracellular copper accumulation and prevents excessive lipid peroxidation, thereby exerting a robust inhibitory effect on neuronal cuproptosis. This review systematically delineates the regulatory mechanisms by which Nrf2 activators modulate pivotal molecular-level biological processes. It further synthesizes and critically appraises the most recent preclinical findings as well as emerging early-stage clinical data regarding Nrf2-targeted therapeutic strategies for PD, while also delineating prevailing challenges and outlining prospective avenues for future investigation in this domain. Collectively, targeting the Nrf2 signaling pathway constitutes a promising integrative therapeutic strategy for the management of PD.
    Keywords:  Cuproptosis; Mitophagy; Neuroprotection; Nrf2 activators; Nrf2 signaling pathway; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-026-06036-y
  40. Front Neurol. 2026 ;17 1842829
    Activin A mitigates ferroptosis in cerebral ischemia/reperfusion injury via the PGC-1α/NRF1/TFAM axis.
    Jiahui Yang, Xiaohua Shi, Ming Ma, Zheng Li, Hongyu Liu, Yang Cui, Zhongxin Xu, Jiaoqi Wang.
       Background: Cerebral ischemia/reperfusion (I/R) injury severely limits the efficacy of recanalization therapy for ischemic stroke. Activin A (Act A), a neurotrophic cytokine, shows protective potential, but its mechanisms related to mitochondrial biogenesis and ferroptosis regulation remain unclear.
    Methods: In vivo, adult male Wistar rats (12/group) underwent 2 h middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Act A (7.5 μg/kg) or vehicle was administered intracerebroventricularly pre-ischemia. TTC, TEM, and IHC were used to analyze cerebral I/R injury and PGC-1α expression. In vitro, HT22 cells exposed to oxygen-glucose deprivation/reoxygenation (OGD/R, 8 h/24 h) were treated with Act A (100 ng/mL). Ferroptosis markers, mitochondrial function and signaling pathways were assessed via qPCR, western blot, flow cytometry, laser confocal and ChIP.
    Results: In vivo, Act A significantly reduced cerebral infarct volume versus vehicle (***p < 0.001), decreased MDA levels (***p < 0.001), and increased PGC-1α expression (***p < 0.001) along with mtDNA copy number (*p < 0.05). In vitro, Act A rescued OGD/R-induced ferroptosis, suppressing lipid ROS (**p < 0.01) and Fe2+ accumulation (*p < 0.05). It activated the PGC-1α/NRF1/TFAM axis (*p < 0.05) and enhanced mitochondrial biogenesis. Mechanistically, Act A promoted PGC-1α transcription via Smad3 binding to its promoter (*p < 0.05) and enhanced PGC-1α activity through p38-MAPK phosphorylation (***p < 0.001). Silencing PGC-1α abolished Act A's neuroprotection effects.
    Conclusion: Act A mitigates cerebral I/R injury by dual activation of PGC-1α through Smad3 and p38-MAPK pathways, enhancing mitochondrial biogenesis and inhibiting neuronal ferroptosis. This highlights Act A as a therapeutic candidate for ischemic stroke.
    Keywords:  Activin A; PGC-1α; cerebral ischemia/reperfusion injury; ferroptosis; mitochondrial biogenesis
    DOI:  https://doi.org/10.3389/fneur.2026.1842829
  41. Biochem Pharmacol. 2026 Jul 02. pii: S0006-2952(26)00550-2. [Epub ahead of print] 118211
    Mapk-driven remodeling of mitochondrial dynamics in melanoma: implications for metabolic plasticity and response to targeted therapy.
    L F L Prado-Souza, L A Grabauskas, R Chaguri, C D Cardoso, F Y Urushima, L G R Mangini, V S Ramos, Tiago Rodrigues.
      Melanoma is the most aggressive form of skin cancer due to its high metastatic potential and resistance to therapy. Current treatment strategies include surgical resection for localized disease, as well as targeted therapy with MAPK inhibitors and immunotherapy for advanced stages. However, therapeutic resistance and disease relapse remain major clinical challenges. Activating mutations in components of the mitogen-activated protein kinase (MAPK) pathway, particularly in BRAF and NRAS, are among the most frequent oncogenic events in melanoma, driving tumor initiation and progression through sustained ERK signaling. Mitochondria are dynamic organelles whose morphology is regulated by the balance between fission and fusion. In melanoma cells, MAPK-dependent signaling has been implicated in the regulation of key components of the mitochondrial dynamics machinery, thereby reshaping the mitochondrial network. These structural alterations have functional consequences for cellular metabolism, contributing to metabolic plasticity and enabling tumor cells to switch between glycolytic and oxidative metabolic states in response to environmental stimuli and therapeutic pressures. In this review, we discuss current evidence linking oncogenic MAPK signaling to the control of mitochondrial dynamics in melanoma and examine how these processes contribute to metabolic reprogramming. We further explore how mitochondrial remodeling influences therapeutic response and resistance, particularly in the context of MAPK pathway inhibition. Finally, we highlight mitochondrial dynamics as key regulators of metabolic plasticity and as promising therapeutic targets to improve treatment response in melanoma.
    Keywords:  Cancer; Drug resistance; Melanoma; Metabolism; Mitochondria; Targeted therapy
    DOI:  https://doi.org/10.1016/j.bcp.2026.118211
  42. Front Oncol. 2026 ;16 1837476
    The multifaceted roles of mitochondria and their therapeutic transformation: a new perspective on triple-negative breast cancer treatment.
    Siyuan Yang, Lei Wang, Jianyun Nie.
      Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, lacking effective targeted therapies and exhibiting pronounced therapeutic resistance. Mitochondria have recently emerged as central regulators of TNBC pathogenesis, functioning beyond their traditional roles as cellular powerhouses. This article synthesizes current understanding of how mitochondrial metabolic reprogramming-particularly the synergistic hyperactivation of oxidative phosphorylation, fatty acid oxidation, and glutamine metabolism-drives TNBC progression, metastasis, and chemoresistance. We further examine the dichotomous roles of mitochondrial dynamics and mitophagy in shaping tumor cell fate, and explore how mitochondria orchestrate diverse programmed cell death pathways and immune modulation. Translational strategies targeting mitochondrial vulnerabilities, including small-molecule inhibitors, nanomaterial-based delivery systems, and combination regimens, are critically evaluated. Despite significant preclinical promise, challenges including tumor selectivity, metabolic plasticity, and clinical translation remain. By integrating mechanistic insights with emerging therapeutic innovations, this perspective highlights the transformative potential of mitochondria-targeted interventions for future TNBC management.
    Keywords:  mitochondria; mitochondria-targeted therapy; mitochondrial dynamics; mitochondrial metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2026.1837476
  43. Curr Med Chem. 2026 Jul 01.
    DHRS2 as a Novel Thalidomide Target Regulating Mitophagy and Inflammation in Head and Neck Squamous Cell Carcinoma.
    Yinghui Wu, Qingwen Yao, Yang Li, Zixiao Song, Mei Gan, Jinghua Zhong, Leifeng Liang.
       BACKGROUND: Radiation Therapy (RT) in Head and Neck Squamous Cell Carcinoma (HNSCC) often induces inflammation. Here, we examined the relationship between mitophagy and inflammation in HNSCC.
    METHODS: The Cancer Genome Atlas and Gene Expression Omnibus were analyzed to identify genes associated with HNSCC, mitophagy, inflammation, and Thalidomide (THD). Differentially Expressed Genes (DEGs) were evaluated for functional enrichment. A prognostic model was constructed using LASSO and COX regression and evaluated using Kaplan-Meier analysis. Based on its reported role in alleviating Radiation-Induced Oral Mucositis (RIOM) and inflammation, THD was assessed using molecular docking to further investigate its potential mechanism. Knockdown cell lines were generated to examine the function of dehydrogenase/reductase 2 (DHRS2).
    RESULTS: In total, 535 related genes were identified, and a 26-gene prognostic model was established, effectively stratifying patients into high- and low-risk groups (AUC: 0.7-0.9). DHRS2 was identified as a key gene of interest, with molecular docking indicating strong binding affinity to THD. in vitro, DHRS2 knockdown significantly inhibited HNSCC cell proliferation, migration, and invasion while promoting apoptosis (p<0.05). THD reduced DHRS2 expression and increased PINK1/Parkin-related mitophagy.
