bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–07–12
sixty papers selected by
Gavin McStay, Liverpool John Moores University
  1. SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
  2. Remodeling of the mitochondrial quality control network: natural products intervening in diabetic retinopathy.
  3. Triptolide-induced hepatotoxicity is mediated by NLRP3-dependent pyroptosis and inhibited by mitophagy.
  4. NME3 promotes clear cell renal cell carcinoma progression and modulates TKI response through MFN1/2-dependent mitochondrial fusion and mitophagy suppression.
  5. Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
  6. Common carp USP30s restrict SVCV replication by attenuating mitophagy.
  7. ER-mitochondria tether ML1 coordinates peripheral fission and wholesale mitophagy for plant adaptation to carbon starvation.
  8. Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
  9. Acylglycerol Kinase Inhibition Restores Mitophagy and Alleviates Alzheimer's Disease Pathology.
  10. Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.
  11. Mitochondrial-targeted actions of lycopene: evidence, mechanisms and future directions.
  12. NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.
  13. Menaquinone-7 alleviates mitochondrial dysfunction and senescence in senile osteoporosis by targeting the PINK1-mediated mitophagy via PXR/ERK/CREB signaling pathway.
  14. Loganin Alleviates CCl4-Induced Acute Liver Injury by Promoting Mitophagy and Inhibiting NLRP3 Inflammasome.
  15. Piperonyl Butoxide Impairs Porcine Oocyte In Vitro Maturation by Suppressing the p38 MAPK Signaling Pathway and Dysregulating Mitophagy.
  16. TRIM65 accelerates VSMC-derived foam cell formation and arteriosclerosis progression by inhibiting mitophagy.
  17. Vitis Vinifera L. Flavones Preserve Mitophagy in the Amyloid-beta 1-42-induced Model of Alzheimer's Disease Neurodegeneration.
  18. HPC restores mitochondrial homeostasis and ameliorates hypoxic stress through the GSK-3β/β-catenin signaling pathway.
  19. AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.
  20. Mitophagy in Cardiovascular Disease: From Mechanistic Insights to Therapeutic Horizons.
  21. PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
  22. Bazedoxifene attenuates lipopolysaccharide-induced acute lung injury by inhibiting NLRP3 inflammasome activation of macrophages in mice.
  23. Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
  24. Hydrogen alleviates sepsis-associated encephalopathy via ATG9B-dependent mitophagy.
  25. Inhalable ROS-Responsive Nanospray Activates PPAR-γ to Restore Macrophage Mitochondrial Homeostasis and Attenuate Radiation-Induced Lung Injury.
  26. Corrigendum to 'Myeloperoxidase (MPO) mediates LPS-induced mitophagy in murine macrophages through AMPK/ULK1 pathway' [Free Radic. Biol. Med. 251 (2026) 333-346].
  27. Fuel-maintenance coupling reprograms mitochondrial homeostasis to enable peripheral nerve regeneration.
  28. LncRNA AP000654.1 attenuates cerebral ischemia-reperfusion injury by regulating mitophagy-mediated NLRP3 inflammasome activation.
  29. Icariin ameliorates gestational diabetes mellitus by targeting the S100A9-mediated RAGE pathway to activate mitophagy.
  30. Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.
  31. Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
  32. Crocetin from saffron ameliorates motor symptoms in Parkinson's disease models by improving mitochondrial function and PINK1/Parkin mediated mitophagy.
  33. Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
  34. Luteolin Triggers Pyroptosis in Pancreatic Ductal Adenocarcinoma by Inhibiting Mitochondrial Fission through the RAS/ERK/DRP1 Pathway.
  35. Henagliflozin promotes mitophagy in renal tubular cells by activating AMPK/ULK1 to alleviate the progression of diabetic kidney disease.
  36. Integration of transcriptome profiling to identify key genes involved in the interplay between oxidative stress and mitophagy in major depressive disorder, followed by multidimensional phenotypic validation.
  37. Sinensetin ameliorates established high-fat diet-induced liver injury and intestinal barrier dysfunction through the mitophagy/TLR4/MAPK signaling pathway.
  38. SPG7-Mediated Regulation of mPTP and Mitochondrial Flickering in COPD: A Bioinformatics-Based Prediction of Mechanistic Framework.
  39. Hypoxia-preconditioned dental pulp stem cells alleviate acetaminophen-induced liver failure via promoting MYC-HIF1A/HIF-1α-BNIP3-mediated mitophagy.
  40. Mechanisms of mitochondrial dysfunction and protective strategies in skin flap ischemia-reperfusion injury.
  41. Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF.
  42. Berbamine improves behavioral impairments in Huntington's disease mice models through inhibiting Src/AKT1/NFκB signaling pathway and attenuating Src-mediated mitophagy suppression.
  43. Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
  44. Polystyrene nanoplastics exacerbated the toxicity of cadmium: from the perspective of the placenta-uterus micro-environment.
  45. Agmatine induces mitophagy via the PTS-I2R pathway to increase autophagic flux and attenuate sepsis-induced intestinal epithelial cell apoptosis.
  46. Elucidation of ACAT1's role in hepatic ischemia-reperfusion injury: TFEB-mediated mitophagy and ferroptosis modulation as therapeutic targets.
  47. IMPA2 ameliorates high-fat diet-induced obesity by enhancing adaptive thermogenesis in a Ca²⁺-activated mitochondrial biogenesis pathway.
  48. In vivo assessment of naringenin-mediated amelioration of lead-induced testicular injury in rats: regulation of Nrf2/Keap1 and PINK1/Parkin pathways.
  49. Corrigendum to "Fatty acid oxidase Ehhadh mediates stem cell fate remodeling via mitophagy activation" [Free Radic. Biol. Med. 248 (2026) 109-126].
  50. Corrigendum to "Maimendong decoction modulates the PINK1/Parkin signaling pathway alleviates type 2 alveolar epithelial cells senescence and enhances mitochondrial autophagy to offer potential therapeutic effects for idiopathic pulmonary fibrosis" [J. Ethnopharmacol., 345, (9 April 2025), 119568].
  51. Hippocampal LANCL1 attenuates postoperative cognitive dysfunction via the SIRT1/PGC-1α-mediated mitochondrial biogenesis.
  52. Psoralen enhances direct cardiac reprogramming via activating PPARα and driving mitochondrial fission and improves cardiac function after myocardial infarction.
  53. ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
  54. ASAP3 deficiency alleviates hepatic senescence and correlates with extended healthspan in mice.
  55. Dopamine signaling reprograms macrophage FAO to alleviate acute lung injury by inhibiting NETosis via the CXCL10-CXCR3 axis.
  56. The role of mitochondrial proteases in inflammation and immunity.
  57. SMSC-EVs restore chondrocyte function through S1PR1-mTORC2-mediated mitochondrial fusion and GPS2-HDAC1-driven epigenetic regulation.
  58. WIPButyrate produced by the Lycium ruthenicum polysaccharide alleviated sleep deprivation-induced chronic fatigue syndrome in mice through promoting microglial autophagy.
  59. Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
  60. Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
  1. Mol Neurobiol. 2026 Jul 10. pii: 753. [Epub ahead of print]63(1):
    SUMOylation in Mitochondrial Quality Control: Mechanisms and Implications for Neurodegenerative Disease.
    Qingya Wu, Dengying Fan, Jianhui Ren, Yafang Xing, Zhengzheng Chen, Haochen Jin, Yisheng Lu, Xiaopeng Wang, Hua Zheng.
      Mitochondria, as the primary energy-generating organelles in neurons, play a pivotal role in regulating cellular metabolism. Given the post-mitotic nature and long lifespan of neurons, they are particularly vulnerable to the cumulative burden of mitochondrial damage. In response to various physiological and stress signals, a sophisticated mitochondrial quality control (MQC) system has evolved, which encompasses mitochondrial biogenesis, dynamics (fission and fusion), and mitophagy. This coordinated network acts as a critical surveillance mechanism to eliminate damaged components and maintain a healthy mitochondrial pool. The small ubiquitin-like modifier (SUMO) pathway, involving reversible SUMOylation and deSUMOylation, has emerged as a key regulator of MQC by directly modifying its core components. Dysregulation of the SUMO pathway disrupts mitochondrial homeostasis, and the resulting mitochondrial dysfunction is increasingly recognized as a central pathogenic mechanism in neurodegenerative diseases. This review systematically examines the role of the SUMO pathway in regulating MQC and its implications in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease. Finally, we discuss the therapeutic potential and translational challenges of targeting the SUMO pathway for the treatment of neurodegenerative diseases.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Neurodegenerative diseases; SUMOylation
    DOI:  https://doi.org/10.1007/s12035-026-06050-0
  2. Front Pharmacol. 2026 ;17 1851846
    Remodeling of the mitochondrial quality control network: natural products intervening in diabetic retinopathy.
    Tingru Chen, Ruolan Wu, Xinyi Liu, Yutong Jiang, Qun Huang, Ninghui Wan.
      Diabetic retinopathy (DR) remains a leading cause of vision loss among working-age adults. Its pathogenesis is increasingly understood as the progressive dysregulation of the mitochondrial quality control (MQC) network, which encompasses mitochondrial dynamics, mitophagy, mitochondrial biogenesis, mitochondria-associated endoplasmic reticulum membranes (MAMs), and intercellular mitochondrial transfer. Under sustained hyperglycemia, this network shifts from compensatory imbalance to irreversible collapse, driving mitochondrial dysfunction, oxidative stress, inflammatory activation, and retinal neurovascular unit (NVU) injury, thus promoting progression from non-proliferative to proliferative DR. Because of their multitarget properties, natural products (NPs) can restore fusion-fission balance, modulate mitophagy in a stage-dependent manner, and promote mitochondrial biogenesis, thereby remodeling the MQC network. However, their clinical translation is constrained by low bioavailability, poor penetration of the blood-retinal barrier (BRB), and potential dose-dependent toxicity. Mitochondria-targeted nano-delivery systems, including liposomes, exosomes, and mitochondrial-derived vesicles, may improve retinal accumulation and mitochondrial targeting. Future studies should refine stage-specific mechanistic understanding, strengthen safety evaluation and structural optimization, and integrate single-cell omics with artificial intelligence to accelerate translation and enable early MQC-targeted intervention, with the potential to delay or even reverse the progression of DR. Critically, MQC-directed NP therapy should not be interpreted as uniformly pro-mitophagy, anti-fission, or pro-biogenesis; the therapeutic benefit depends on disease stage, cell type, autophagic flux integrity, target engagement, and retinal pharmacokinetic/pharmacodynamic exposure.
    Keywords:  diabetic retinopathy; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; natural products
    DOI:  https://doi.org/10.3389/fphar.2026.1851846
  3. Food Chem Toxicol. 2026 Jul 10. pii: S0278-6915(26)00344-3. [Epub ahead of print] 116270
    Triptolide-induced hepatotoxicity is mediated by NLRP3-dependent pyroptosis and inhibited by mitophagy.
    Yuerui Su, Pengcheng Li, Kun Zhou, Yinxia Chang, Zhihua Luan, Bo Han, Huifang Li, Jinhong Ren, Haixue Zhang, Yanming Wei.
      This study investigated the regulatory effects of triptolide on PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy and NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis. Furthermore, it aimed to elucidate the potential relationship between mitophagy and pyroptosis in triptolide-induced hepatotoxicity. We established in vitro and in vivo models using a human normal hepatic cell line, HL7702, and C57BL/6J mice treated with triptolide. Furthermore, mitophagy inhibition experiments were performed using cyclosporin A, chloroquine, or PINK1 knockdown. The results revealed that triptolide induced severe hepatic cell damage accompanied by mitochondrial impairment. PINK1/Parkin-mediated mitophagy was concurrently induced, which manifested via increased levels of PINK1, Parkin, and microtubule-associated protein light chain 3II, and decreased p62. Moreover, triptolide increased the levels of NLRP3-mediated pyroptotic markers, including NLRP3, caspase-1, cleaved caspase-1, and gasdermin D N-terminal fragment, and promoted the extracellular release of IL-1β and IL-18. Notably, mitophagy inhibition further augmented the triptolide-induced hepatic cell pyroptosis and worsened hepatic damage. Taken together, our results indicate that the triptolide-activated pyroptosis induces hepatotoxicity, which is subsequently suppressed by mitophagy. Therefore triptolide-induced hepatotoxicity is mediated by NLRP3-dependent pyroptosis and inhibited by mitophagy.
    Keywords:  Hepatotoxicity; Mitophagy; NLRP3 inflammasome; PINK1/Parkin pathway; Pyroptosis; Triptolide
    DOI:  https://doi.org/10.1016/j.fct.2026.116270
  4. Oncogene. 2026 Jul 10.
    NME3 promotes clear cell renal cell carcinoma progression and modulates TKI response through MFN1/2-dependent mitochondrial fusion and mitophagy suppression.
    Senming Cao, Xinran Chen, Chi Zhang, Yi Feng, Changwei Shi, Jichen Wang, Qingjiang Xu, Xing Huang, Xin Ma, Wenmei Fan.