    DISCUSSION: These findings suggest that dysregulation of mitophagy and inflammation contributes to HNSCC progression and may underlie radiation-induced inflammatory injury. DHRS2 was identified as a potential THD-responsive target, linking bioinformatics findings with pharmacological intervention. These findings also provide a basis for exploring therapeutic strategies targeting mitophagy and inflammation in HNSCC.
    CONCLUSION: We developed a prognostic model based on mitophagy- and inflammation-related genes in HNSCC and identified DHRS2 as a potential THD target. These results highlight the interplay between mitophagy and inflammation in HNSCC, offering insights for the prognosis and management of inflammation.
    Keywords:  DHSR2; HNSCC; inflammation; mitophagy; prognostic signature
    DOI:  https://doi.org/10.2174/0109298673457941260609055708
  44. Cell Death Discov. 2026 Jun 27.
    KLF15 activates PGC1α to rewire mitochondrial homeostasis and overcome cisplatin resistance in lung adenocarcinoma.
    Wan Lin, Lijuan Li, Yuwen Bai, Mai Wen, Wenjie Dong, Ruikun Ji, Jianqun Ma, Xiaodong Ling.
      Cisplatin resistance represents a major barrier to effective treatment of lung adenocarcinoma (LUAD), yet its metabolic underpinnings remain incompletely defined. Here, we demonstrate that the transcription factor KLF15 governs cisplatin sensitivity by orchestrating mitochondrial biogenesis and redox homeostasis. KLF15 is downregulated in cisplatin-resistant LUAD cells, which display reduced mitochondrial content and suppressed reactive oxygen species (ROS) accumulation. Restoring KLF15 expression resensitizes LUAD cells to cisplatin both in vitro and in vivo. Mechanistically, KLF15 directly transactivates PGC1α, and loss of PGC1α abrogates KLF15-mediated cisplatin sensitization, restoring drug resistance by attenuating apoptosis. Functionally, LUAD subpopulations with low mitochondrial mass or low KLF15 expression exhibit intrinsic resistance, whereas Mito-high xenografts show enhanced therapeutic response. Together, our findings identify a KLF15-PGC1α regulatory axis that dictates mitochondrial reprogramming and cisplatin responsiveness, highlighting a potential therapeutic axis to overcome chemoresistance in LUAD.
    DOI:  https://doi.org/10.1038/s41420-026-03235-3
  45. Biol Res. 2026 Jun 29.
    Phenotyping of post-fertilization sperm mitophagy determinants discovered in a mammalian gamete-based cell-free system.
    Alexis Jones, Natálie Zelenková, Erica Mantle, Chloe Gardner, Barbora Klusáčková, Dalen Zuidema, Miriam Sutovsky, Pavla Postlerová, Michal Zigo, Peter Sutovsky.
      The targeted, substrate-specific degradation of paternal mitochondria inside the zygote, known as post-fertilization sperm mitophagy, is a crucial and evolutionarily conserved early embryonic event. It ensures the exclusive maternal inheritance of the mitochondrial genome. Post-fertilization sperm mitophagy was initially thought to only be achieved via the ubiquitin-proteasome system. Until pro-autophagic receptor proteins such as SQSTM1, GABARAP, as well as the proteasome-interacting ubiquitinated protein dislocase VCP, were identified as contributors to the degradation of the sperm mitochondria early after mammalian fertilization. This synergy of proteasomal and autophagic pathways ensures a timely degradation of sperm mitochondria shortly after fertilization. The discovery of these autophagic receptors lead researchers to believe there might be other autophagic receptors and determinants necessary for proper post-fertilization sperm mitophagy. Based on the established inventory of proteins from mass spectrometry trials of boar spermatozoa exposed to porcine oocyte extracts in an intra-specific porcine cell-free system (CFS), five candidate mitophagy determinants were further investigated in this study, namely LACTB, PRDX3, PSMA8, TOMM34, and FUNDC1. These proteins of interest were studied and validated by using in vitro fertilization (IVF) protocols, cell imaging of spermatids, spermatozoa, oocytes and zygotes, protein interactome analysis, and the porcine CFS. The proteins PSMA8 and TOMM34 behaved in accordance with our proteomic study predictions. The PSMA8 labeling increased after exposure to CFS; in agreement with the classification PSMA8 was given from the mass spectrometry findings. TOMM34 underwent a visible decrease in labeling after exposure to CFS, which also agreed with its proteomic classification; this labeling persisted in IVF zygotes. Except for LACTB, the examined proteins showed mutual interactions as well as interactions with previously identified sperm mitophagy factors in the STRING interactome analysis. Results from this study validate the novel porcine CFS as a valuable tool for the exploration of early fertilization events at a molecular level. Future phenotyping and functional studies using porcine CFS will advance the understanding of mitochondrial inheritance and zygotic development and potentially shed light on the origins of certain mitochondrial diseases arising from the failure of post-fertilization sperm mitophagy.
    Keywords:  Autophagy; Fertilization; Inheritance; Mitochondria; Sperm; Zygote
    DOI:  https://doi.org/10.1186/s40659-026-00713-x
  46. bioRxiv. 2026 Jun 15. pii: 2026.06.11.731199. [Epub ahead of print]
    A Forward Genetic Screen in Caenorhabditis elegans for Genes that Modulate α-synuclein-Induced Neurodegeneration through the Mitochondrial UPR.
    Karolina Willicott, Joy D Iroegbu, Madeline R Greene, Aidan C Meyers, Rachel Martin, Rose Davidson-Tullis, Laura A Berkowitz, Guy A Caldwell, Kim A Caldwell.
      Overexpression of α-synuclein (α-syn), an inherently disordered protein, triggers chronic activation of the mitochondrial unfolded protein response (UPR mt ) pathway in Caenorhabditis elegans with enhanced dopaminergic (DAergic) neurodegeneration. Introduction of a loss-of-function (lf) mutation in atfs-1 , the main transcriptional regulator of the UPR mt , into α-syn nematodes results in significant neuroprotection from α-syn-induced DA neuron loss, indicating that compensatory mechanisms provide neuroprotection. We performed a F3 forward genetic screen in C. elegans atfs-1(lf) mutants to identify molecular components associated with the modulation of neurodegeneration via UPR mt signaling in α-syn-expressing DA neurons. Homozygous mutant animals were examined for enhanced neurodegeneration; multiple independent alleles were uncovered. Among these, we identified new nonsense alleles encoding the histone lysine demethylases (H3K27me3), jmjd-1.2 and jmjd-3.1 . Another line carried a nonsense allele of twk-14. This gene encodes a conserved protein termed KCNK12 in mammals that facilitates passive background K + leak currents to set and stabilize resting membrane potential. To further examine the association of these gene products in DA neurodegeneration, mutants and/or RNA interference were employed. DA neurodegeneration was observed in the α-syn + atfs-1(lf) background when jmjd-1.2 , jmjd-3.1, or twk-14 were individually depleted. These results provide evidence that jmjd-1.2 and jmjd-3.1 , which encode previously characterized H3K27me3 demethylases, and the uncharacterized twk-14 gene product, orthologous to human KCNK12, naturally confer protection from α-syn neurotoxicity.
    DOI:  https://doi.org/10.64898/2026.06.11.731199
  47. Exp Mol Med. 2026 Jul 03.
    Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.
    Ju-Hyeon Bae, Chang-Lim You, Jeongmin Park, Jong-Sun Kang.
      Sarcopenia and neuromuscular degeneration are key drivers of functional decline during ageing and arise not solely from muscle loss but also from failure of mitochondrial and metabolic stress adaptation across the neuromuscular system. Mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, defective quality control and redox imbalance, contributes directly to muscle weakness, neuromuscular junction instability and motor unit degeneration. However, the upstream mechanisms governing the transition from adaptive remodelling to degenerative collapse remain incompletely defined. Protein arginine methyltransferases (PRMTs) have emerged as critical modulators of mitochondrial and metabolic stress signalling. Beyond epigenetic regulation, PRMTs influence signalling pathways that intersect with AMP-activated protein kinase (AMPK)-Forkhead box O (FOXO) and mechanistic target of rapamycin (mTOR), thereby regulating mitochondrial biogenesis, selective autophagy and mitophagy, proteostatic balance, and anabolic restraint. Distinct PRMT family members exert non-redundant functions across muscle fibres, satellite cells and motor neurons, collectively shaping neuromuscular stress resilience. We propose that PRMTs act as molecular rheostats that bias cellular responses to mitochondrial stress towards adaptive resolution or progression to neuromuscular degeneration, thereby positioning PRMT-regulated metabolic signalling as a unifying mechanism underlying sarcopenia and compromised healthspan.