      Renal cell carcinoma (RCC), particularly the clear cell subtype (ccRCC), is a prevalent malignancy characterized by aggressive progression and heterogeneous therapeutic responses. Although mitochondrial dynamics are increasingly recognized as critical regulators of cancer metabolism and survival, the role of nucleoside diphosphate kinase 3 (NME3) in this process remains poorly understood. In this study, we integrated bioinformatic analyses of public datasets with validation in patient-derived tissues, in vitro functional assays, and in vivo xenograft models to elucidate the role of NME3 in ccRCC. We found that NME3 is significantly upregulated in ccRCC and correlates with poor survival, serving as an independent prognostic factor. Functionally, NME3 knockdown suppresses proliferation, migration, invasion, and xenograft tumor growth, while its overexpression promotes malignant phenotypes. Mechanistic investigations revealed that NME3 knockdown induces mitochondrial fragmentation, reduces ATP production, increases reactive oxygen species (ROS) levels, and activates PINK1/Parkin-mediated mitophagy; whereas NME3 overexpression enhances mitochondrial fusion and oxidative phosphorylation. Further analyses revealed that NME3 forms homomeric or heteromeric hexamers with NME2 and interacts with the mitochondrial fusion regulators MFN1 and MFN2 to facilitate mitochondrial fusion. Importantly, NME3 expression modulated the cellular response to tyrosine kinase inhibitors (TKIs), including sorafenib and sunitinib, with NME3 depletion enhancing drug sensitivity in vitro and in xenograft models. Collectively, these findings identify NME3 as a regulator of mitochondrial dynamics in ccRCC and highlight a potential link between mitochondrial remodeling and therapeutic response.
    DOI:  https://doi.org/10.1038/s41388-026-03892-9
  5. Protein Sci. 2026 Aug;35(8): e70703
    Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
    Lena J Reichert, F-Nora Vögtle, Carlotta Peselj.
      Mitochondria respond to proteotoxic stress through the mitochondrial unfolded protein response, traditionally viewed as a transcriptional program that restores proteostasis by inducing chaperones and proteases. Emerging evidence indicates that mitochondrial membrane remodeling constitutes an additional adaptive component of this response. Regulated changes in mitochondrial lipid composition, particularly involving the signature phospholipid cardiolipin, support mitochondrial function during stress by stabilizing protein import machineries, promoting mitochondrial protein biogenesis, and facilitating recovery from dysfunction. In addition, stress originating in other organelles, especially the endoplasmic reticulum, reshapes mitochondrial membranes through altered lipid biosynthesis, inter-organelle lipid trafficking, and stress signaling pathways. These findings suggest that mitochondrial membrane remodeling represents a regulatory layer of organelle quality control integrated within interconnected stress response networks and may provide new opportunities to enhance mitochondrial resilience in disease.
    Keywords:  ER–mitochondria crosstalk; cardiolipin; mitochondrial membrane remodeling; mitochondrial protein biogenesis; mitochondrial unfolded protein response (UPRmt); organelle stress signaling
    DOI:  https://doi.org/10.1002/pro.70703
  6. Fish Shellfish Immunol. 2026 Jul 06. pii: S1050-4648(26)00487-0. [Epub ahead of print]177 111583
    Common carp USP30s restrict SVCV replication by attenuating mitophagy.
    Chen Li, Songjie Qi, Mengxi Zhang, Yunli Zhang, Shu Zhou, Jiangxing Dong, Xianghui Kong.
      As a selective autophagic process, mitophagy is deeply involved in antiviral immunity by eliminating damaged mitochondria and requires the participation of various enzymes. Among these, the deubiquitinating enzyme USP30 is known to regulate mitophagy in mammals, yet its function in teleost antiviral defense remains entirely unexplored. In this study, we identified two USP30 homologs from the common carp (Cyprinus carpio), CcUSP30-A and CcUSP30-B, both containing a conserved USP domain and the atypical catalytic triad (Cys73, His445, Ser470). In vitro, spring viremia of carp virus (SVCV) infection induced PINK1-Parkin-dependent mitophagy that was subsequently exploited to promote viral replication. Overexpression of CcUSP30-A and CcUSP30-B significantly upregulated mitochondrial protein levels, reduced SVCV-induced mitophagy, and restricted SVCV replication. Notably, CcUSP30-B displayed stronger anti-mitophagy and anti-SVCV activities than CcUSP30-A. These findings demonstrate that CcUSP30s antagonize the PINK1-Parkin pathway, thereby counteracting excessive SVCV-induced mitophagy and ultimately limiting viral replication. This study provides the first evidence that USP30 acts as an antiviral regulator by preserving mitochondrial integrity in teleosts, and it may serve as a promising target for a novel strategy to control SVCV infection in aquaculture.
    Keywords:  Antiviral; Cyprinus carpio; Mitophagy; SVCV; USP30
    DOI:  https://doi.org/10.1016/j.fsi.2026.111583
  7. Sci Adv. 2026 Jul 10. 12(28): eaef6631
    ER-mitochondria tether ML1 coordinates peripheral fission and wholesale mitophagy for plant adaptation to carbon starvation.
    Benhui Shi, Baolei Li, Songyang Wang, Xu Zhang, Yu Tang, Jun Jiang, Liting Zhai, Yang Shao, Jiaqi Sun.
      Plants frequently encounter carbon starvation from extended darkness or canopy shading or in nonphotosynthetic tissues, requiring rapid mitochondrial remodeling to match reduced metabolic flux. Here, we reveal a coordinated program integrating peripheral fission-mediated damage segregation and wholesale mitophagy. Carbon starvation triggers a shift from symmetric midzone fission to asymmetric peripheral fission, generating small depolarized fragments alongside larger polarized mitochondria. Unexpectedly, damage-independent wholesale mitophagy targets medium-sized mitochondria for both burden reduction and resource mobilization while excluding small peripheral fission products. We identify mitochondria-ER (endoplasmic reticulum) linker 1 (ML1), a carbon starvation-inducible ER-mitochondria tether, as the central coordinator. At ER-mitochondria contact sites, ML1 promotes peripheral fission and recruits ATG18a (autophagy-related protein 18a) for wholesale mitophagy. Loss of ML1 impairs this coordinated remodeling, resulting in elongated mitochondria, compromised function, and hypersensitivity to carbon starvation. These findings reveal how plants achieve rapid metabolic adaptation through coordinated mitochondrial remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef6631
  8. Front Aging Neurosci. 2026 ;18 1865383
    Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
    Lingzhe Wang, Bin Xu.
      Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of nigral dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited. Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network. This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.
    Keywords:  PINK1; Parkin; Parkinson’s disease; functional uncoupling; lysosomal dysfunction; mitochondrial quality control; mitophagy; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2026.1865383
  9. MedComm (2020). 2026 Jul;7(7): e70863
    Acylglycerol Kinase Inhibition Restores Mitophagy and Alleviates Alzheimer's Disease Pathology.
    Wensheng Li, Xuan Yu, Cuiping Guo, Yuting Huang, Zhen Wei, Yi Liu, Jian-Zhi Wang, Rong Liu, Weike Ji, Qiuhong Duan, Jing Wang, Guihua Wang, Xiaochuan Wang.
      Mitophagy is a conserved cellular process that removes dysfunctional or excess mitochondria. Increasing evidence suggests that impaired mitophagy plays a crucial role in AD development. Promoting mitophagy has been shown to be protective in models of AD, representing an important target of Alzheimer's disease (AD). However, the molecular mechanisms underlying impaired mitophagy in AD are still elusive. Here, we provide evidence that highly expressed acylglycerol kinase (AGK), a mitochondrial lipid kinase associated with mitochondrial protein transport, glycolysis, and platelet formation, is a key mediator of mitophagy in AD. We found that AGK promoted the binding of ATPase family AAA domain containing 3A to translocase of the inner mitochondrial membrane 23 and sequentially increased mitochondrial import of PTEN-induced putative kinase 1, leading to the decrease of mitophagy. Further investigations revealed that the AGK downregulation in neuronal cells and APP/PS1 mice enhanced mitophagy, increased mitochondrial membrane potential, decreased pathological Tau/Aβ and neuroinflammation, and alleviated cognitive dysfunctions in the mice. Altogether our findings indicate that AGK plays a critical role in mediating mitophagy defects in AD; furthermore, downregulation of AGK promotes mitophagy and the decrease of Aβ and pathological Tau, providing an encouraging therapeutic treatment for AD.
    Keywords:  ATPase family AAA domain containing 3A; Alzheimer's disease; acylglycerol kinase; mitophagy; translocase of the inner mitochondrial membrane 23
    DOI:  https://doi.org/10.1002/mco2.70863
  10. Free Radic Biol Med. 2026 Jul 07. pii: S0891-5849(26)00931-7. [Epub ahead of print]
    Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.
    Xiangna Guo, Huiyi Jiang, Yitian Lu, Yixin Lin, Junwei Liu, Zaisheng Qin, Tao Tao.
      Increasing evidence highlights the protective role of mitophagy in eliminating damaged mitochondria during ischemic stroke. As a mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1) mediates the elimination of damaged mitochondria through mitophagy. However, whether VDAC1 contributes to cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms remain unexplored. In this study, we demonstrated that inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological function following cerebral I/R. We further confirmed that inhibiting VDAC1 oligomerization promoted mitophagy, thereby exerting neuroprotective effects. Additionally, VDAC1 knockdown restored mitochondrial membrane potential and decreased mitochondrial reactive oxygen species generation, thereby alleviating mitochondria damage in neurons subjected to oxygen-glucose deprivation /reoxygenation (OGD/R). Mechanistically, we identified the interaction between VDAC1 oligomers and Lon protease 1 (LONP1) as a critical regulator of mitophagy during cerebral I/R injury. Taken together, our findings provide novel insights into the regulation of mitophagy in cerebral I/R injury and suggest that VDAC1 represents a promising therapeutic target for ischemic stroke.
    Keywords:  Cerebral ishemia-reperfusion injury; FUNDC1; LONP1; VDAC1; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.010
  11. Front Pharmacol. 2026 ;17 1818572
    Mitochondrial-targeted actions of lycopene: evidence, mechanisms and future directions.
    Marcos Roberto de Oliveira.
      Lycopene (LYC; C40H56), a dietary carotenoid, has emerged as a promising modulator of mitochondrial physiology across multiple cell types and animal models. Here we critically synthesize experimental evidence that LYC attenuates mitochondrial oxidative stress, preserves oxidative phosphorylation complex function and ATP production, reduces mitochondrial permeability transition and cytochrome-c-dependent apoptosis, and regulates mitochondrial quality-control pathways including mitophagy and (less consistently) biogenesis. Mechanistic readouts indicate activation of antioxidant axes (Nrf2/HO-1), modulation of SIRT1/SIRT3 and PGC-1 signaling, and downstream effects on Bcl-2 family proteins and caspase activation; targeted delivery systems (mitochondria-directed nanodots) further enhance mitochondrial targeting and functional rescue in neurodegeneration models. However, the literature shows substantial heterogeneity in experimental designs (dose, route, timing), mostly relies on injury/toxin paradigms, and frequently reports molecular changes without causal perturbation (genetic or pharmacologic) to establish mechanism. Importantly, data on mitochondrial dynamics (fusion/fission) remain sparse and mechanistic links between mitophagy, biogenesis and improved bioenergetics are often associative rather than causal. The objective of this review is to evaluate available evidence on how LYC modulates mitochondrial function, redox biology, biogenesis, dynamics, and autophagy (mitophagy), as well as mitochondria-dependent apoptosis, in animal and human cells, identify critical gaps, and propose experimental priorities to move the field toward translational studies. This work is concluded with concrete recommendations for mechanistic and translational research to validate LYC as a mitochondria-targeting agent.
    Keywords:  LYCOPENE; apoptosis; mitochondria; mitochondrial biogenesis; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1818572
  12. Autophagy. 2026 Jul 09.
    NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.
    Maria J Lagartos-Donate, Beatriz Escobar-Doncel, Caroline Shi-Qi Zhang, Evandro Fei Fang.
      Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD+ -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological and cognitive decline in experimental AD models. Our study highlights REST as a promising target to preserve mitochondrial and neuronal function.Abbreviations:Alzheimer's disease, AD; Repressor Element 1-Silencing Transcription factor, REST; Nicotinamide Adenine Dinucleotide, NAD+.
    Keywords:  Alzheimer’s disease; NAD+; REST; SIRT1; transcriptional regulation
    DOI:  https://doi.org/10.1080/15548627.2026.2701599
  13. J Pharm Anal. 2026 Jun;16(6): 101432
    Menaquinone-7 alleviates mitochondrial dysfunction and senescence in senile osteoporosis by targeting the PINK1-mediated mitophagy via PXR/ERK/CREB signaling pathway.
    Yu Xu, Wencan Zhang, Wenpeng Xu, Shangzhi Li, Dingxin Zhang, Xiangyu Lin, Jincheng Liu, Qingyang Fu, Peijie Hu, Haipeng Si.
      Current therapeutic strategies for senile osteoporosis inadequately address its low-turnover pathology driven by mitochondrial dysfunction and cellular senescence. This study identifies menaquinone-7 (MK-7), a vitamin K2 isoform, as a novel therapeutic agent targeting mitochondrial homeostasis in senile osteoporosis. Through RNA sequencing analysis and intramedullary adeno-associated virus (AAV)-based gene manipulation in aged mice, cellular communication network factor 2 (Ccn2) was identified as a critical mediator of MK-7's bone-protective effects. Biochemical and proteomic assays revealed that MK-7 binds to the nuclear receptor pregnane X receptor (PXR), activating the extracellular signal-regulated kinases 1/2 (ERK1/2)/cyclic AMP-responsive element-binding protein (CREB) signaling cascade to upregulate Ccn2 in senescent bone marrow mesenchymal stem cells (BMSCs). This pathway enhanced PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy, reducing mitochondrial DNA damage, reactive oxygen species (mtROS), and senescence-associated secretory phenotype (SASP), while restoring metabolic function. MK-7 redirected BMSC differentiation from adipogenic to osteogenic lineages, effectively mitigating age-related bone loss in vivo. Mechanistically, MK-7 stabilized PXR via direct interaction at the F285 residue, as confirmed by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and molecular docking. PXR activation further promoted ERK1/2/CREB-dependent Ccn2 expression, which orchestrated mitochondrial quality control and cellular energy metabolism. Our findings establish MK-7 as a dual-function agent that concurrently alleviates senescence and metabolic imbalance in bone tissue, offering a safe and targeted strategy for senile osteoporosis. This study provides critical insights into the pharmacological modulation of mitochondrial pathways and highlights MK-7's translational potential in geriatric bone health.
    Keywords:  Cellular senescence; Menaquinone-7 (MK-7); Mitochondrial homeostasis; Mitophagy; PXR/ERK/CREB signaling; Senile osteoporosis
    DOI:  https://doi.org/10.1016/j.jpha.2025.101432
  14. Chin J Integr Med. 2026 Jul 04.
    Loganin Alleviates CCl4-Induced Acute Liver Injury by Promoting Mitophagy and Inhibiting NLRP3 Inflammasome.
    Meng Jiang, Xiao-Jia Yang, Li-Quan Liu, Yi-Li Zhang, Ping Huang, Min Wu, Yuan Deng.
       OBJECTIVE: To explore the protective effect and mechanism of loganin, a iridoid glycoside isolated from Corni Fructus, on carbon tetrachloride (CCl4)-induced acute liver injury (ALI) mice model and L-02 cells.
    METHODS: ALI mice model was developed by an intraperitioneal injection of 0.3% CCl4. Thirty 8-week-old male C57BL/6 mice were randomly divided into 5 groups using a random number table, including control, model, loganin (40 and 80 mg/kg), and silybin (100 mg/kg) groups (n=6). After 6 consecutive days of intragastric administration, serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured using an automatic biochemical analyzer. Hepatic pathological changes were observed by hematoxylineosin (HE) staining. Levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) in liver tissue were detected by enzyme-linked immunosorbent assay (ELISA). Superoxide dismutase (SOD) activity and malondialdehyde (MDA) contents were measured using biochemical kits. Mitochondrial ultrastructure and autophagosome formation were observed by transmission electron microscopy (TEM). Co-localization of mitophagy markers LC3 and TOMM20 were assessed by immunofluorescence (IF). Protein expressions of NOD-like receptor protein 3 (NLRP)3, LC3 II/LC3 I, p62, Beclin-1, Atg-7, Parkin, and PINK1 were determined by Western blot. In vitro, an injury model was established in L-02 hepatocytes stimulated with CCl4. Cell viability was assessed by CCK-8 assay, and related mechanisms were evaluated using the aforementioned methods. Besides, CCl4-stimulated L-02 cells were intervened with NLRP3 shRNA or Mdivi-1.
    RESULTS: Compared with the model group, pre-treatment with loganin (40 and 80 mg/kg) significantly reduced serum AST and ALT levels (P<0.01), alleviated pathological injuries such as swelling, necrosis, inflammatory infiltration, and lipid vacuolation in liver tissue. Loganin also markedly decreased the levels of IL-6 and TNF-α, increased SOD activity, and reduced MDA content in liver tissues (P<0.05 or P<0.01). Mechanistically, loganin up-regulated the ratios of LC3 II/LC3 I and expressions of Beclin-1, Atg-7, Parkin, and PINK1, while down-regulated p62 and NLRP3 protein expressions (P<0.05). In vitro experiments further confirmed that loganin attenuated CCl4-induced injury in L-02 cells by enhancing mitophagy and inhibiting NLRP3 inflammasome activation, which was reversed by the mitophagy inhibitor Mdivi-1.
    CONCLUSION: Loganin protected against CCl4-induced ALI both in vivo and in vitro by suppressing the NLRP3 inflammasome and enhancing mitophagy.
    Keywords:  NOD-like receptor family pyrin domain containing 3; acute liver injury; loganin; mitophagy
    DOI:  https://doi.org/10.1007/s11655-026-3851-3
  15. J Appl Toxicol. 2026 Jul 08.
    Piperonyl Butoxide Impairs Porcine Oocyte In Vitro Maturation by Suppressing the p38 MAPK Signaling Pathway and Dysregulating Mitophagy.
    Biao Zhang, Genkui Zhang, Heye Liang, Yijing He, Qinfeng Sun, Miaoyu Chen, Qiao Li, Shiqiang Ju, Weihan Wang.
      Piperonyl butoxide (PBO) is one of the most widely used insecticide synergists in agricultural and veterinary applications worldwide. There is increasing concern regarding the potential reproductive risks to livestock from its environmental persistence, while its reproductive toxicity in livestock species remains largely unknown. A porcine oocyte in vitro maturation (IVM) model was employed to explore how PBO exposure affects oocyte maturation and its underlying cellular mechanisms. SMART-seq-based single-cell transcriptomics was used to elucidate the molecular pathways involved. PBO exposure significantly inhibited cumulus expansion, reduced first polar body (PB1) extrusion, and caused meiotic arrest. It also disrupted gene expression associated with mitochondrial dynamics and oxidative stress, leading to pronounced mitochondrial dysfunction. Transcriptomic analysis showed significant enrichment of differentially expressed genes in autophagy, mitophagy, and MAPK signaling pathways. PBO exposure increased LC3-mitochondria colocalization and upregulated key mitophagy-related proteins, indicating excessive mitophagy. Activation of p38 MAPK by anisomycin partially rescued PBO-induced mitophagy abnormalities in porcine oocytes. These findings indicate that PBO impairs porcine oocyte maturation by suppressing the p38 MAPK signaling pathway, thereby triggering excessive mitophagy.
    Keywords:  mitophagy; oxidative stress; p38 MAPK; piperonyl butoxide; porcine oocyte
    DOI:  https://doi.org/10.1002/jat.70336
  16. Mol Cell Biochem. 2026 Jul 09.
    TRIM65 accelerates VSMC-derived foam cell formation and arteriosclerosis progression by inhibiting mitophagy.
    Liyuan Guo, Wei Deng, Zhixiang Zhou, Qian Xu, Kun Zhou, Yuexin Zhang, Yiyuan Bin, Huiting Liu, Zhong Ren, Yisong Qian, He Zheng, Zhisheng Jiang.
      Atherosclerosis (AS) is a chronic inflammatory vascular disorder driven by dyslipidemia and characterized by foam cell formation originating from vascular smooth muscle cells (VSMCs). Mitophagy is a critical pathway for the selective clearance of dysfunctional mitochondria and also contributes to macrophage foaming. Tripartite motif-containing protein 65 (TRIM65), a key protein within the TRIM family, plays a significant role in immune and inflammatory responses and is integral to the pathogenesis of AS. In vivo and in vitro models of as were established using ApoE-/- mice fed a high-fat diet and mouse aortic vascular smooth muscle (MOVAS) cells treated with oxidized low-density lipoprotein (ox-LDL), respectively. Results indicated a significant increase in TRIM65 expression in atherosclerotic models. The generation of TRIM65-/-ApoE-/- mice demonstrated that TRIM65 knockdown reduced atherosclerotic plaque burden and lipid accumulation. In vitro experiments revealed that TRIM65 knockdown inhibited the formation of VSMC-derived foam cells while promoting mitochondrial autophagy. Mechanistic investigations showed that TRIM65 facilitates the degradation of key mitochondrial autophagy proteins (e.g., PINK1, Parkin), thereby inhibiting mitochondrial autophagy. This inhibition leads to the accumulation of dysfunctional mitochondria, resulting in excessive ROS generation and exacerbating oxidative stress. By inhibiting mitochondrial autophagy, TRIM65 accelerates the formation of VSMC-derived foam cells, thereby promoting the onset and progression of as. This discovery not only deepens our understanding of the molecular mechanisms of as but also provides theoretical support for positioning TRIM65 as a potential novel therapeutic target for the prevention and treatment of this disease.
    Keywords:  Atherosclerosis; Autophagy; Foam cell; Mitophagy; TRIM65; VSMC
    DOI:  https://doi.org/10.1007/s11010-026-05619-6
  17. Basic Clin Neurosci. 2025 May;16(3): 641-656
    Vitis Vinifera L. Flavones Preserve Mitophagy in the Amyloid-beta 1-42-induced Model of Alzheimer's Disease Neurodegeneration.
    Peng Zhang, Hui Xiao.
       Introduction: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation, leading to inflammation, oxidative stress, and impaired synaptic function. This study aimed to investigate the neuroprotective mechanisms of Vitis vinifera L. flavones (VTF) against Aβ-induced neurodegeneration and their potential as AD therapeutics.
    Methods: In an in vitro analysis, Aβ1-42 oligomers were used to induce mitophagy in SHSY5Y neuroblastoma cells. Cells were treated with VTF alone and in combination with chloroquine (CQ), a lysosomal inhibitor, to assess Aβ1-42-induced mitophagy. Transmission electron microscopy (TEM) and immunofluorescence (IFC) were used to investigate the effects of Aβ1-42 on autophagosomes and deposition. Cellular protection against Aβ-induced damage was assessed using the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to determine the expression of autophagy-lysosomal pathway proteins (Beclin-1, Atg7, p62, and BACE1) and the LC3-II/LC3-I ratio, which serves as a marker of autophagy.
    Results: CQ and VTF demonstrated significant neuroprotection against Aβ1-42-induced neurodegeneration (P<0.05). VTF, alone or with CQ, increased viable cell count (~1.2-fold; P<0.05), indicating reparative capabilities. TEM and IFC showed robust protection by VTF and CQ against Aβ protein deposition, as well as preservation of mitochondrial and autophagosomal structures. VTF and CQ treatments reduced Beclin-1, Atg7, and BACE1 levels, indicating the modulation of mitophagy and autophagy-lysosomal suppression. VTF+CQ maintained LC3-II/LC3-I balance, confirming VTF's role in preserving autophagy (P<0.01).
    Conclusion: This study reveals the novel neuroprotective role of VTF, emphasizing its potential as an AD therapeutic. Future research should extend investigations to in vivo models and clinical settings to enhance our understanding of VTF's neuroprotective efficacy.
    Keywords:  Alzheimer’s disease; Amyloid-beta (Aβ)1-42-Aβ1-42-induced neurodegeneration; Chloroquine (CQ); Mitophagy; Neuroprotective efficacy; Vitis vinifera L. flavones (VTF)
    DOI:  https://doi.org/10.32598/bcn.2025.6592.1
  18. Cell Death Dis. 2026 Jul 08.
    HPC restores mitochondrial homeostasis and ameliorates hypoxic stress through the GSK-3β/β-catenin signaling pathway.
    Wenxin Li, Qian Qu, Xingling Liu, Caixu Guo, Guo Shao, Baohui Ma, Jun Lv, Xiaoqiong Hao, Ruifang Qi.
      Hypoxic preconditioning (HPC) can increase the hypoxia tolerance of the mouse hippocampus both in vivo and in vitro by upregulating ATP levels, which may depend on mitochondrial homeostasis. The GSK-3β/β-catenin signaling pathway is involved in neuroprotection after brain ischemia. The aim of this study was to explore whether HPC can activate GSK-3β/β-catenin to improve the hypoxia tolerance of neuronal cells by enhancing mitochondrial homeostasis. In vitro and in vivo analyses revealed that HPC upregulates the activity of the GSK-3β/β-catenin pathway, maintaining mitochondrial morphological stability. Mechanistically, GSK-3β activity is negatively correlated with mitochondrial homeostasis. Pharmacological inhibition of GSK-3β reduced mitochondrial fission, whereas HPC suppressed GSK-3β expression to attenuate fission and preserve mitochondrial integrity. Conversely, GSK-3β overexpression abrogated HPC-mediated protection and exacerbated mitochondrial dysfunction. These findings elucidate a neuroprotective mechanism whereby HPC stabilizes mitochondrial dynamics via modulation of the GSK-3β/β-catenin pathway, providing novel experimental insights into HPC-mediated neuroprotection.
    DOI:  https://doi.org/10.1038/s41419-026-09080-7
  19. Hum Gene Ther. 2026 Jul 09. 10430342261466685
    AAV.hBAG3 Gene Therapy Improves Phenotype in a Valosin Containing Protein Mouse Model of Hereditary Inclusion Body Myositis.
    Burcak Ozes, Lingying Tong, Morgan Myers, Kyle Moss, Edward Son, Tatyana A Vetter, Gabriela Vasquez-Martinez, Diana Zepeda-Orozco, Zarife Sahenk.