    DOI:  https://doi.org/10.1038/s12276-026-01762-8
  48. FASEB J. 2026 Jul 15. 40(13): e72087
    Domain-Specific Genotype-Phenotype Correlations in DNM1L Disorders: Insights Into Mutation Hotspots and Clinical Severity.
    Hui Liang, Zefu Chen, Shixiong Huang, Huolan Wei, Jiyi Xu, Shijun Hu.
      DNM1L-related disorders are rare mitochondrial diseases characterized by defective fission dynamics, often presenting with severe neurological manifestations. Current diagnostic and prognostic challenges stem from incomplete knowledge of domain-specific genotype-phenotype correlations and limited clinical data. We report a novel GTPase effector domain (GED) variant (p.Val687del) and conduct a systematic analysis of 80 reported DNM1L cases with variants in the GTPase, Middle, or GED domains. Clinical, genetic, and survival data were extracted and analyzed to evaluate associations between mutation localization and clinical outcomes. Statistical comparisons of phenotypic severity, survival, and hotspot prevalence were performed. Functional validation of the novel variant was performed through in vitro overexpression, Western blot, immunofluorescence, and transmission electron microscopy. A novel GED deletion (p.Val687del) associated with peripheral neuropathy was identified, expanding the mutational spectrum. In vitro functional studies confirmed that this variant impairs DRP1 mitochondrial localization and induces severe ultrastructural damage, including fragmentation, swelling, and vacuolation. The preserved protein expression level excludes haploinsufficiency, consistent with a dominant-negative mechanism. Within the total cohort of 81 patients (including our case), de novo variants were predominant (74.1%), with R403C representing a major mutational hotspot (28.4%). Middle domain mutations conferred the most severe prognosis, manifesting high frequencies of developmental delay (90.7%), epilepsy (83.7%), abnormal muscle tone (67.4%), abnormal EEG findings (74.4%), and cerebral atrophy (73.2%). In contrast, GTPase domain mutations primarily affected sensory pathways, with optic atrophy (57.6%) and peripheral neuropathy (27.3%) as hallmark features. Carriers of the R403C variant exhibited a 3.9-year delay in disease onset compared to non-carriers. This study establishes that mutation location in DNM1L dictates clinical severity, with Middle domain variants defining a severe encephalopathic subtype, while GTPase domain mutations predominantly target sensory pathways, leading to optic atrophy and peripheral neuropathy. These findings provide a framework for precision prognostication and targeted therapeutic strategies in DNM1L-related disorders.
    Keywords:  DNM1L; developmental encephalopathy; genotype–phenotype correlation; mitochondrial dynamics; sensory neuropathy
    DOI:  https://doi.org/10.1096/fj.202502759RR
  49. Autophagy. 2026 Jul 02.
    Tegument protein UL16 of herpes simplex virus 1 suppresses the innate immune response by downregulating MAVS abundance via mitophagy.
    Jingwen Wang, Rongli Zhu, Ping Yi, Mengyao Gan, Feng Long.
      Herpes simplex virus 1 (HSV-1) is a globally prevalent pathogen that poses a significant health threat due to its lifelong latency. This persistence is driven by intricate immune evasion mechanisms, the deciphering of which remains a challenge. Here, we identified the HSV-1 tegument protein UL16 as a novel viral immunosuppressive factor, which significantly suppresses the RIGI-like receptor (RLR)-mediated antiviral immunity. We found that UL16 can interact with MAVS (mitochondrial antiviral signaling protein) and induce its degradation, thereby inhibiting type I interferon (IFN-I) production. Further investigation revealed that UL16-induced MAVS degradation was facilitated via mitophagy involving the mitochondrial cargo receptor FUNDC1 (FUN14 domain containing 1). Knockout of FUNDC1 expression completely disrupted UL16-induced MAVS degradation and restricted HSV-1 replication. In contrast, overexpression of FUNDC1 augmented the suppressive effect of UL16 on MAVS-triggered IFN-I signaling and consequently benefited viral replication. Notably, the C-terminal domain (CTD) of UL16 primarily accounted for its immunosuppressive function, which was also demonstrated to be essential for UL16 engagement with MAVS, FUNDC1 and MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). A conserved LC3-interacting region (LIR) motif within the UL16 CTD was identified to play a critical role in LC3 recruitment enhancement. Furthermore, the UL16-deficient HSV-1 exhibited markedly attenuated viral infectivity and pathogenicity in vivo. In summary, our findings uncover a previously uncharacterized pathway through which HSV-1 UL16 subverts host immunity by inducing mitophagy. This study provides critical insights into host-pathogen interactions and establishes a rational foundation for developing novel therapeutics against HSV-1 infection.Abbreviations:3-MA: 3-methyladenine; BNIP3L/NIX: BCL2 interacting protein 3 like; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; Cas9: CRISPR-associated system 9; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; COX8: cytochrome c oxidase subunit 8; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; CTD: C-terminal domain; Ctrl: control; CXCL10: C-X-C motif chemokine ligand 10; DAPI: 4,'6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; ds: double-stranded; FBS: fetal bovine serum; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK: human embryonic kidney; HSV-1: herpes simplex virus 1; IAV: influenza A virus; IFIH1/MDA5: interferon induced with helicase C domain 1; IFIT1/ISG56: interferon induced protein with tetratricopeptide repeats 1; IFN-I: type I interferon; IgG: Immunoglobulin G; IRF3: interferon regulatory factor 3; ISGs: IFN-stimulated genes; kDa: kilodalton; KO: knockout; KSHV: Kaposi sarcoma-associated herpesvirus; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NanoBiT: NanoLuc Binary Technology; NC: negative control; NTD: N-terminal domain; OPTN: optineurin; p-: phosphorylated; PFU: plaque-forming unit; PINK1: PTEN induced kinase 1; poly(I:C): polyinosinic-polycytidylic acid; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; qPCR: quantitative polymerase chain reaction; RIGI/RIG-I: RNA sensor RIG-I; RLR: RIGI-like receptor; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SeV: Sendai virus; sgRNA: single guide RNA; shRNA: short hairpin RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TM: transmembrane; TOMM20: translocase of outer mitochondrial membrane 20; TRAF: TNF receptor associated factor; TUFM: Tu translation elongation factor, mitochondrial; UL16: unique long region 16; VSV: vesicular stomatitis virus; VZV: varicella zoster virus; WCL: whole-cell lysate; WT: wild-type; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone.
    Keywords:  FUNDC1; HSV-1; MAVS; UL16; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2698747
  50. J Nanobiotechnology. 2026 Jun 28.
    A magnetic-acoustic dual-fesponsive nanoplatform for targeted PPARδ activation attenuates adolescent idiopathic scoliosis progression.
    Chong Zhao, Shuaiqi Zhu, Yonghao Wu, Jie Huang, Hongzhen Li, Chen Guo, Jinying Zhang, Jiacheng Wang, Yan Zeng, Haiying Liu, Shuai Xu.
      Paraspinal muscle asymmetry is a characteristic feature of adolescent idiopathic scoliosis (AIS), yet the underlying molecular mechanisms driving this degeneration remain unclear. Here, we identify the suppression of the FNDC5-associated PPARδ signaling as a key factor in the asymmetric atrophy and fibrosis of concave paraspinal muscles. We demonstrate that FNDC5 downregulation in concave myofibers is associated with impaired mitochondrial quality control and a reduction in oxidative slow-twitch fibers. Mechanistically, FNDC5 regulates mitochondrial biogenesis and fatty acid oxidation through the functionally associated nuclear receptor PPARδ. The concurrent reduction of FNDC5 and PPARδ activity leads to intracellular lipid accumulation and mitochondrial dysfunction. To overcome the systemic toxicity and hydrophobicity of PPARδ agonists, we developed a magnetic-acoustic dual-responsive nanodelivery system (LIP@PFP/GW/SPIO) for targeted delivery of the PPARδ agonist GW501516. In a bipedal AIS mouse model, this targeted intervention effectively restored mitochondrial function and muscle fiber composition, thereby retarding scoliosis progression. Overall, our findings reveal a metabolic mechanism of AIS pathogenesis and demonstrate a potential targeted therapeutic strategy for its management.