      Mutations in the valosin-containing protein (VCP) gene lead to a hereditary type of inclusion body myositis (hIBM), in which sarcoplasmic and myonuclear inclusions with TAR DNA-binding protein 43 (TDP-43) pathology and mitochondrial abnormalities are observed in histological analysis. Pathophysiological conditions in the cell cause the protein quality control system to depend on the autophagy-lysosome pathway (ALP) for degradation of accumulated misfolded proteins and mitochondrial turnover. BCL2-associated athanogene 3 (BAG3) protein has a role in initiating the ALP. Our aim was to ameliorate disease processes resulting from mitochondrial abnormalities and misfolded protein aggregation by upregulating the ALP through overexpression of human BAG3 (hBAG3). The VCP-A232E mouse, a model for hIBM, received AAVrh74.tMCK.hBAG3 systemically at 3 months of age, and outcome measures, including functional, histological, and molecular studies, were assessed 9 months post-gene delivery. hBAG3 treatment improved treadmill running distance and rotarod duration, reduced the number of TDP-43-positive aggregates, and decreased the number of fibers showing abnormalities in mitochondrial enzyme histochemistry, compared with the untreated cohort. Moreover, hBAG3 gene therapy resulted in improvements in mitophagy and mitochondrial homeostasis observed as increased levels in mitophagy markers Parkin and Bnip3, mitochondria biogenesis marker Pgc1α and mitochondrial DNA-encoded subunits of complex IV, Cox1 and Cox3. In addition, the LC-II/I ratio increased, indicating increased autophagic flux. Our study presents evidence that the strategy of supporting the ALP system by overexpressing BAG3 has potential therapeutic use for myodegenerative conditions associated with abnormal protein aggregates and mitochondrial turnover.
    Keywords:  BAG3; IBM; VCP; autophagy; mitophagy
    DOI:  https://doi.org/10.1177/10430342261466685
  20. J Cardiol. 2026 Jul 06. pii: S0914-5087(26)00137-1. [Epub ahead of print]
    Mitophagy in Cardiovascular Disease: From Mechanistic Insights to Therapeutic Horizons.
    Deyi Guo, Kun Wang, Jingwen Zhang, Hongliang Li, Yufeng Hu.
      Cardiovascular diseases (CVDs) remain a leading cause of death worldwide, with a complex and multifactorial pathophysiology. Given its high energy demands, the heart is critically dependent on mitochondrial energy production and metabolic homeostasis. Mitophagy, a selective form of autophagy, represents a crucial intracellular mechanism for preserving cardiac cellular function. This review summarizes the roles of mitophagy in various cardiovascular pathologies, including cardiac aging, myocardial hypertrophy, heart failure, myocardial infarction, ischemia-reperfusion injury. Evidence indicates that mitophagy is mediated through both Parkin-dependent and -independent pathways. Moreover, several natural compounds and small-molecule agents have demonstrated potential in attenuating myocardial injury and improving cardiac function by modulating mitophagy-related signaling. Despite significant advances in understanding mitophagy's role in CVDs, the precise molecular mechanisms and regulatory networks across different pathological contexts require further elucidation. Future research should focus on deciphering the complex regulatory landscape of mitophagy, developing targeted therapies, and advancing their clinical translation and safety evaluation.
    Keywords:  Cardiovascular diseases; Mitophagy; Molecular mechanisms; Myocardial protection; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.jjcc.2026.07.004
  21. Cell Death Dis. 2026 Jul 10.
    PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
    José Manuel Rodríguez-Vargas, Jerónimo Borrego-Pérez, Vanesa Cabeza-Fernández, Esteban Zamudio-Martínez, Francisco Javier Ríos-Sola, David Martín-Oliva, Francisco Abadía-Molina, Françoise Dantzer, F Javier Oliver.
      Hypoxia, or low oxygen availability, is one of the main factors that determine tumor growth and metastatic survival. The hypoxic response is orchestrated by HIF transcription factors, which activate genetic and metabolic programs that promote angiogenesis, metabolic reprogramming, migration, and ultimately a clinically aggressive phenotype. Mitochondria play a central role in this process, as they are not only the main consumers of oxygen but also undergo morphological and biochemical adaptations that shape how tumor cells respond to a hostile microenvironment. Because the contribution of ADP ribosylation to these mitochondrial adaptations remains unclear, we aimed to define how PARP inhibition influences mitochondrial behavior during hypoxia. To address this question, we first examined how PARP inhibitors affect mitochondrial structure and function under oxygen deprivation. We found that PARP inhibition drives a shift toward a small, globular mitochondrial phenotype characterized by membrane depolarization (ΔΨm) and enhanced fission. Given that mitochondrial morphology is tightly linked to metabolic state, we next investigated whether these structural changes altered hypoxia induced metabolic reprogramming. PARP inhibition prevented the typical shift toward anaerobic glycolysis, forcing tumor cells to activate the AMPk/mitophagy axis as an alternative survival pathway. Finally, to determine the functional consequences of this adaptive response, we assessed tumor cell fitness when mitophagy was impaired. Blocking mitophagy markedly reduced the proliferative and malignant potential of hypoxic tumor cells, thereby increasing their sensitivity to PARP inhibition. Collectively, our results uncover a previously unrecognized pathway of mitochondrial adaptation to hypoxia and reveal a therapeutically relevant crosstalk between mitochondrial dynamics and ADP ribosylation that may be exploited in future anticancer strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09079-0
  22. Eur J Pharmacol. 2026 Jul 09. pii: S0014-2999(26)00615-1. [Epub ahead of print] 179133
    Bazedoxifene attenuates lipopolysaccharide-induced acute lung injury by inhibiting NLRP3 inflammasome activation of macrophages in mice.
    Hai-Yan Xiao, Ming-Hao Jiang, Wen-Jing Zhong, Jia-Xi Duan, Nan-Shi-Yu Yang, Hui Chen, Cha-Xiang Guan, Yong Zhou, Chen-Yu Zhang, Ren Guo, Dai Li.
      Acute Lung Injury (ALI) is a common clinical emergency. Currently, most available treatments are primarily supportive, highlighting the urgent need for effective therapeutic strategies. A key driver of ALI pathogenesis is the uncontrolled pulmonary inflammatory response. Bazedoxifene (BAZ), approved by the FDA since 2013 for postmenopausal osteoporosis, has demonstrated anti-inflammatory properties in chronic inflammatory diseases. However, the effects of BAZ on ALI remain unclear. The NLRP3 inflammasome, a critical pattern recognition receptor, contributes to ALI progression by sensing diverse damage signals and amplifying the inflammatory cascade. In this study, we found that BAZ pretreatment alleviated lipopolysaccharide (LPS) -induced lung inflammation in ALI mice and suppressed NLRP3 inflammasome activation in mouse macrophages. Given that dysregulation of mitochondrial dynamics is a known trigger for NLRP3 inflammasome activation under inflammatory stress, we further explored this relationship. Our results indicated that BAZ attenuated LPS-induced ALI by curbing excessive mitochondrial fission and promoting mitochondrial fusion in macrophages. In conclusion, our study reveals that BAZ confers protective effects against LPS-induced ALI by modulating mitochondrial dynamics to inhibit NLRP3 inflammasome activation, providing new perspectives for the development of ALI therapies.
    Keywords:  NLRP3 inflammasome; acute lung injury; bazedoxifene; macrophage; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179133
  23. Brain Behav. 2026 Jul;16(7): e71418
    Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
    Tianyi Gu, Hangyan Guo, Zixin Guo, Shengyu Hua.
       INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD.
    METHODS: A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis.
    RESULTS: The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (Aβ) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death.
    CONCLUSION: Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates Aβ/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.
    Keywords:  Alzheimer's disease; inflammation; mitochondrial dysfunction; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1002/brb3.71418
  24. Mol Med. 2026 Jul 10.
    Hydrogen alleviates sepsis-associated encephalopathy via ATG9B-dependent mitophagy.
    Xiaoli Yu, Xiaofan Huang, Yu Song, Jianfeng Liu, Fei Huang, Jiatian Cui, Keliang Xie, Yan Cui.
       BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe complication with high mortality and limited therapeutic options. Molecular hydrogen (H₂) has shown neuroprotective potential, but its mechanism remains elusive.
    METHODS: SAE was induced in C57BL/6J mice by cecal ligation and puncture, with or without 2% H2 inhalation. HT22 hippocampal neurons were challenged with lipopolysaccharide in hydrogen-rich medium. H₂ intervention was administered via inhalation or hydrogen-rich medium. Cognitive function was evaluated by novel object recognition and Y-maze tests. Transcriptome sequencing was used to identify key signaling pathways regulated by H₂. The neuroprotective mechanism of H₂ was explored by assessing mitophagy, apoptosis, reactive oxygen species, and mitochondrial membrane potential. ATG9B was knocked down using siRNA in vitro and AAV-shRNA in the hippocampal CA1 region in vivo to clarify its function.
    RESULTS: H₂ inhalation increased 7-day survival in CLP-induced septic mice from 40% to 75%, reduced systemic and hippocampal pro-inflammatory cytokines, and alleviated hippocampal neuronal damage and cognitive dysfunction. Transcriptomic profiling identified ATG9B as the most significantly upregulated mitophagy-related gene by H2. Mechanistically, H₂ upregulated ATG9B expression, which in turn enhanced PINK1-Parkin-mediated mitophagy flux, thereby coordinating mitophagosome formation and lysosomal fusion, leading to clearance of damaged mitochondria and reduced neuronal apoptosis. ATG9B knockdown completely abolished H₂-induced mitophagy flux, mitochondrial protection, and cognitive improvement.
    CONCLUSIONS: H₂ alleviates SAE by upregulating ATG9B and restoring PINK1-Parkin-dependent mitophagy. The ATG9B-mitophagy axis represents a novel therapeutic target, and H₂ inhalation emerges as a potential strategy for sepsis-associated cognitive impairment.
    Keywords:  ATG9B; Cognitive dysfunction; Hydrogen; Mitophagy; Sepsis-associated encephalopathy
    DOI:  https://doi.org/10.1186/s10020-026-01566-6
  25. Adv Sci (Weinh). 2026 Jul 08. e76447
    Inhalable ROS-Responsive Nanospray Activates PPAR-γ to Restore Macrophage Mitochondrial Homeostasis and Attenuate Radiation-Induced Lung Injury.
    Mingquan Gao, Xudong Yu, Ziqian Shang, Mengyao Tan, Xie Huang, Zaizhi Du, Xiaojiao Wang, Xinrui Yang, Ximei Luo, Weidong Wang, Rong Li, Shenglin Luo.
      Radiation-induced lung injury (RILI) is a major complication of nuclear radiation exposure and thoracic radiotherapy, driven in part by a vicious cycle of oxidative stress and mitochondrial dysfunction. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a key regulator of mitochondrial homeostasis and inflammatory resolution, therefore represents a potential therapeutic target, yet multi-omics analyses revealed that this immunometabolic checkpoint remains functionally constrained in irradiated macrophages. To reactivate this pathway, we developed an inhalable, ROS-responsive nanospray (HANP) by loading nicotinamide adenine dinucleotide (NAD+) and astaxanthin (ASX) into a hollow mesoporous polydopamine (HMPDA) shell. Excess ROS in microenvironment triggers oxidative degradation of the HMPDA shell, enabling intracellular release of NAD+ and ASX. Mechanistically, NAD+ promotes SIRT1-mediated deacetylation of PPAR-γ, whereas ASX serves as an activating ligand, thereby cooperatively restoring PPAR-γ signaling. This response re-establishes macrophage mitochondrial homeostasis by coordinating mitochondrial biogenesis and mitophagy, which subsequently promotes a shift toward a reparative macrophage phenotype. In murine models of focal thoracic irradiation and lethal whole-body irradiation, HANP markedly attenuated lung injury and improved survival. Collectively, these findings identify macrophage PPAR-γ as a therapeutically actionable redox-immunometabolic regulator and support inhaled dual-activation of this pathway as a promising strategy for protection against RILI in both clinical and emergency settings.
    Keywords:  NAD+; PPAR‐γ activation; astaxanthin; macrophage reprogramming; mitochondrial quality control; radiation‐induced lung injury
    DOI:  https://doi.org/10.1002/advs.76447
  26. Free Radic Biol Med. 2026 Jul 07. pii: S0891-5849(26)00928-7. [Epub ahead of print]
    Corrigendum to 'Myeloperoxidase (MPO) mediates LPS-induced mitophagy in murine macrophages through AMPK/ULK1 pathway' [Free Radic. Biol. Med. 251 (2026) 333-346].
    Wei Lin, Yan Zeng, Jia Li, Xinyu Zhang, Zhengyi Wang, Di Zhao, Xijing Chen, Yongjie Zhang, Chaorui Guo.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.007
  27. Mater Today Bio. 2026 Aug;39 103411
    Fuel-maintenance coupling reprograms mitochondrial homeostasis to enable peripheral nerve regeneration.
    Jun-Kuan Shan, Jia-Qi Fang, Xue-Han Jin, Bo Xu, Li-Ping Nan, Zhi-Jie Weng, Shu-Hao Liu, Xin-Hui Wu, Zhong Wu, Jun-Jian Liu.
      Peripheral nerve regeneration is frequently stalled by a "metabolic bottleneck" characterized by mitochondrial dysfunction and bioenergetic exhaustion. Although nerve guidance conduits (NGCs) provide structural support, most remain metabolically inactive and fail to address this energetic deficit. Here, we developed a fuel-maintenance coupling metabolic reprogramming strategy to support peripheral nerve repair. A biomimetic NGC was engineered with an aligned electrospun polycaprolactone (PCL) sheath filled with an injectable, in situ photocrosslinkable Magnolol-loaded chitosan-lipoic acid hydrogel (LA-CS@Mag). In this synergistic system, α-lipoic acid serves as the metabolic fuel to restore ATP production, while Mag functions as a mitochondrial quality controller to promote mitophagy-associated mitochondrial clearance. In vitro, LA-CS@Mag protected rat Schwann cells (RSCs) from oxidative stress, restored mitochondrial membrane potential, reduced ROS accumulation, and improved ATP production, accompanied by activation of BNIP3/Parkin-related mitophagy. Moreover, conditioned medium from LA-CS@Mag-treated RSCs reduced M1-like macrophage polarization and promoted an M2-like reparative phenotype, suggesting Schwann cell-mediated immunomodulatory effects. In vivo, implantation of the LA-CS@Mag/PCL conduit modulated macrophage polarization, suppressed excessive early inflammatory responses, and promoted a reparative immune microenvironment. In a rat sciatic nerve defect model, the bioactive conduit significantly accelerated axonal regeneration and remyelination, prevented target muscle atrophy, and achieved functional recovery comparable to autografts. Collectively, this study identifies mitochondrial homeostasis as a therapeutic target and provides a metabolically instructive strategy for next-generation nerve guidance conduits.
    Keywords:  Autophagy activation; Magnolol; Mitochondrial repair; Peripheral nerve regeneration; α-lipoic acid
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103411
  28. J Transl Med. 2026 Jul 07.
    LncRNA AP000654.1 attenuates cerebral ischemia-reperfusion injury by regulating mitophagy-mediated NLRP3 inflammasome activation.
    Chi Zhang, Yixiang Cui, Zhaojing Zhang, Manyue Zhang, Qiong Zhang, Yanyang Huang, Yatian Xu, Tianyi Han, Dongzhi Yang, Ying He.
       BACKGROUND: Ischemic stroke (IS) remains a leading cause of disability worldwide, and its therapeutic window is very narrow. Ischemia-reperfusion injury exacerbates secondary brain damage. Microglial NLRP3 inflammasome activation drives neuroinflammation, yet its upstream regulation requires further elucidation. We previously identified lncRNA AP000654.1 as significantly downregulated in the peripheral blood of stroke patients, prompting our investigation into its potential role in microglial biology.
    METHODS: Using an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model in HMC3 human microglial cells, we investigated the role of lncRNA AP000654.1-previously identified as significantly downregulated in peripheral blood of stroke patients-in regulating microglial inflammatory responses.
    RESULTS: OGD/R treatment upregulated NLRP3 inflammasome-related genes, induced pyroptosis-associated changes, and altered mitophagy markers. LncRNA AP000654 0.1 overexpression suppressed this excessive mitophagy by inhibiting the PINK1-Parkin pathway, thereby improving mitochondrial function. This suppression subsequently attenuated NLRP3 inflammasome assembly and pyroptosis. Crucially, enforcing mitophagy with rapamycin exacerbated the injury, which was effectively rescued by lncRNA AP000654.
    CONCLUSION: LncRNA AP000654.1 is associated with suppression of excessive mitophagy-assocated mitochondrial stress and NLRP3 inflammasome activation in microglia, suggesting its potential relevance as a therapeutic target in ischemic stroke.
    Keywords:  Ischemic stroke; Microglia; Mitophagy; NLRP3 inflammasome; Neuroinflammation; lncRNA AP000654.1
    DOI:  https://doi.org/10.1186/s12967-026-08541-z
  29. Placenta. 2026 Jun 30. pii: S0143-4004(26)00308-5. [Epub ahead of print]182 293-301
    Icariin ameliorates gestational diabetes mellitus by targeting the S100A9-mediated RAGE pathway to activate mitophagy.
    Jinzhi Yang, Huihui Sun, Yong Wan, Yali Wu.
       OBJECTIVE: Gestational diabetes mellitus (GDM) is a common metabolic complication during pregnancy, which can readily lead to adverse pregnancy outcomes. Studies have shown that icariin (ICA) possesses anti-inflammatory and anti-oxidative stress properties and can mitigate high glucose-induced cellular damage. This study aims to investigate the effects and underlying mechanisms of ICA on a GDM cell model.
    METHODS: An in vitro GDM model was established by exposing HTR-8/Svneo cells to high glucose (HG) medium. Cell viability was measured using the CCK-8 assay. Cytotoxicity was assessed with the lactate dehydrogenase (LDH) assay kit. Flow cytometry was employed to evaluate apoptosis, mitophagy flux, and intracellular mitochondrial reactive oxygen species (ROS) levels. Western blotting and JC-1 staining were used to assess mitophagy and mitochondrial membrane potential, respectively.
    RESULTS: ICA alleviated the inhibitory effect of HG on the proliferation of HTR-8/SVneo cells and reduced high glucose-induced intracellular LDH level and apoptosis. Furthermore, ICA promoted mitophagy flux, decreased mitochondrial ROS levels, and attenuated mitochondrial damage in HG-treated HTR-8/SVneo cells. Mechanistically, ICA protected HTR-8/SVneo cells from HG-induced injury by targeting the S100A9/RAGE pathway.
    CONCLUSIONS: ICA ameliorates high glucose-induced trophoblast injury by modulating the S100A9/RAGE pathway, offering a potential therapeutic strategy for the treatment of GDM.
    Keywords:  Gestational diabetes mellitus; Icariin; Mitophagy; RAGE; S100A9
    DOI:  https://doi.org/10.1016/j.placenta.2026.06.019
  30. Inflammation. 2026 Jul 07.
    Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.
    Zhiqiu Liu, Shuyang Zhang, Tianshu Zeng.
      Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver disorder globally, with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis. Mitochondrial dysfunction is central to MASLD progression, and mitophagy-a selective form of autophagy that clears damaged mitochondria-plays a crucial role in maintaining cellular homeostasis. This review systematically delineates the molecular mechanisms, regulatory networks, and therapeutic implications of mitophagy in MASLD. We first outline the core machinery of mitophagy, encompassing both ubiquitin-dependent and ubiquitin-independent pathways. We then discuss how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types. Furthermore, we summarize the multilayered upstream regulatory network governing mitophagy in the context of MASLD, involving key signaling pathways, metabolic reprogramming, inflammatory cues, epigenetic modifications, and intercellular crosstalk. Finally, we examine therapeutic strategies targeting mitophagy-including clinical and preclinical agents, natural compounds, physical interventions, and emerging technologies-and highlight the challenges posed by its dualistic nature. Moving forward, integrating spatiotemporal dynamics with precision targeting will be essential to translate mitophagy modulation from mechanistic insight into viable clinical therapies for MASLD.
    Keywords:  MASH mitophagy inflammation intercellular crosstalk regulatory network therapeutic targets; MASLD
    DOI:  https://doi.org/10.1007/s10753-026-02548-w
  31. Stem Cell Rev Rep. 2026 Jul 09.
    Cell-Type-Specific Calibration of Mitochondrial Ubiquitination in Stem Cell Fate Decisions.
    Hao-Cheng Liu, Si-Yuan Chen, Nan-Nan Yu, Mei-Hua Jin, Hu-Nan Sun, Ying-Hao Han.
      Stem cell fate decisions-whether to self-renew, differentiate, or senesce-are inextricably linked to the metabolic identity and quality-control status of mitochondria. The ubiquitin-proteasome system and selective autophagy pathways assemble into an integrated surveillance network at the mitochondrial outer membrane that gauges organelle health, sculpts morphology, and transduces metabolic information into lineage-determining transcriptional programmes. This Review examines how the ubiquitination machinery-spanning the canonical PINK1-Parkin axis and non-Parkin E3 ligases including MARCH5, MUL1, and the emerging Cullin-RING component RBX2-orchestrates outer-membrane protein degradation, mitochondria-derived vesicle biogenesis, and the balance between fusion and fission. We discuss how these post-translational events govern stem cell identity across haematopoietic, muscle, neural, mesenchymal, and pluripotent compartments. Recent 2024-2025 advances include an Nicotinamide Adenine Dinucleotide (NAD+)-dependent metabolic checkpoint governing haematopoietic stem cell activation and aging, the crystallographic resolution of USP30 inhibitor binding, molecular glue activators that allosterically enhance Parkin RING-domain activity, ClpP-based mitochondria-targeted PROTAC platforms, and HIF-1α/BNIP3-mediated pharmacological rejuvenation of aged mesenchymal stem cells. We further discuss the WAC-PINK1-Parkin axis in mesenchymal stem cell aging, the bidirectional interplay between reactive oxygen species and E3 ligase activity, and the ACC1-FIS1 ubiquitination axis. Finally, we consider the cell-type-specific calibration of mitochondrial ubiquitination as a unifying principle for precision therapeutics and the inverted quality-control logic exploited by cancer stem cells. We propose that the cell-type-specific calibration of mitochondrial ubiquitination-whereby identical molecular events carry divergent functional consequences across stem cell compartments-offers a unifying framework for precision therapeutics.
    Keywords:  Mitochondrial dynamics; Mitochondrial ubiquitination; Mitophagy; PINK1-Parkin; Stem cell fate
    DOI:  https://doi.org/10.1007/s12015-026-11189-3
  32. Phytomedicine. 2026 Jun 28. pii: S0944-7113(26)00736-1. [Epub ahead of print]159 158505
    Crocetin from saffron ameliorates motor symptoms in Parkinson's disease models by improving mitochondrial function and PINK1/Parkin mediated mitophagy.
    Jingqi Li, Zhanchi Zhu, Zhaojun Wang, Jiawei Li, Zhaoming Song, Chen Wang, Yun Xie, Ying Hao, Chen Wang, Hongli Dong, Guosheng Cheng, Rui Tan.
       BACKGROUND: Parkinson's disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons and is closely associated with mitochondrial dysfunction. Given the limited therapeutic options available for disease intervention, there is growing interest in identifying natural compounds that can modulate core pathological processes such as mitochondrial dysfunction. Traditional Chinese Medicine (TCM) has been identified as a promising candidate for PD, offering reduced side effects and holistic regulatory effects. Crocetin (CRO) is a bioactive compound isolated from saffron, a TCM component with reported neuroprotective properties; however, whether it improves mitochondrial function and mitophagy in PD remains unknown.
    PURPOSE: This study aimed to investigate the therapeutic potential of CRO in PD and to explore its underlying mechanisms, focusing on mitochondrial function and PINK1/Parkin-mediated mitophagy.
    METHODS: MES23.5 cells were modeled in vitro using MPP⁺. CRO was rationally screened from eight candidates through CCK-8 assay, and its effects on alpha-synuclein expression, oxidative stress, mitochondrial membrane potential, ATP production, and PINK1/Parkin-mediated mitophagy were evaluated in vitro. A PD model was established in C57BL/6 mice in vivo using MPTP. Motor function, tyrosine hydroxylase expression, Nissl body numbers, and neuronal firing rates were assessed in PD mice model.
    RESULTS: A reduction in alpha-synuclein expression was observed following CRO treatment, accompanied by a decrease in intracellular ROS levels to approximately one-tenth of those in the model group. Mitochondrial membrane potential and ATP production were markedly restored, with ATP levels elevated 1.6-fold compared with those in the model group. In vivo, CRO may also improve motor function in PD mice, restore tyrosine hydroxylase expression in nigrostriatal regions to a normal level, and increase Nissl body numbers. Critically, CRO was proven to have the capacity to restore neuronal firing function and rescue neuronal electrophysiology.
    CONCLUSION: CRO has been shown to attenuate PD-related symptoms through the restoration of mitochondrial function and the activation of PINK1/Parkin-mediated mitophagy. These findings highlight CRO as a novel therapeutic option and deepen the understanding of PD-associated mitochondrial dysfunction.
    Keywords:  Crocetin; Mitochondrial dysfunction; Mitophagy; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.phymed.2026.158505
  33. J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):
    Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
    Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.
      Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.
    DOI:  https://doi.org/10.1083/jcb.202511211
  34. Am J Chin Med. 2026 Jul 10. 1-34
    Luteolin Triggers Pyroptosis in Pancreatic Ductal Adenocarcinoma by Inhibiting Mitochondrial Fission through the RAS/ERK/DRP1 Pathway.
    Wai-Mei Si, Xin Li, Yuan Zhang, Li-Xia Yi, Pei-Wen Yang, Lin-Jie Ruan, Xiang-Yu Kong, He Ba, Zhen Chen.
      Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and lacks effective therapies. Luteolin, a dietary flavonoid with broad antitumor activity, has shown anti-PDAC potential, yet whether it acts through RAS/ERK/DRP1-dependent mitochondrial fission and pyroptosis remains unclear. Human PDAC cells were treated with luteolin to evaluate its effects on malignant phenotypes, including proliferation, apoptosis, migration, and invasion. Mitochondrial function and morphology were assessed by measuring mitochondrial membrane potential, mitochondrial ROS production, and mitochondrial network remodeling. Pyroptosis was evaluated by measuring NLRP3 inflammasome activation, pyroptosis-related proteins, and cell injury-associated indicators. Mechanistically, MCC950, RAS overexpression, DRP1 overexpression, EGF stimulation, and Mdivi-1 treatment were used to determine the involvement of NLRP3 inflammasome activation and the RAS/ERK/DRP1-mediated mitochondrial fission pathway. A subcutaneous xenograft model was further established to validate the antitumor effect of luteolin in vivo. Luteolin significantly inhibited the growth, migration, and invasion of PANC-1 and MIA PaCa-2 cells, while increasing apoptosis. It induced mitochondrial membrane potential loss, enhanced mitochondrial ROS production, reduced mitochondrial number, suppressed mitochondrial fission, and promoted mitochondrial network remodeling. Luteolin also upregulated NLRP3 inflammasome- and pyroptosis-related proteins, and these effects were partially reversed by MCC950. Mechanistically, luteolin inhibited the RAS/ERK/DRP1 pathway, whereas RAS or DRP1 overexpression partially attenuated luteolin-induced mitochondrial dysfunction and pyroptosis-related changes. Mdivi-1 produced effects similar to those of luteolin, supporting the involvement of mitochondrial fission disruption. In vivo, luteolin inhibited tumor growth without obvious systemic toxicity. These findings indicate that luteolin suppresses PDAC progression by inhibiting RAS/ERK-dependent, DRP1-mediated mitochondrial fission, thereby inducing mitochondrial dysfunction and triggering pyroptosis.