    Keywords:  Adolescent idiopathic scoliosis; FNDC5; GW501516; Mitochondrial homeostasis; PPARdelta; Paraspinal muscle asymmetry; Targeted nanodelivery
    DOI:  https://doi.org/10.1186/s12951-026-04753-z
  51. J Poult Sci. 2026 ;63 2026014
    Effects of Quercetagetin on Gut-Liver Axis Function and Cecal Microbial Diversity in Broilers via PINK1/Parkin-Mediated Mitophagy.
    Min Huo, Mengxuan Sun, Wanying Qu, Shuo Yang.
      Oxidative stress is a major constraint on broiler health and productivity. Mitochondrial dysfunction and gut-liver axis disruption play pivotal roles in this process. The present study investigated whether dietary quercetagetin (QG) alleviated diquat (DQ)-induced oxidative stress in broiler chickens through modulation of PINK1/Parkin-mediated mitophagy and gut-liver axis homeostasis. A total of 144 1-day-old WOD168 broilers were randomly assigned to four treatments with six replicate cages of six birds per cage: control group (non-challenged, basal diet), DQ group (DQ-challenged, basal diet), D_QG group (DQ-challenged, basal diet with 20 mg/kg QG), and QG group (non-challenged, basal diet with 20 mg/kg QG). On day 35, the DQ and D_QG groups were intraperitoneally administered DQ (20 mg/kg body weight). Dietary QG significantly increased body weight and attenuated the loss in average daily gain induced by DQ, while reducing serum aspartate aminotransferase levels. DQ challenge impaired gut barrier function, as indicated by decreased villus height, villus height/crypt depth ratio, and mRNA expression of Claudin-1 and ZO-1 (P < 0.05), exacerbated hepatic lesions, and significantly altered cecal microbial diversity. QG supplementation significantly attenuated the drop in glutathione peroxidase activity and downregulated PINK1 and LC3-II in hepatic mitochondria. It also significantly increased complex I activity, mitochondrial DNA copy number, and adenosine triphosphate content, while decreasing DQ-induced reactive oxygen species. Collectively, these results indicate that dietary QG alleviates DQ-induced oxidative stress by preserving mitochondrial function, potentially modulating PINK1/Parkin-related mitophagy, enhancing intestinal barrier integrity, and modulating cecal microbial composition.
    Keywords:  antioxidant capacity; broilers; gut–liver axis; mitophagy; quercetagetin
    DOI:  https://doi.org/10.2141/jpsa.2026014
  52. Front Physiol. 2026 ;17 1873221
    When mitochondria lose their fold: matrix proteostasis and stress signaling.
    Nils Bertram, Dejana Mokranjac.
      A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.
    Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3389/fphys.2026.1873221
  53. Mol Med. 2026 Jul 02.
    Cardiac extracellular vesicle proteomics identifies mitochondrial and contractile dysfunction in carbon monoxide poisoning and their reversal by hyperbaric oxygen therapy.
    Chien-Wei Hsiung, Yu-Chang Liu, Tzu-Hao Chen, Wei-Ting Chang, Ching-Ping Chang, Chien-Cheng Huang, Pao-Chi Liao.
       BACKGROUND: Carbon monoxide poisoning (COP) induces systemic hypoxia and oxidative stress-related injury, leading to myocardial injury and persistent cardiac dysfunction. However, reliable biomarkers for monitoring long-term cardiac sequelae and therapeutic responses remain lacking. Extracellular vesicles (EVs), which reflect the molecular status of their cells of origin, may serve as candidate biomarkers for organ-specific injury. This study investigated whether cardiac EV proteins capture COP-induced myocardial and mitochondrial dysfunction and reflect the therapeutic effects of hyperbaric oxygen (HBO) therapy.
    METHODS: A rat model of COP was established with or without HBO treatment. Cardiac function was assessed by echocardiography, and myocardial injury was evaluated using histological, ultrastructural, and biochemical analyses. Cardiac-enriched EVs isolated from ex vivo whole-heart perfusate were used for global proteomic profiling. Candidate differentially abundant proteins were analyzed with emphasis on pathways related to mitochondrial dynamics, mitochondrial energy metabolism, calcium handling, and myocardial contractility. Key EV-associated and tissue proteins were further validated, and selected candidates were examined in serum-derived EVs as preliminary targeted circulating EV validation.
    RESULTS: COP induced significant cardiac dysfunction, as evidenced by reduced ejection fraction and fractional shortening, together with histological myocardial injury, all of which were attenuated by HBO treatment. Proteomic analysis demonstrated that COP reshaped the cardiac EV proteome in a manner consistent with mitochondrial abnormalities, altered calcium-handling protein profiles, and impaired myocardial contractile function. These EV proteomic alterations were enriched in pathways related to mitochondrial dynamics, calcium signaling, and cardiac contractile regulation. Specifically, COP was associated with dysregulation of mitochondrial dynamics regulators, including optic atrophy type 1 (Opa1) and mitochondrial fission protein 1 (FIS1), as well as calcium-handling proteins such as ryanodine receptor 2 (Ryr2) and phospholamban (Pln). Ultrastructural and biochemical analyses showed mitochondrial cristae disruption, altered mitochondrial fusion-fission protein profiles, mitophagy-related protein changes, and pyroptosis-associated signaling in cardiac tissue following COP, whereas HBO mitigated these abnormalities. Notably, EV-associated Opa1 and FIS1 were associated with COP-related alterations in mitochondrial dynamic balance, whereas EV-associated Ryr2 and Pln were associated with impaired myocardial contractile parameters. Additional analysis of EV proteins related to mitochondrial function and ATP energy production further supported COP-associated mitochondrial energy metabolism-related protein remodeling. Targeted analysis of serum-derived EVs further showed that selected calcium-handling proteins, including Ryr2 and Pln, were detectable in circulating EVs and exhibited COP-associated changes consistent with cardiac tissue alterations. These findings support selected cardiac-enriched EV proteins as candidate molecular readouts of COP-associated myocardial, mitochondrial, and contractile abnormalities.
    CONCLUSIONS: Cardiac EV proteomic remodeling reflects COP-associated mitochondrial and contractile abnormalities and captures the therapeutic effects of HBO. These findings identify cardiac-enriched EV proteins as candidate molecular readouts of myocardial injury and treatment response, providing a cardiac-enriched EV discovery framework for future blood-based biomarker development. The observed alterations in mitochondrial dynamics-, mitochondrial energy metabolism-, and calcium-handling-related proteins provide hypothesis-generating insight into molecular pathways associated with COP-induced cardiac dysfunction. Further validation using circulating EV proteomics, biomarker classifier analyses, and dedicated redox proteomics will be required to establish clinical utility and redox-regulated mechanistic relevance.
    Keywords:  Calcium signaling; Carbon monoxide poisoning; Cardiac dysfunction; Cardiac extracellular vesicles; Hyperbaric oxygen therapy; Mitochondrial dynamics; Proteomics
    DOI:  https://doi.org/10.1186/s10020-026-01534-0
  54. Bioact Mater. 2026 Nov;65 829-844
    3D matrix stiffness drives energy metabolism to orchestrate stem cell osteogenesis via microtubule acetylation and mitochondrial dynamics.
    Zhijie Yang, Jing Na, Yu Liu, Gan Yue, Fei Song, Chiyu Li, Qiusheng Shi, Yubo Fan, Lisha Zheng.
      Hydrogels are widely recognized as promising materials for bone regeneration. However, how their biophysical properties, particularly stiffness, affect stem cell behavior in three-dimensional (3D) environments remains poorly understood. It is also unclear whether energy metabolism and mitochondrial dynamics play a role in mediating stiffness-regulated stem cell differentiation. Our study demonstrates that a soft extracellular matrix (ECM) enhances cytoskeletal polymerization and cell elongation. In vitro, a soft ECM promoted osteogenic differentiation, while in vivo it facilitated bone regeneration by regulating the formation of a uniform mitochondrial network and promoting mitochondrial fusion. Additionally, a soft matrix increased ATP production by enhancing both glycolysis and oxidative phosphorylation (OXPHOS), indicating a metabolic shift. Microtubule acetylation was upregulated in the soft ECM through the activity of αTAT1, accompanied by increased expression of Kinesin 1, which contributed to mitochondrial network formation and dynamic remodeling. These findings highlight the critical role of microtubule acetylation in mitochondrial organization and dynamics during stiffness-mediated osteogenesis in 3D environments. This work provides valuable insights for the rational design of biomaterials aimed at improving bone regeneration.
    Keywords:  3D; Energy metabolism; Microtubule acetylation; Mitochondria dynamics; Osteogenesis; Stiffness
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.025
  55. Cell. 2026 Jun 30. pii: S0092-8674(26)00697-5. [Epub ahead of print]
    Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data.
    Eric Arkfeld, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg.
      We introduce a whole-cell digital twin framework that integrates four-dimensional (4D) (x, y, z, and t) lattice light-sheet microscopy with particle-based reaction-diffusion simulations in ReaDDy to model mesoscale intracellular organelle dynamics. Using fluorescence microscopy data from live Cal27 cells, we construct spatially resolved digital twins incorporating mitochondrial networks, microtubule networks, dynein and kinesin motors, the plasma membrane, and the nucleus. Mitochondrial dynamics include fusion/fission remodeling, diffusion, and motor-driven active transport along microtubules. Our simulations reproduce experimental trends in mitochondrial dynamics across control and two microtubule-perturbed conditions, demonstrating predictive capability without reparameterization. We then use stress-mimicking to predict emergent perinuclear mitochondrial clustering. Crucially, these simulations reveal that microtubule topology acts as a structural gate for this reorganization, demonstrating that upregulated retrograde motor kinetics alone are insufficient to drive clustering without permissive filament connectivity. This digital twin framework provides an approach for investigating intracellular dynamics and perturbation effects in an interpretable and biologically grounded manner.
    Keywords:  ReaDDy; digital twin; lattice light-sheet microscopy; microtubule cytoskeleton; mitochondrial dynamics; mitochondrial fusion-fission; molecular motors; perinuclear clustering; reaction-diffusion simulation; whole-cell modeling
    DOI:  https://doi.org/10.1016/j.cell.2026.06.010
  56. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2026 Apr 28. pii: 1672-7347(2026)04-0667-15. [Epub ahead of print]51(4): 667-681
    [Chrysophanol alleviates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and inhibiting M1 macrophage polarization].
    Wei Zhang, Lele Wang, Ruihan Ge, Haotian Cui, Xinmin Wang, Le Zhang.
       OBJECTIVES: Sepsis-associated acute kidney injury (SA-AKI) is a major cause of mortality in critically ill patients. Imbalanced macrophage polarization plays a crucial role in the progression of SA-AKI, in which classically activated M1 macrophages aggravate renal injury by releasing pro-inflammatory cytokines, whereas mitochondrial homeostasis disruption is a key driver of macrophage inflammatory phenotypic switching. Chrysophanol (CHR), a monomeric active component derived from traditional Chinese medicine, has been shown to ameliorate SA-AKI by regulating macrophage polarization. This study aimed to investigate whether CHR suppresses M1 macrophage polarization by maintaining mitochondrial homeostasis in the SA-AKI microenvironment, thereby elucidating its anti-inflammatory and renoprotective mechanisms.
    METHODS: A SA-AKI model was established in C57BL/6 mice using cecal ligation and puncture (CLP), and mice were assigned to sham, CLP, and CHR treatment (CLP+CHR) groups. In vitro experiments were performed using human monocytic leukemia cells (THP-1) and human renal tubular epithelial cells (HK-2). Two cell models were established: 1) A Transwell co-culture system of M1 macrophages and lipopolysaccharide (LPS)-stimulated HK-2 cells treated with CHR to evaluate the overall protective effects of CHR in SA-AKI; and 2) a monoculture model of CHR-treated M1 macrophages to specifically assess its effects on mitochondrial homeostasis. Renal pathological alterations were examined by hematoxylin and eosin (HE) staining. Blood urea nitrogen (BUN) and serum creatinine (Cr) levels were measured to evaluate renal function. Enzyme-linked immunosorbent assay (ELISA) was used to quantify interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) levels in serum and co-culture supernatants. HK-2 cell viability was assessed using cell counting kit-8 (CCK-8), and apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay and Western blotting. Mitochondrial ultrastructure was observed by transmission electron microscopy. Adenosine triphosphate (ATP) levels, mitochondrial membrane potential (MMP), and nicotinamide adenine dinucleotide phosphate oxidized/reduced (NADP⁺/NADPH) ratios were measured. Quantitative polymerase chain reaction (qPCR) was performed to determine the mRNA expression of mitochondrial biogenesis-related genes, including peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1α), mitochondrial transcription factor A (TFAM), nuclear respiratory factor 1 (NRF1), and the M1 polarization marker cluster differentiation 86 (CD86), with protein expression validated by Western blotting. CD86 expression was further evaluated by immunofluorescence staining.
    RESULTS: Compared with the sham group, mice in the CLP group exhibited marked renal tubular dilation, epithelial necrosis and detachment, tubular cast formation, and significantly increased renal injury scores (P<0.05), whereas CHR treatment markedly alleviated these pathological changes. In vitro, CHR significantly reversed the LPS-induced reduction in HK-2 cell viability (P<0.01). Serum levels of BUN, Cr, IL-6, and TNF-α were significantly elevated in the CLP group compared with the sham group (all P<0.01). CHR treatment significantly improved renal function, reduced pro-inflammatory cytokine levels in serum and co-culture supernatants (all P<0.05), and suppressed apoptosis in both tissues and cells. Transmission electron microscopy revealed disrupted mitochondrial cristae and blurred membrane structures in the CLP group, which were markedly restored following CHR treatment. CHR significantly increased the reduced ATP levels in the SA-AKI model (P<0.001), improved mitochondrial membrane potential in M1 macrophages, decreased NADP+/NADPH ratios, and restored mitochondrial redox balance (P<0.05). Western blotting and qPCR demonstrated that CHR significantly upregulated mitochondrial-related gene and protein expression in the injured model (all P<0.05), while significantly downregulating M1 macrophage marker expression at both the mRNA and protein levels (all P<0.05). Immunofluorescence analysis showed strong CD86 fluorescence intensity in the M1 group, which was significantly attenuated after CHR treatment (both P<0.05).
    CONCLUSIONS: CHR significantly alleviates renal pathological injury and improves renal function in SA-AKI model mice. Its anti-inflammatory and renoprotective effects may be associated with maintaining mitochondrial energy and redox homeostasis and suppressing macrophage M1 polarization.
    Keywords:  M1 polarization; chrysophanol; lipopolysaccharide; macrophages; mitochondrial homeostasis; sepsis-associated acute kidney injury
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2026.250629
  57. Front Mol Biosci. 2026 ;13 1861303
    CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations.
    Zheng Tai Kuai, Xiao Min Zheng, Yue Yue Li, Tian Qi Wang.
      Mitochondrial bioenergetic competence critically depends on cristae architecture, which is organized and stabilized by the mitochondrial contact site and cristae organizing system (MICOS) complex. As a core MICOS subunit, CHCHD3 (also known as MIC19) contributes to assembly of the mitochondrial intermembrane space bridging (MIB) supercomplex and regulates cristae morphology, endoplasmic reticulum-mitochondria contact sites, and cellular metabolic homeostasis. Aberrant CHCHD3 expression or functional deficiency is implicated in the pathogenesis of neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and cancers. Notably, CHCHD3 function is governed by a dose-dependent "Goldilocks" principle, wherein both insufficient and excessive expression-as well as preserved abundance with impaired functional integrity-can compromise mitochondrial homeostasis, underscoring the need for context-specific therapeutic modulation. Here, we systematically summarize CHCHD3 molecular characteristics and post-translational modification networks, with emphasis on its roles in energy metabolism, organelle crosstalk, and apoptosis. We further examine the mechanistic links between CHCHD3 dysregulation and disease pathogenesis, evaluate current targeting strategies and their pharmacological limitations, and identify remaining controversies and knowledge gaps to guide future research toward clinical translation.