    Keywords:  Luteolin; Mitochondrial Dysfunction; Pancreatic Ductal Adenocarcinoma; Pyroptosis; RAS/ERK/DRP1 Signaling
    DOI:  https://doi.org/10.1142/S0192415X26500606
  35. Histol Histopathol. 2026 Jul 09. 25121
    Henagliflozin promotes mitophagy in renal tubular cells by activating AMPK/ULK1 to alleviate the progression of diabetic kidney disease.
    Yanqiu Wang, Ziang Chen, Yali Zhang, Chen Shao, Xiujing Zha, Diwen Wang.
       BACKGROUND: Diabetic Kidney Disease (DKD) is a leading cause of end-stage kidney disease. As an inhibitor of sodium-glucose cotransporter 2 (SGLT2), Henagliflozin (Hen) has been shown to have significant renoprotection effects. However, the underlying mechanisms remain to be elucidated.
    METHODS: In clinical studies, patients with DKD were treated with Hen and Metformin (MET) for three months to examine their protection against renal injury. In vivo, C57BL/6 mice were subject to streptozotocin and a high-fat diet to induce DKD, followed by Hen (50 mg/kg/d) and MET (200 mg/kg/d) for eight weeks. In vitro, HK2 cells were exposed to high glucose (HG) (30 mM) and Hen (10 μM) for 24h. In rescue experiments, HK2 cells were transfected with sh-AMPK plasmids and subsequently treated with HG and Hen for 24h.
    RESULTS: Renal injury and the inhibition of autophagy were both observed in patients with DKD and DKD mice. Consistent with these observations, HG-treated HK2 cells exhibited reduced cell viability and impaired autophagy activity. Hen treatment significantly ameliorated renal injury in DKD mice and enhanced cell viability in HG-treated HK2 cells. Furthermore, Hen exerts its protective effects by activating AMPK/ULK1-mediated mitophagy. Notably, AMPK downregulation effectively inhibited the activation of mitophagy induced by Hen treatment in HK2 cells.
    CONCLUSION: Hen exerts renoprotection effects by regulating AMPK/ULK1-dependent mitophagy, offering a novel therapeutic strategy for the clinical application of Hen.
    DOI:  https://doi.org/10.14670/HH-25-121
  36. Front Psychiatry. 2026 ;17 1814473
    Integration of transcriptome profiling to identify key genes involved in the interplay between oxidative stress and mitophagy in major depressive disorder, followed by multidimensional phenotypic validation.
    Haiyan Fang, Guangjun Zhu, Jin Chen, Tao Zou.
       Background: Major depressive disorder (MDD) is recognized as a pressing global public health burden. However, its molecular mechanisms remain incompletely understood.
    Methods: In this study, an integrative analysis of transcriptome datasets from the GEO database was conducted. GEO2R and the R programming language were used to identify differentially expressed genes (DEGs) related to oxidative stress and mitophagy. Key hub genes, such as EEF2, CCT3, EIF3I, and RPS5, were further identified through enrichment analysis and protein-protein interaction (PPI) network construction. Following validation using an independent human dataset, we established a corticosterone-induced C8-D1A cell model. Reactive oxygen species and mitochondrial membrane potential were measured via flow cytometry. The results demonstrated that this model reliably recapitulates key pathological features of elevated oxidative stress and mitochondrial dysfunction in MDD. Finally, using an in vivo mouse model, we assessed synapse-associated proteins and mitophagy markers using Western blotting and measured the mRNA expression levels of candidate genes by qPCR to comprehensively validate the associations between the expression of the aforementioned genes and oxidative stress, mitophagy, and synaptic damage.
    Results: This study combined bioinformatics screening and multidimensional phenotypic validation to construct an MDD-specific molecular regulatory network focused on carbon metabolism, thereby elucidating the interplay between four genes and oxidative stress and mitophagy. Although CCT3 and RPS5 demonstrated modest diagnostic utility in the independent validation dataset (AUC ≈ 0.6, Padj < 0.05), subsequent in vivo experiments revealed that the mRNA expression levels of these genes were significantly downregulated in MDD models (EEF2: P < 0.05; CCT3: P < 0.005; EIF3I: P < 0.05). Furthermore, the expression levels of these genes were positively correlated with those of synaptic proteins and negatively correlated with those of mitophagy markers. The downregulation of these genes may impair protein synthesis and folding, which acts in synergy with oxidative stress and mitochondrial dysfunction to perpetuate the vicious cycle of bioenergetic crisis and proteostasis collapse in MDD.
    Conclusion: Although this study did not experimentally validate the regulatory functions of the target genes or identify highly specific diagnostic biomarkers, it offers a novel molecular perspective for deciphering the complex pathology of MDD. Notably, this highlights the synergistic interaction between translational regulation and metabolic homeostasis. Further validation in larger independent cohorts is warranted to assess the viability of these genes as mechanistic therapeutic targets.
    Keywords:  CCT3; EIF3i; eEF2; major depressive disorder; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fpsyt.2026.1814473
  37. Front Nutr. 2026 ;13 1812651
    Sinensetin ameliorates established high-fat diet-induced liver injury and intestinal barrier dysfunction through the mitophagy/TLR4/MAPK signaling pathway.
    Zhuoqun Meng, Qin Zhang, Zhichang Zhao, Yuan Zhang, Zhijie Lu, Guirong Liu, Wenliang Xiang, Qing Zhang, Jie Tang.
       Introduction: Long-term consumption of a high-fat diet (HFD) causes liver injury characterized by steatosis, inflammation, and fibrosis. Mitophagy, as a selective autophagy, is reported to be involved in the regulation of liver injury. Sinensetin, a polymethoxylated flavonoid abundant in citrus fruit peels, exhibits various biological activities, including anti-inflammatory and hepatoprotective properties. However, whether sinensetin can target mitophagy and protect against HFD-induced liver damage via the gut-liver axis remains inadequately explored.
    Methods: In order to further investigate the relationships involved, we conducted histopathology analysis, biochemical analysis, 16S rRNA sequencing, and short-chain fatty acid (SCFA) levels.
    Results: Sinensetin administration ameliorated hepatic steatosis, inflammation, and restored intestinal integrity in HFD-fed mice. Mechanistically, sinensetin remodeled the gut microbiota, elevating SCFA levels, which activated mitophagy and cleared damaged mitochondria in liver and intestinal tissues, thereby suppressing the toll-like receptor 4 (TLR4)/mitogen-activated protein kinase (MAPK) signaling.
    Conclusion: Sinensetin may contribute to protecting against HFD-induced liver injury and intestinal barrier dysfunction by orchestrating the integrated "microbiota-SCFA-mitophagy" defensive network, providing a novel paradigm beyond the classical TLR4/MAPK axis.
    Keywords:  gut–liver axis; high-fat diet; intestinal barrier dysfunction; liver injury; mitophagy; sinensetin
    DOI:  https://doi.org/10.3389/fnut.2026.1812651
  38. Int J Chron Obstruct Pulmon Dis. 2026 ;21 597903
    SPG7-Mediated Regulation of mPTP and Mitochondrial Flickering in COPD: A Bioinformatics-Based Prediction of Mechanistic Framework.
    Anran Xu, Yaping Lv, Shaobin Li, Xinhui Zhang, Jirong Zhang, Chengyan Zhan, Yanqi Cheng, Ling Tang, Chen Zhang, Siyang Xiang, Hong Fang, Donghua Zhou.
       Background: During the staged progression of chronic obstructive pulmonary disease (COPD), mitophagy homeostasis is disrupted and exhibits a typical dual role. Mitophagy is tightly regulated by ion channel-controlled mitochondrial membrane potential (ΔΨm) and may associate with mitochondrial permeability transition pore (mPTP) dynamics. However, this regulatory mechanism remains largely unknown, and the stage-specific requirements of mitophagy in COPD progression have yet to be established.
    Methods: This study proposed a novel theoretical framework from prior literature. Using public databases, we linked mPTP-related genes to COPD state transitions via differential analysis and Mendelian randomization (MR). Key biomarkers were validated through gene enrichment, functional annotation, immune infiltration, and single-cell RNA sequencing (scRNA-seq) to assess biological significance. Finally, molecular docking confirmed their potential roles.
    Results: We preliminarily aligned the "mitochondria-cell survival architecture" hypothesis with COPD progression. Compared with stable COPD (STCOPD), acute exacerbation of COPD (AECOPD) showed massive type II alveolar epithelial (AT2) cell death, hyperinflammation, increased energy demand, and impaired intercellular communication, consistent with activated ubiquitin-proteasome system (UPS), mitochondrial gene expression, macroautophagy initiation, and vesicle trafficking. Six biomarkers (including SPG7) were associated with AECOPD (AUC=0.705, 95% CI 0.554-0.705). SPG7 was positively correlated with AECOPD (OR=1.126, 95% CI 1.008-1.257), while the other five showed negative correlations. These markers were enriched in ion channel and G protein-coupled receptors (GPCRs) pathways. SPG7 expression paralleled energy demand and strongly interacted with AFG3L2 and PPIF, implicating it in mPTP regulation.
    Conclusion: This study preliminarily supports the mitochondria-cell survival hypothesis. Bioinformatic analysis suggests that mPTP-triggered mitochondrial flickering maintains mitochondrial quality control. Furthermore, transient mPTP opening via SPG7-mediated CypD activation may constitute an independent protective pathway, potentially involving unique SPG7-CypD modifications. However, non-significant colocalization limits study robustness, necessitating rigorous experimental validation of these predictions.
    Keywords:  bioinformatics analysis; chronic obstructive pulmonary disease; mitochondrial flickering; mitochondrial permeability transition pore; mitophagy
    DOI:  https://doi.org/10.2147/COPD.S597903
  39. Autophagy. 2026 Jul 05. 1-27
    Hypoxia-preconditioned dental pulp stem cells alleviate acetaminophen-induced liver failure via promoting MYC-HIF1A/HIF-1α-BNIP3-mediated mitophagy.
    Junyi Li, Qianyu Yang, Pengcheng Pang, Ye Liu, Xiaojing Liu, Wanyang Zhong, Rui Zhang, Wenao Sun, Yan He, Qingsong Ye.
      Acetaminophen (APAP)-induced acute liver injury (AILI) is a prevalent clinical liver condition caused mostly by oxidative stress and mitochondrial damage. Dental pulp stem cells (DPSCs) possess antioxidant, anti-inflammatory, and immunomodulatory capabilities, demonstrating significant potential in liver diseases. However, during in vitro culture, they are typically maintained under normoxic conditions (21% O2), which is very different from the hypoxic oxygen level that is found in vivo. It remains unclear whether hypoxic-conditioned dental pulp stem cells (Hyp-DPSCs) exhibit superior therapeutic effects compared to normoxic-conditioned dental pulp stem cells (Nor-DPSCs). This study demonstrated that 24-h exposure to 1% O2 significantly enhanced HIF1A/HIF-1α expression in DPSCs. It promoted mitophagy through the MYC-HIF1A-BNIP3 pathway, enhancing mitochondrial shape and function while reducing oxidative stress in DPSCs. Furthermore, in vitro and in vivo experiments demonstrated that Hyp-DPSCs were far more potent than Nor-DPSCs in boosting the expression of hepatic antioxidant factors and enhancing macroautophagy/autophagy to reduce AILI. These findings revealed that hypoxia activated mitophagy in DPSCs, enhancing their therapeutic efficacy against AILI and providing a novel strategy for stem cell-based AILI treatment.Abbreviations: AILI: acetaminophen-induced acute liver injury; ANOVA: analysis of variance; APAP: acetaminophen; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CASP3: caspase 3; CAT: catalase; CCK-8: cell counting kit-8; CM: conditioned medium; COX4I1: cytochrome c oxidase subunit 4I1; CPT1A: carnitine palmitoyltransferase 1A; CQ: chloroquine; DPSCs: dental pulp stem cells; ELISA: enzyme-linked immunosorbent assay; GO: Gene Ontology; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; GPX4: glutathione peroxidase 4; GSH: glutathione; Hyp-DPSCs: hypoxic-conditioned dental pulp stem cells; H&E: hematoxylin and eosin; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; HMOX1/HO-1: heme oxygenase 1; HUVECs: human umbilical vein endothelial cells; IF: immunofluorescence; IHC: immunohistochemistry; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; i.p.: intraperitoneally; i.v.: intravenous injection; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MSCs: mesenchymal stem cells; MYC: MYC proto-oncogene, bHLH transcription factor; NAC: N-acetylcysteine; NAPQI: N-acetyl-p-benzoquinone imine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; Nor-DPSCs: normoxic-conditioned dental pulp stem cells; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PLIN2: perilipin 2; PINK1: PTEN induced kinase 1; PPARA/PPARα: peroxisome proliferator activated receptor alpha; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; ROS: reactive oxygen species; SEM: standard error of the mean; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TNF/TNF-α: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1: voltage dependent anion channel 1; WB: western blot.
    Keywords:  Acetaminophen-induced acute liver injury; BNIP3; HIF1A/HIF-1α; hypoxia; MYC; dental pulp stem cells; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2694664
  40. Front Pharmacol. 2026 ;17 1865091
    Mechanisms of mitochondrial dysfunction and protective strategies in skin flap ischemia-reperfusion injury.
    Quan Shi, Zairong Wei.
      Flap transplantation remains a cornerstone of reconstruction of complex tissue defects and restoration of local form and function. However, ischemia-reperfusion (I/R) injury continues to compromise flap viability and is a major cause of distal necrosis. Emerging evidence suggests that mitochondria are among the earliest and most severely affected organelles during flap I/R, placing them at the center of tissue injury. Once disrupted, mitochondrial dysfunction may aggravate microcirculatory failure, amplify inflammatory responses, and accelerate tissue damage through excessive mitochondrial reactive oxygen species (mtROS) generation, mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential, and impaired mitochondrial quality control. Disruption of mitochondrial homeostasis also reshapes the behavior of endothelial cells, macrophages, fibroblasts, and vascular smooth muscle cells, thereby influencing flap repair outcomes. In this review, we focus on mitochondrial homeostasis as a unifying framework for understanding flap I/R injury. We discuss its involvement in oxidative stress, calcium overload, mPTP opening, metabolic dysfunction, defective mitochondrial quality control, and mitochondria-related programmed cell death. We further summarize recent therapeutic strategies designed to preserve or restore mitochondrial homeostasis, with the goal of informing future approaches to improve flap survival and tissue repair.
    Keywords:  flap ischemia-reperfusion injury; mitochondrial homeostasis; mitochondrial quality control; oxidative stress; programmed cell death; tissue repair
    DOI:  https://doi.org/10.3389/fphar.2026.1865091
  41. Exp Mol Med. 2026 Jul 10.
    Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF.
    Hangyul Song, Chahyeon Yun, Yunju Choi, Wooju Jeong, Yumin Kim, Jaeyoung Kim, Ju-Yeon Lee, Dongryeol Ryu, Sang-Wook Park, Chang-Myung Oh.
      Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases. However, effective therapies targeting its underlying pathophysiological mechanisms remain lacking. Previous studies have indicated mitochondrial dysfunction and impaired mitophagy as key contributors to HFpEF pathophysiology. In this study, we investigated whether urolithin A (UA), a gut microbiome-derived mitophagy-activating compound, can ameliorate HFpEF. A two-hit mouse model was established using a high-fat diet and Nω-nitro-L-arginine methyl ester, and UA was administered during disease progression. In vitro and in vivo experiments, together with multi-omics analyses, showed that UA alleviated diastolic dysfunction, cardiac hypertrophy, and fibrosis in HFpEF mice. These effects were accompanied by restoration of mitochondrial ultrastructure and enhanced mitochondrial respiration and glycolytic capacity. Notably, UA activated AMPK signaling while inhibiting mTOR, promoting ULK1-dependent autophagy initiation and restoring impaired mitophagic flux. These effects were associated with improved mitochondrial quality control and function. Concurrently, multi-omics analyses revealed that UA remodels the gut microbiome-ceramide axis and reduces circulating ceramide accumulation, thereby alleviating lipotoxic stress. Furthermore, single-nucleus transcriptomic analysis revealed that UA treatment leads to the attenuation of fibrosis-related cellular programming in human induced pluripotent stem cell-derived cardiomyocytes. Taken together, these findings indicate that UA improves cardiac remodeling in HFpEF by activating mitophagy-dependent mitochondrial quality control and modulating the gut microbiome-ceramide axis, highlighting its potential as a mechanism-based, mitochondria-targeted therapeutic strategy for HFpEF.
    DOI:  https://doi.org/10.1038/s12276-026-01776-2
  42. Int Immunopharmacol. 2026 Jul 06. pii: S1567-5769(26)00938-0. [Epub ahead of print]186 117092
    Berbamine improves behavioral impairments in Huntington's disease mice models through inhibiting Src/AKT1/NFκB signaling pathway and attenuating Src-mediated mitophagy suppression.
    Chunling Yuan, Li Zheng, Hongxia Hu, Xue Cheng, Peng Liu.
       BACKGROUND: Investigate the effects of berbamine (BBM) on alleviating motor and cognitive impairment in animal models of Huntington's disease (HD).
    METHODS: Intraperitoneal injection of 3-nitropropionic acid (3-NP) mice and B6-hHTT130-N transgenic mice were used as the HD models. We evaluated the anti-HD effect of BBM through behavioral experiments and employed molecular biological techniques, network pharmacology analysis, to test the potential mechanisms.
    RESULTS: BBM improved motor and cognitive impairment in 3-NP-injected and B6-hHTT130-N mice. BBM improved pathological damage in the brain, reduced the expression of mHTT in B6-hHTT130-N mice. BBM increased the ATP and mtDNA content, attenuated PINK1/Parkin-mediated mitophagy suppression. Furthermore, network pharmacology analysis, molecular docking and CETSA identified two targets: Src and AKT1. By using the Src inhibitor KX2-391, AKT inhibitor MK-2206 and NFκB inhibitor QNZ, we found that BBM showed a similar experimental results to Src inhibitor in Q74 plasmid transfected BV2 cells. BBM could inhibit the Src/AKT1/NFκB/NLRP3 signaling pathway-mediated neuroinflammation, and enhance PINK1/Parkin expression may through inhibiting Src.
    CONCLUSION: BBM ameliorates motor and cognitive impairments in HD model mice through inhibition of neuroinflammation and mHTT expression, maintenance of mitochondrial function, which was mediated by inhibiting Src/AKT1/NFκB signaling pathway and attenuating Src-mediated mitophagy suppression.
    Keywords:  Berbamine; Huntington's disease; Mitochondria; Network pharmacology; Neuroinflammation; Src/AKT1
    DOI:  https://doi.org/10.1016/j.intimp.2026.117092
  43. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2529208123
    Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
    Stefano Bettinazzi, Avishikta Chakraborty, Finley Grover-Thomas, Damian K Dowling, M Florencia Camus.
      Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.
    Keywords:  Drosophila; ageing; mitochondrial metabolism; mitohormesis; mitonuclear discordance
    DOI:  https://doi.org/10.1073/pnas.2529208123
  44. Free Radic Biol Med. 2026 Jul 08. pii: S0891-5849(26)00919-6. [Epub ahead of print]
    Polystyrene nanoplastics exacerbated the toxicity of cadmium: from the perspective of the placenta-uterus micro-environment.
    Ruiying Zhang, Penghui Nie, Fen Fu.
      Heavy metal and plastic pollution are one of most serious environmental problems, which threaten ecological environment and human health. Herein, plastics could be aged fragmented to nanoplastics (NPs) and Cadmium (Cd) as one of the most prevalent heavy metals was found in polluted soil in China. Additionally, Cd and NPs are widespread coexistence in aquatic and mammals. Additionally, the rate of premature births and the death of infants is increasing, and environmental pollution is one of main factors. Therefore, the impact of environmental pollution on pregnant women deserves more attention. In this study, the pregnant C57BL/6J mice were exposed to PS-NPs and/or Cd from gestational day 0.5 to 15.5, and we explored the impact and potential mechanism of maternal co-exposure to PS-NPs and Cd on placenta-uterus micro-environment in mice and using inhibitors for verification. The results indicated that co-exposure PS-NPs and Cd caused more serious impairment in gut, placenta and uterus barrier, promoted more Cd accumulation, and affected the metal transporters and the homeostasis of glycolipid metabolism, thereby inducing mtROS mediated excessive mitophagy, causing the impairment of uterus and placenta structure and function. Additionally, mtROS and VDAC1 plays a vital role in this process via inhibitors intervention. Generally, we have proven that PS-NPs can adsorb Cd, impair the uterine-placental barrier, thereby promoting the accumulation of Cd and mtROS mediated VDAC1-mitophagy is the key signal pathway for the adverse effects caused by Cd and PS-NPs co-exposure during pregnancy.
    Keywords:  Cadmium; Ion channel protein; Mitophagy; Placenta-uterus micro-environment; Polystyrene nanoplastics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.004
  45. Inflamm Res. 2026 Jul 06. pii: 171. [Epub ahead of print]75(1):
    Agmatine induces mitophagy via the PTS-I2R pathway to increase autophagic flux and attenuate sepsis-induced intestinal epithelial cell apoptosis.
    He Jin, Shuangqin Yin, Yongming Li, Xiangwei Hou, Lin Qiao, Tianyin Kuang, Jing Zhou, Xue Yang, Wanting Zeng, Chao Fan, Li Luo, Lihui Wang, Hongyan Xiao, Shengxiang Ao, Shan Su, Quanwei Bao, Yibin Ouyang, Huaping Liang, Junyu Zhu.
       BACKGROUND: The therapeutic options for sepsis-induced intestinal injury, which drives multiple organ dysfunction and mortality, are limited, but the role of polyamine supplements remains unclear. This study aimed to elucidate the protective effect of agmatine (AGM) on sepsis-induced intestinal injury and its mitochondrial-targeted antiapoptotic mechanism in intestinal epithelial cells (IECs).
    METHODS: We verified the transport and subcellular localization of AGM in IECs via fluorescence assays and established in vitro and in vivo IEC apoptosis models. Functional evaluations using cell viability assays, laser confocal imaging, flow cytometry, transmission electron microscopy, and multiomics techniques were performed.
    RESULTS: AGM attenuated sepsis-induced intestinal injury, as evidenced by its ability to lower the serum levels of intestinal damage markers in septic mice, attenuate inflammatory factor production and pathological damage in the intestine, and reduce IEC apoptosis. AGM entered IECs via the polyamine transport system (PTS), but not the NMDA receptor, and inhibited IEC apoptosis induced by TNFα/CHX or TNFα/ActD. Notably, AGM exerted its antiapoptotic effect by targeting the mitochondrial imidazoline I2 receptor (I2R). Mechanistically, AGM induced mitophagy by decreasing the mitochondrial membrane potential without altering mitochondrial number or function, as ROS production, calcium ion influx, ATP generation, and oxygen consumption were unchanged. AGM also increased autophagic flux, as confirmed upon treatment with various autophagy inhibitors.
    CONCLUSION: AGM alleviates sepsis-induced intestinal injury via the PTS-I2R axis by promoting mitophagy and autophagic flux to inhibit IEC apoptosis, laying a foundation for the use of AGM as a potential nutritional supplement or therapeutic agent for sepsis-induced intestinal injury.
    Keywords:  Agmatine; Apoptosis; Imidazoline I2 receptor; Mitophagy; Polyamine transport system; Sepsis-induced intestinal injury
    DOI:  https://doi.org/10.1007/s00011-026-02314-6
  46. J Pharm Anal. 2026 Jun;16(6): 101542
    Elucidation of ACAT1's role in hepatic ischemia-reperfusion injury: TFEB-mediated mitophagy and ferroptosis modulation as therapeutic targets.
    Xiangwei Li, Ting Xu, Shaochuang Wang, Long Ma, Xiangyou Yu, Yi Wang, Linlin Bai, Jun Cao, Zuyi Zhao, Meiting Du, Hao Wen, Kun Wu.
      Hepatic ischemia-reperfusion injury (HIRI) remains a critical clinical challenge, significantly impacting the success of liver transplantation and postoperative recovery following resection. The study investigated the roles of mitochondrial acetyl-CoA acetyltransferase1 (ACAT1) and transcription factor EB (TFEB) in orchestrating cellular responses to HIRI, specifically focusing on mitophagy and ferroptosis pathways. Using a combination of in vivo models and cellular molecular techniques,we found that ACAT1 plays a pivotal hepatoprotective role. By fostering TFEB-mediated mitophagic processes and curtailing ferroptosis, ACAT1 emerges as a critical moderator of cellular resilience against oxidative stresses induced by reperfusion. These findings elucidate the molecular interplay underlying HIRI and identify ACAT1 as a potential therapeutic target for mitigating hepatic damage and enhancing patient outcomes in liver surgery and transplantation scenarios.
    Keywords:  Acetyl-CoA acetyltransferase 1; Acetylproteomics; Hepatic ischemia reperfusion injury; Single-cell transcriptomics; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.jpha.2025.101542
  47. J Transl Med. 2026 Jul 08.
    IMPA2 ameliorates high-fat diet-induced obesity by enhancing adaptive thermogenesis in a Ca²⁺-activated mitochondrial biogenesis pathway.
    Li Lin, Yudan Zhou, Lulu Ning, Ruiqi Mao, Yuhang Wang, Meng Du, Le Chen, Kai Huang, Min Chen.
       BACKGROUND: Obesity poses a significant threat to global human health. The identification of thermogenic adipocytes in humans proves that enhanced adaptive thermogenesis may help mitigate obesity. Although some evidence suggests a role for IMPA2 in cellular metabolism, its specific impact on obesity and the underlying mechanisms remain underexplored.
    METHODS: High-fat-diet (HFD)-induced obese mice were employed as experimental models. Cold exposure (4 °C) or administration of the β3-adrenoceptor agonist CL316,243 was used to stimulate adipose thermogenesis. In vivo modulation of IMPA2 function was achieved through subcutaneous injection of adeno-associated virus (AAV). Body weight and energy metabolism were monitored by the CLAMS, and browning was determined. The role and mechanisms of IMPA2 in thermogenesis were examined through adenovirus (Adv) treatment, followed by in vitro and in vivo analyses.