    Keywords:  CHCHD3; MIC19; MICOS complex; apoptosis; energy metabolism; mitochondrial contact sites; mitochondrial cristae
    DOI:  https://doi.org/10.3389/fmolb.2026.1861303
  58. Biomater Adv. 2026 Jun 26. pii: S2772-9508(26)00342-0. [Epub ahead of print]188 215044
    A multifunctional graphene oxide-based nanoplatform sensitizes ovarian cancer to cisplatin via ROS-PINK1/Parkin mitophagy under chemo-photothermal-photodynamic synergy.
    Xiaoning Li, Yumeng Guo, Xiaonan Wang, Chen Liu, Meijuan Shi, Huirui Zhu, Xiang Zhai, Yuyao Wang, Tao Yang, Hong Zhao, Bingmei Chang, Zhizhen Liu, Wenting Liang, Xiaojing Yang, Baofeng Yu, Tao Gong, Rui Guo.
      Ovarian cancer is the gynecological malignancy with the highest mortality rate. Platinum resistance remains a major clinical challenge, severely limiting the therapeutic efficacy of cisplatin-based chemotherapy. In recent years, nanomedicine delivery systems have emerged as a promising strategy to enhance the efficacy of conventional cancer treatments. Herein, we constructed a multifunctional graphene oxide-based nanoplatform by functionalizing graphene oxide with hyaluronic acid, gold nanorods, and indocyanine green, followed by loading of cisplatin to form GO-HA-GNRs-ICG@Pt. This nanoplatform exhibits remarkable photothermal and photodynamic conversion efficiency, active tumor-targeting capability, and pH/near-infrared light dual-responsive cisplatin release. More importantly, in vitro and in vivo studies demonstrate that GO-HA-GNRs-ICG@Pt achieves significantly higher therapeutic efficacy and better biosafety compared to cisplatin monotherapy in A2780 ovarian cancer cells. Mechanistically, we discovered that GO-HA-GNRs-ICG@Pt activates the ROS-PINK1/Parkin-mediated mitophagy signaling axis, ultimately enhancing the cisplatin sensitivity of ovarian cancer cells. This work not only provides a theoretical foundation for the development of targeted multifunctional nanoplatforms for integrated cancer therapy but also offers a new synergistic treatment strategy with potential for addressing drug resistance in clinical ovarian cancer.
    Keywords:  Antitumor efficacy; Graphene oxide; Mitophagy; Ovarian cancer; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bioadv.2026.215044
  59. Biochem Biophys Res Commun. 2026 Jun 27. pii: S0006-291X(26)00976-9. [Epub ahead of print]829 154212
    GPR4 promotes ferroptosis in nucleus pulposus cells via MAPK-dependent mitophagy suppression.
    Jie Zhao, Zhaoqiang Xu, Jiawen Niu, Hang Du, Yang Zhang, Yachao Zhao, Chunzheng Gao, Dongjin Wu.
      Inflammatory diseases are known to lower the pH value of the extracellular microenvironment. However, the role of proton-activated G protein-coupled receptors (GPCRs) in the progression of intervertebral disc degeneration (IVDD) remains largely unexplored. In this study, we identified GPR4 as a key regulator of IVDD progression. Our analysis revealed a significant upregulation of GPR4 in degenerative human intervertebral discs. The expression of GPR4 was assessed using immunohistochemistry (IHC). Functional assays, including flow cytometry, immunofluorescence and WB, were performed to evaluate the impact of GPR4 on ferroptosis. We observed that GPR4 expression was significantly elevated in tert-butyl hydroperoxide (TBHP)-treated degenerative nucleus pulposus cells. Proteomic sequencing further demonstrated that GPR4 overexpression altered gene expression related to the mitochondrial energy metabolism and ferritin homeostasis. Notably, knockdown of GPR4 via shRNA (shGPR4) enhanced the MAPK-mediated mitophagy while suppressing ferroptosis in TBHP-exposed NP cells. These findings suggested that GPR4 played a critical role in IVDD pathogenesis and may serve as a potential therapeutic target for mitigating disc degeneration.
    Keywords:  Ferroptosis; GPR4; IVDD; MAPK; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154212
  60. Phytomedicine. 2026 Jul 02. pii: S0944-7113(26)00730-0. [Epub ahead of print] 158500
    Corrigendum to "Bushentongluo formula counteracts BMSCs senescence to alleviate postmenopausal osteoporosis by activating mitophagy via the SENP1-SIRT3 pathway" [Phytomedicine 152 (2026) 157827].
    Shuai Chen, Lingling Yu, Ningsheng Tian, Qilong Zhao, Miaochao Qin, Liansheng Shao, Pengfei Sun, Peng Ma, Junwu Wang, Penghua Fang, Wen Min.
      
    DOI:  https://doi.org/10.1016/j.phymed.2026.158500
  61. BMC Genomics. 2026 Jun 29.
    Metabolic reprogramming, oxidative stress, and mitophagy in JSRV Env-transformed BEAS-2B cells: insights from integrated transcriptomics and metabolomics.
    Xujie Duan, Wenjing Lan, Rui Liu, Pei Zhang, Sixu Chen, Yufei Zhang, Liang Zhang, Huiping Li, Shuying Liu.
       BACKGROUND: Jaagsiekte sheep retrovirus (JSRV) causes ovine pulmonary adenocarcinoma (OPA), and its pathogenesis is primarily mediated by the viral envelope (Env) protein. However, the detailed oncogenic mechanisms underlying JSRV infection remain incompletely understood. In this study, we integrated transcriptomic and metabolomic analyses to characterize JSRV Env-induced alterations in human bronchial epithelial BEAS-2B (cells).
    RESULTS: BEAS-2B cells transfected with the pcDNA4.0myc-his-JSRV-env plasmid, those transfected with the empty pcDNA4.0myc-his vector, and untreated BEAS-2B cells served as the experimental, negative control, and blank control groups, respectively. Transcriptomic analysis identified a total of 2733 differentially expressed genes (DEGs). Specifically, relative to the blank and negative control groups, 1178 genes were upregulated and 307 were downregulated in the JSRV-env group. These DEGs were significantly enriched in pathways related to altered cellular energy metabolism, cell cycle regulation, and oncogenic signaling. Metabolomic analysis revealed 451 differentially expressed metabolites (DEMs), with 192 detected in positive ion mode and 259 in negative ion mode. Compared with both control groups, the JSRV-env group exhibited 33 upregulated and 46 downregulated DEMs in positive ion mode, as well as 22 upregulated and 55 downregulated DEMs in negative ion mode. These DEMs were significantly enriched in pathways such as cellular metabolism, purine metabolism, amino acid metabolism, and the tricarboxylic acid cycle. Notably, cellular and mitochondrial energy metabolism pathways were closely linked. Analyses of mitochondrial- and mitophagy-related genes, alongside an integrated transcriptomic and metabolomic evaluation of their interactions, suggested mitochondrial damage and the potential activation of mitophagy. Furthermore, JSRV Env-transformed BEAS-2B cells exhibited elevated reactive oxygen species, decreased mitochondrial membrane potential, and abnormal mitochondrial morphology-characterized by swelling, as well as fragmented, dissolved, or disappearing cristae-along with the presence of myelin-like mitochondrial lesions and mitophagosomes. Mitochondrial and lysosomal probe co-localization further confirmed mitochondrial degradation in the transformed cells.
    CONCLUSIONS: Overall, these results highlight the potential involvement of altered mitochondrial energy metabolism and mitophagy in JSRV Env-induced BEAS-2B cell transformation. These findings offer novel insights into the mechanisms of viral oncoproteins, cellular metabolic reprogramming, and mitophagy, while identifying potential targets for understanding JSRV pathogenesis.
    Keywords:  Jaagsiekte sheep retrovirus; Metabolic reprogramming; Metabolomics; Mitophagy; Transcriptomics
    DOI:  https://doi.org/10.1186/s12864-026-13125-8
  62. Orphanet J Rare Dis. 2026 Jun 30.
    Mitochondrial stress markers associate with phenotypic variability in Fabry disease.
    Lucia Lavalle, Hibba Kurdi, David Moreno Martinez, Vincent Muczynski, Simon Heales, Derralynn Hughes.
       BACKGROUND: Fabry disease (FD) exhibits marked clinical heterogeneity that cannot be fully explained by residual α-galactosidase A activity. Mitochondrial dysfunction has been reported in FD, but the role of mitochondrial stress remains unexplored.
    OBJECTIVE: To investigate whether mitochondrial unfolded protein response (mtUPR) related markers associate with phenotypic variability and correlates with disease severity.
    METHODS: We measured intracellular heat-shock protein 60 (Hsp60) expression by western blotting in fibroblasts and peripheral blood mononuclear cells (PBMCs). In the clinical cohort, intracellular Hsp60 was measured in PBMC whole-cell lysates from 27 FD patients (14 males, 13 females). Serum fibroblast growth-factor-21 and growth differentiation-factor-15 were measured in 35 patients. Clinical outcomes included Mainz Severity Score Index, Age-Adjusting Severity Score, estimated glomerular filtration rate, and left-ventricular mass index (LVMI).
    RESULTS: Hsp60 showed variability, with sex-specific associations. In males, higher Hsp60 correlated with lower LVMI (r2 = -0.82, p = 0.01) and preserved renal function in late-onset patients (r2 = 0.89, p = 0.006). In females, higher Hsp60 associated with higher LVMI (r2 = 0.66, p = 0.045) and greater clinical severity. Male patients had elevated growth differentiation-factor-15 vs controls (935 vs 559 pg/ml, p = 0.002). Both mitokines correlated with age and disease severity.
    CONCLUSIONS: mtUPR related markers exhibit sex- and genotype-specific patterns associated with disease severity, suggesting that mitochondrial stress contributes to phenotypic heterogeneity and support further longitudinal evaluation of Hsp60, FGF-21 and GDF-15 as candidate biomarkers of disease burden and treatment response.
    Keywords:  Fabry disease; Hsp60; Mitochondrial unfolded protein response; Mitokines (FGF-21, GDF-15); Phenotypic heterogeneity
    DOI:  https://doi.org/10.1186/s13023-026-04461-9
  63. Sleep Biol Rhythms. 2026 Jul;24(3): 433-435
    Correction: Mitophagy protects renal tubular epithelial cells from intermittent hypoxia-induced injury via the HIF-1α/BNIP3 pathway.
    Xiao-Bin Zhang, Qi-Feng Gan, Yu-Xin Guo, Li-Da Chen, Li-Qin Zhang, Ling Cai, Ya-Ting Yuan, Jing-Huang Cai, Xiang-Xin Chen.
      [This corrects the article DOI: 10.1007/s41105-025-00625-5.].
    DOI:  https://doi.org/10.1007/s41105-026-00652-w
  64. Redox Biol. 2026 Jun 30. pii: S2213-2317(26)00282-X. [Epub ahead of print]95 104283
    Norepinephrine attenuates acute lung injury by protecting mitochondria via the β2-AR-AKAP1 axis and inhibiting alveolar epithelial pyroptosis.
    Yiyuan Yin, Zhaojin Zeng, Senhao Wei, Xiaoyun Wei, Zhukai Cong, Xi Zhu.
      Acute lung injury (ALI) is a common and life-threatening critical illness with persistently high mortality, yet effective pharmacological therapies remain lacking. Norepinephrine (NE), a first-line vasopressor for septic shock, has been suggested to confer organ-protective and immunomodulatory effects in sepsis and related organ injury; however, its specific role and molecular mechanisms in ALI remain poorly defined. Here, we demonstrate both in vitro and in vivo that NE significantly attenuates ALI, and this protective effect is primarily attributable to the suppression of alveolar epithelial cell pyroptosis. Transcriptomic profiling and functional analyses reveal that NE activates the β2-adrenergic receptor (β2-AR)-cAMP/PKA signaling axis and, through the A-kinase anchoring protein AKAP1, preserves mitochondrial homeostasis, thereby interrupting the vicious cycle between mitochondrial damage and pyroptosis. Further mechanistic dissection identifies AKAP1 as an indispensable molecule for NE-mediated protection and caspase-11 as the critical downstream effector through which NE inhibits pyroptosis. Collectively, this study uncovers a novel mechanism by which NE suppresses alveolar epithelial pyroptosis and alleviates ALI via the β2-AR-AKAP1 axis, providing a potential therapeutic target for ALI.
    Keywords:  AKAP1; Acute lung injury; Alveolar epithelial pyroptosis; Mitochondrial homeostasis; Norepinephrine
    DOI:  https://doi.org/10.1016/j.redox.2026.104283
  65. Neurosci Bull. 2026 Jul 03.
    Hierarchical Studies in TRAP2 Mice Demonstrate that Neuronal Activation and Mitochondrial Networks Integration Constitute the Key Mechanism Underlying Painful Syncope.
    Xueyin Pu, Yulu Xia, Ziwei Ni, Changlei Zhu, Kunlong Zhang, Bozhi Liu, Rui Lin, Jingxuan Zhu, Hui Liu, Shujiao Li, Yunqiang Huang, Feifei Wu, Nannan Liu, Shuai Zhang, Yousheng Wu, Fei Tian, Yanling Yang, Yayun Wang.
      Approximately 40% of the global population experiences at least one syncope episode during their lifetime. However, the neurobiological mechanisms underlying these effects remain unclear. In this study, facial administration of formalin in mice was used to induce painful syncope. Whole-brain atlas analysis of 116,283 c-Fos+ neurons in 856 brain regions revealed 11 key brain regions associated with painful syncope. Subsequent analysis of approximately 300,000 mitochondrial networks revealed that their morphology in the locus coeruleus (LC), nucleus tractus solitarius (NTS), gigantocellular reticular nucleus (GR), lateral reticular nucleus (LRN), and parabrachial nucleus, spinal trigeminal nucleus pars caudalis (SPVC) underwent significant changes during syncope. Furthermore, downregulation of the mitochondrial dynamin-related protein 1 (DRP1) in the NTS could mediate the exacerbation of weakly lying on the ground in painful syncope. Our findings reveal that abnormal neuronal activity and mitochondrial network remodeling may serve as key mechanisms underlying painful syncope.
    Keywords:  Coordination; Mitochondrial networks; Neuronal activation; Painful syncope; TRAP2-MITO-GFP mice; TRAP2-tdTomato mice
    DOI:  https://doi.org/10.1007/s12264-026-01670-x
  66. Nat Metab. 2026 Jun 29.
    Mitochondrial quality control in human ageing and longevity.
    Anna Picca, Luigi Ferrucci.
      Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.
    DOI:  https://doi.org/10.1038/s42255-026-01563-3
  67. Acta Physiol (Oxf). 2026 Aug;242(8): e70272
    RyR1 Calcium Leak and Mitochondrial Ca2+ Homeostasis in Skeletal Muscle.
    Nicolas Place.
      
    DOI:  https://doi.org/10.1111/apha.70272
  68. Cancer Genomics Proteomics. 2026 Jul-Aug;23(4):23(4): 806-823
    NRF1 Activates the AMPK/SIRT1/PGC-1α/TFAM Axis to Suppress EMT and Tumor Progression in Lung Adenocarcinoma.
    Hsing-Hsien Wu, Pei-Fang Hsieh, Ming-DER Shi, Chun-Hung Ko, Chun-Hsien Wu, Victor C Lin, Shu-Fen Liu, Yu-Ju Hung, Tzu-Sui Hung, I-Chou Wang, Yu-Lin Yang.
       BACKGROUND/AIM: Lung cancer is the leading cause of cancer-related mortality globally, emphasizing the need for identifying molecular mechanisms that drive its progression and therapeutic resistance. Nuclear respiratory factor 1 (NRF1) is a transcription factor involved in mitochondrial biogenesis, apoptosis, and epithelial-mesenchymal transition (EMT), all of which contribute to cancer initiation and metastasis. This study investigated the role of NRF1 in lung cancer progression and its potential as a therapeutic target.
    MATERIALS AND METHODS: A549 lung adenocarcinoma cells were used to evaluate the effects of NRF1 overexpression (pcDNA-NRF1) and silencing (shRNA-NRF1). Moreover, western blotting were used to assess EMT markers (E-cadherin, N-cadherin, vimentin), mitochondrial biogenesis factors (T-fam), and apoptotic markers (caspase-3, caspase-9). Functional assays were performed to measure cell migration, and apoptosis. SCID mice implanted with NRF1-modified tumors were used for in vivo validation. Statistical analyses included analysis of variance (p<0.05).
    RESULTS: NRF1 overexpression increased E-cadherin while reducing N-cadherin and vimentin, inhibiting EMT. It suppressed cell migration while enhancing mitochondrial biogenesis and apoptosis, as indicated by elevated caspase-3 and caspase-9 activity. Conversely, NRF1 silencing promoted EMT, reduced mitochondrial biogenesis, and decreased apoptosis. In vivo, NRF1-overexpressing tumors exhibited higher levels of E-cadherin, T-fam, and caspase-3, supporting NRF1's role in EMT suppression and mitochondrial and apoptotic pathway enhancement.
    CONCLUSION: NRF1 acts as a suppressor of EMT and a promoter of mitochondrial biogenesis and apoptosis in lung cancer. Its regulatory role suggests NRF1 as a potential therapeutic target for inhibiting tumor progression and overcoming resistance to conventional therapies.
    Keywords:  Lung cancer; NRF1; RNA interference; apoptosis; cell apoptosis; epithelial–mesenchymal transition; mitochondrial biogenesis; mitochondrial dysfunction; therapeutic target; tumor progression
    DOI:  https://doi.org/10.21873/cgp.20602
  69. Front Genet. 2026 ;17 1826214
    Single-cell and pseudobulk analyses reveal hidden mitochondrial expression imbalance in gastric cancer.
    Le Chang, Jingwen Hou, Yingying Li, Simeng Liu, Pengya Feng, Ya Li, Chunjing Qiu, Pengyuan Zheng, Xia Xue, Yang Mi.
       Background: Mitochondrial function is essential for biology, particularly in cancer. However, cell-type-specific expression patterns of conserved mitochondrial genes in gastric cancer (GC) remain unclear. We herein raised and tested a novel hypothesis of "mitochondrial conserved gene expression homeostasis imbalance" in GC cohorts with single-cell resolution.
    Methods: This work analyzed an open-accessed scRNA-seq dataset (GSE206785, 24 GC patients, 48 samples) with Seurat and defined 43 clusters grouped into 15 cell subtypes. In parallel, Pseudobulk profiles were generated to simulate bulk RNA-seq. A mitochondrial conserved gene score was computed by Seurat AddModuleScore, GSVA, and AUCell. Mitochondria-related biomarkers were also screened, validated, and incorporated into a mitochondria-dependent prognostic model that was further evaluated.
    Results: Without considering cell-type-specific expression patterns, Pseudobulk analysis showed no significant differences in mitochondrial conserved gene expression between GC and control samples. In contracst, single-cell analysis found a cell-type-specific imbalance, under which tumor-associated epithelial cells displayed relatively elevated mitochondrial conserved gene expression, while non-epithelial cells showed reduced. Notably, survival analyses identified gene KRT7 and KLRC1 as robust prognostic biomarkers for early GC.
    Conclusion: Our findings support a mitochondrial conserved gene expression homeostasis imbalance in GC, which is characterized by compartment-specific mtGene expression imbalance. Also, KRT7 and KLRC1 emerge as prognostic markers for therapies aimed at restoring mitochondrial homeostasis in GC.
    Keywords:  gastric cancer; gene expression; mitochondrial homeostasis; precise medicine; single cell sequencing data
    DOI:  https://doi.org/10.3389/fgene.2026.1826214
  70. J Mater Sci Mater Med. 2026 Jun 29.
    Zinc-polydopamine nanozyme promotes mitochondrial biogenesis and alleviates inflammation and muscle atrophy during the perioperative period of surgery.
    Haoran Guo, Ruixing Wan, Qingqing Qin, Wenqiang Liang, Huaibin Zhang, Xin Wang.
      Cisplatin is a commonly used chemotherapeutic agent for the treatment of diverse malignancies; however, its clinical use often results in skeletal muscle atrophy (SMA). Excessive generation of reactive oxygen species (ROS) and persistent unsettled inflammation are significant contributors to cisplatin (CPT)-induced skeletal muscle atrophy (CiSMA). Nanoparticles capable of scavenging ROS and alleviating inflammation may effectively address CiSMA. We developed a straightforward, fast one-step method for fabricating tailored zinc-polydopamine (Zn-PD) nanozymes and confirmed their promising therapeutic agents for CiSMA. Zn-PD, which exhibits diverse enzyme-mimicking capabilities, Zn-PD effectively inhibits ROS-triggered myotube apoptosis, rectifies mitochondrial dysfunction, and enhances mitochondrial biogenesis, demonstrating significant anti-inflammatory effects by obstructing the M1 macrophage infiltration into the muscle milieu, thereby mitigating CiSMA in mice. Collectively, this study proposes a treatment approach for CiSMA and underscores the potential of Zn-PD-based therapies for treating muscle atrophy during the perioperative period of surgery.
    DOI:  https://doi.org/10.1007/s10856-026-07080-9
  71. J Control Release. 2026 Jun 30. pii: S0168-3659(26)00546-8. [Epub ahead of print] 115143
    Bio-recruiting hydrogel targeting mitochondrial homeostasis under neutrophil extracellular traps for diabetic wound repair.
    Junying Song, Binyu Song, Yuhan Zhu, Yifu Zhu, Yufei Zhang, Yajuan Song, Tong Wang, Yi Shi, Yan Jiao, Guodong Yang, Zhou Yu, Baoqiang Song.
      Diabetic wound healing is a complex process that requires precise coordination among functional cells, with endothelial cells (ECs) playing a critical role in tissue vascularization. We begin by identifying neutrophil extracellular traps (NETs) as one of critical stressors that disrupts mitochondrial homeostasis in ECs. In addition, inadequate recruitment of ECs often leads to unsatisfactory regenerative outcomes. To address these issues, we developed a composite hydrogel formulation co-encapsulating C-X-C motif chemokine ligand 12 (CXCL12) mRNA-loaded exosomes to promote pro-regenerative endothelial cell homing, and leonurine (Leo) to regulate cellular functionalities, thereby preserving endothelial function essential for neovascularization. By pairing exosomal mRNA delivery with the MS2 coat protein (MCP)-MS2 tethering system for mRNA payload multiplication, we achieved sustained CXCL12 production and cascade-amplified recruitment of CXCR4-positive cells. Moreover, Leo released from the composite hydrogel protectively rescued mitochondrial dysfunction. Further, application of this hydrogel to full-thickness skin defects led to significantly improved wound regeneration in diabetic mice. In summary, this study establishes a therapeutic "recruit-reinforce" platform based on a dual-delivery hydrogel armed with CXCL12 mRNA-enriched exosomes and Leo, thereby precisely targeting mitochondrial homeostasis under NETs stress for efficient diabetic wound repair.
    Keywords:  CXCL12; Exosomes; Hydrogel; Leonurine; Mitochondrial homeostasis; Neutrophil extracellular traps
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115143
  72. Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00075-9. [Epub ahead of print]91 102185
    DNM1L depletion leads to accelerated heteroplasmy shifting of m.10191C allele through ATG7-dependent pathways.
    Melissa Geng, Dahai Wang, Sam Kavoosi, Brett A Kaufman, Neal Sondheimer.
      Nucleotide composition bias in mitochondrial DNA (mtDNA) makes the heavy strand prone to form a DNA secondary structure called a guanine quadruplex (G4). This secondary structure has been shown to inhibit polymerase processivity in vitro. We previously identified pathogenic mtDNA variants that lead to increased G4-forming propensity, including a T to C mutation at m.10191 (m.10191 T > C) that causes Leigh syndrome. Cells treated with G4 binding agent (G4BA) berberine show a reduction in m.10191C pathogenic heteroplasmy levels. To help better understand the underlying mechanism behind berberine-induced heteroplasmy shift, we examined the relationship between mitochondrial fission and berberine-mediated shift. Here we show that knockdown of the fission factor DNM1L leads to an accelerated heteroplasmy shift towards the healthy mtDNA allele, lowering m.10191C by 10% in 3 weeks, compared to the 5 weeks required for berberine alone. The specific mechanism involves ATG7, as knockdown of ATG7 is able to partially delay this accelerated heteroplasmy shift. Taken together, we show that DNM1L knockdown is able to accelerate berberine-induced m.10191C heteroplasmy shifting through an autophagy-related mechanism.
    Keywords:  Autophagy; Guanine quadruplex; Heteroplasmy shifting; Mitochondrial fission; Mitochondrial heteroplasmy
    DOI:  https://doi.org/10.1016/j.mito.2026.102185
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