    RESULTS: Thermogenic stimulation increased IMPA2 level in murine inguinal white adipose tissue (iWAT), whereas obesity resulted in its downregulation. IMPA2 overexpression in iWAT accelerated iWAT browning and thermogenesis, conferring protection against HFD-induced obesity and metabolic disturbances. Conversely, silencing IMPA2 reduced thermogenic gene levels in iWAT and inhibited WAT browning. Mechanistically, IMPA2 elevated myo-inositol (MI), inositol-1,4,5-trisphosphate (IP3) and intracellular calcium ion (Ca²⁺) levels, which subsequently activated Ca²⁺-dependent protein kinase IIα (CamKIIα) and PGC1α axis to increase mitochondrial biogenesis and thermogenic capacity in adipocytes.
    CONCLUSIONS: IMPA2 plays a crucial role in adaptive thermogenesis and energy expenditure. IMPA2 improves obesity and metabolic disorders, with its thermogenic enhancement mediated by the Ca²⁺-activated mitochondrial biogenesis pathway.
    DOI:  https://doi.org/10.1186/s12967-026-08592-2
  48. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2026 Jul 09. 1-16
    In vivo assessment of naringenin-mediated amelioration of lead-induced testicular injury in rats: regulation of Nrf2/Keap1 and PINK1/Parkin pathways.
    Jing Zhu, Mengmeng Gao, Hao Ling, Phar Ku Ngwe, Chengxiang Guo, Yinan Hu, Jicang Wang.
      This study investigated the protective effects of naringenin (Nar) against lead (Pb)-induced testicular injury in rats, focusing on the Nrf2/Keap1 antioxidant pathway and PINK1/Parkin-mediated mitophagy. To this end, male SD rats were exposed to Pb (60 mg/kg) and co-treated with Nar (50 mg/kg) for 8 consecutive weeks, followed by assessments via biochemical detection, oxidative stress (OS) evaluation, hematological examination, histopathological observation, qPCR, WB, and IHC analyses. Pb exposure caused hematological disturbances, reduced serum LH and T levels, and OS imbalance (lower GSH, SOD, CAT; higher MDA), aggravating testicular damage. Meanwhile, it suppressed the Nrf2/NQO1 pathway, elevated Keap1, impaired autophagy (elevated p62, declined LC3‑II/LC3‑I ratio), and induced aberrant accumulation of PINK1/Parkin. Co-treatment with Nar mitigated these alterations, ameliorating testicular injury, restoring redox homeostasis and serum reproductive hormone levels, and normalizing key molecular expressions in both pathways. In conclusion, Nar alleviates Pb-induced rat testicular damage by reactivating the Nrf2/Keap1 axis to suppress OS, and by restoring autophagic flux to facilitate PINK1/Parkin-mediated clearance of damaged mitochondria.
    Keywords:  Naringenin; autophagy; lead; mitophagy; oxidative stress; testicular injury
    DOI:  https://doi.org/10.1080/10934529.2026.2699582
  49. Free Radic Biol Med. 2026 Jul 04. pii: S0891-5849(26)00912-3. [Epub ahead of print]
    Corrigendum to "Fatty acid oxidase Ehhadh mediates stem cell fate remodeling via mitophagy activation" [Free Radic. Biol. Med. 248 (2026) 109-126].
    Jingxuan Zhou, Longyun Zhang, Tingjun Liu, Jiatong Sun, Yuxi Sun, Shaorong Gao, Kerong Shi.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.057
  50. J Ethnopharmacol. 2026 Jul 07. pii: S0378-8741(26)01012-3. [Epub ahead of print] 122158
    Corrigendum to "Maimendong decoction modulates the PINK1/Parkin signaling pathway alleviates type 2 alveolar epithelial cells senescence and enhances mitochondrial autophagy to offer potential therapeutic effects for idiopathic pulmonary fibrosis" [J. Ethnopharmacol., 345, (9 April 2025), 119568].
    Yuhe Zhou, Wen Su, Mengzhen Xu, Aijun Zhang, Shaoli Li, Hong Guo, Kai Gong, Kaihui Lu, Xin Yu, Jiang Zhu, Qingjun Zhu, Chuanguo Liu.
      
    DOI:  https://doi.org/10.1016/j.jep.2026.122158
  51. Exp Neurol. 2026 Jul 10. pii: S0014-4886(26)00269-4. [Epub ahead of print] 115904
    Hippocampal LANCL1 attenuates postoperative cognitive dysfunction via the SIRT1/PGC-1α-mediated mitochondrial biogenesis.
    Jun-Yan Zhang, Ming-Yue Yu, Tian-Yan Luo, Sheng Huang, Zhong-Qiong Wang, Yuexin Liu, Jie Zheng, Ying Zhang.
      Postoperative cognitive dysfunction (POCD) is a prevalent and clinically significant complication in elderly surgical patients, yet effective therapeutic interventions remain scarce. Mitochondrial dysfunction, particularly impaired biogenesis, has been implicated as a central mechanism. LANCL1 is known for its neuroprotective properties against oxidative stress, but its role in POCD has not been explored. Here, we observed marked downregulation of LANCL1 in the hippocampi of aged mice following surgical trauma, correlating with cognitive decline and neuronal damage. Hippocampal-specific overexpression of Lancl1 via lentiviral vector significantly ameliorated cognitive deficits, including novel object recognition impairment, reduced neuronal injury, restored mitochondrial ultrastructure. Moreover, LANCL1 overexpression increased hippocampal ATP content and elevated the ratios of mitochondrial DNA-encoded genes (16S rRNA and ND1) relative to the nuclear gene HK2, indicating enhanced mitochondrial biogenesis. Histological analyses further revealed increased neuronal survival in the CA1 and CA3 subfields. Single-cell sequencing data demonstrated that LANCL1 expression in neurons was specifically reduced after LPS challenge compared to saline controls, supporting its vulnerability to inflammatory stress. LANCL1 overexpression also reduced hippocampal MDA levels and restored SOD activity, mitigating oxidative stress. Mechanistically, LANCL1 overexpression was associated with upregulation of the SIRT1/PGC-1α signaling axis and its downstream transcription factors NRF1 and TFAM essential for mitochondrial biogenesis. Importantly, co-administration of the SIRT1-specific inhibitor EX-527 completely abolished the protective effects of LANCL1, including the restoration of ATP levels, mtDNA copy number, neuronal survival, and cognitive performance, demonstrating that SIRT1 activity is required for LANCL1-mediated protection. Collectively, these findings establish LANCL1 as a critical regulator of mitochondrial health in the postoperative brain and highlight its therapeutic potential for mitigating POCD via enhancing SIRT1/PGC-1α-mediated mitochondrial biogenesis.
    Keywords:  Cognitive function; LANCL1; Mitochondrial biogenesis; Postoperative cognitive dysfunction (POCD); SIRT1/PGC-1α pathway
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115904
  52. Stem Cell Res Ther. 2026 Jul 08.
    Psoralen enhances direct cardiac reprogramming via activating PPARα and driving mitochondrial fission and improves cardiac function after myocardial infarction.
    Wenjie Li, Haixia Liu, Xinyu Wan, Ding Cheng, Zhiguo Zhang, Ruyuan Zhu.
       BACKGROUND: Direct cardiac reprogramming offers a promising strategy to regenerate cardiomyocytes for heart repair, but its efficiency and maturation remain limited. Psoralen, a natural compound isolated from Psoralea corylifolia L., has been widely studied for its bioactive properties. This study aimed to determine whether psoralen enhances chemical cardiac reprogramming and improves functional maturation, and to evaluate its therapeutic potential in myocardial infarction.
    METHODS: Mouse embryonic fibroblasts were treated with a chemical reprogramming cocktail containing RepSox and Forskolin, with or without psoralen. Gene expression was assessed by quantitative PCR and Western blotting. Sarcomere ultrastructure was examined by transmission electron microscopy. Mitochondrial content and morphology were analyzed using MitoTracker staining. Calcium handling was evaluated in Fluo-4 loaded induced cardiomyocytes. Metabolic profiles were measured with Seahorse assays. RNA sequencing and protein-protein interaction analysis were used to identify signaling pathways activated by psoralen. To investigate the functional role of mitochondrial fission in psoralen enhanced reprogramming, the DRP1 inhibitor Mdivi-1 was added to the reprogramming cocktail. An immortalized human skin fibroblast cell line was additionally used to evaluate cardiac marker expression and mitochondrial morphology following treatment with RepSox, Forskolin, and psoralen. For in vivo evaluation, a myocardial infarction model was generated in male C57BL/6J mice, which were subsequently treated for 7 days. Cardiac function was measured by echocardiography, and histological changes were assessed by HE and Masson's trichrome staining.
    RESULTS: Psoralen (10 µM) significantly increased the induction efficiency of induced cardiomyocytes, leading to the rapid appearance of beating clusters(day 1 vs. day 6-8) and marked upregulation of cardiac structural genes. Psoralen-treated cells displayed enhanced sarcomere organization, improved calcium transients, and a metabolic shift toward oxidative phosphorylation characterized by higher mitochondrial respiration and reduced glycolysis. Transcriptomic profiling identified activation of the PPAR signaling pathway, with PPARα, RXRG, and UCP1 as central nodes. Psoralen also enhanced mitochondrial fission by upregulating fission-related genes and proteins. Mdivi-1 attenuated psoralen-induced cardiac gene expression and mitochondrial fragmentation. In immortalized human skin fibroblasts, psoralen combined with RepSox and Forskolin increased cardiac marker expression and promoted mitochondrial fragmentation. In vivo, psoralen combined with RepSox and Forskolin enhanced cardiac function and reduced fibrosis after myocardial infarction compared to RepSox and Forskolin alone.
    CONCLUSION: Psoralen enhances chemical direct cardiac reprogramming by activating metabolic and structural maturation programs through mitochondrial fission and PPARα-dependent signaling. The combined treatment provides functional benefits in myocardial infarction, highlighting psoralen as a promising small molecule for cardiac regeneration.
    Keywords:  Chemical cardiac reprogramming; Induced cardiomyocyte; Mitochondrial fission; Myocardial infarction; PPARα; Psoralen
    DOI:  https://doi.org/10.1186/s13287-026-05160-9
  53. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00693-5. [Epub ahead of print]45(7): 117615
    ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
    Anastasia Chugunova, Isabelle Schütz, Hannah Keresztes, Roksolana Kobylinska, Maria Novatchkova, Thomas Lendl, Marcus Strobl, Jörg Fallmann, David Márquez Oller, Michael Schutzbier, Gerhard Dürnberger, Richard Imre, Elisabeth Roitinger, Phylicia Kidd, Pawel Pasierbek, Alberto Moreno Cencerrado, Marlene Brandstetter, Thomas Köcher, Benedikt Agerer, Jakob-Wendelin Genger, Andreas Bergthaler, Andrea Pauli.
      Increased mitochondrial activity is essential for embryo development. Although conserved across organisms, the molecular basis of this increase is unknown, as detailed biochemical analysis in vertebrates is hampered by the limited availability of material. Using zebrafish as a model for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome, and phospho-proteome, as well as respiratory chain activity. Our data show that the mitochondrial proteome undergoes major changes during embryogenesis. While respiratory chain complex levels remain largely constant, we identify a marked increase in mitochondrial-ER association during early embryogenesis. Moreover, time-lapse imaging of mitochondrial dynamics reveals a transition from fragmented to elongated mitochondria starting during somitogenesis. Overall, our systematic profiling of the molecular and morphological changes of mitochondria during embryogenesis provides a valuable resource for further investigation of mitochondrial function. Our study reveals that increased mitochondrial-ER interaction and changes in mitochondrial morphology may contribute to its regulation during vertebrate development.
    Keywords:  CP: cell biology; CP: developmental biology; ER-mitochondrial interaction; metabolism; mitochondria; mitochondrial activation; proteomics; vertebrate embryogenesis; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117615
  54. Free Radic Biol Med. 2026 Jul 10. pii: S0891-5849(26)00945-7. [Epub ahead of print]
    ASAP3 deficiency alleviates hepatic senescence and correlates with extended healthspan in mice.
    Zhen Tian, Yuhua Song, Xinyue Ao, Changhao Sun.
      The aging liver not only declines in function but also accelerates systemic aging and shortens lifespan. Identifying key molecular targets to delay liver aging is important for promoting health and longevity. ASAP3 is involved in cytoskeletal remodeling, but its role in aging remains unexplored. Here, we found that ASAP3 expression was upregulated in aged mouse livers and H2O2-induced AML12 cells. In AML12 hepatocytes, ASAP3 knockdown attenuated H2O2-induced senescence, enhanced autophagic flux, reduced mitochondrial ROS, and restored mitochondrial membrane potential, whereas ASAP3 overexpression had opposite effects. Phalloidin staining and western blot analysis showed that ASAP3 knockdown significantly reduced the abnormal accumulation of F-actin and F-actin/G-actin ratio, while ASAP3 overexpression aggravated F-actin accumulation, and increased F-actin/G-actin ratio in AML12 cells. In addition, inhibition of autophagy abolished the alleviating effect of ASAP3 knockdown on senescence, whereas enhancing autophagy protected against cellular senescence induced by ASAP3 overexpression. Furthermore, disruption of F-actin assembly with cytochalasin D rescued the suppression of autophagic flux caused by ASAP3 overexpression. In vivo, ASAP3 knockout extended lifespan, improved cognitive and motor functions, and remodeled systemic metabolism in both sexes. ASAP3 knockout mice also showed reduced senescence phenotype, maintained F-actin structure, and enhanced autophagic flux in the liver. Furthermore, serum lipidomics revealed significant enrichment of pathways related to actin cytoskeleton regulation, autophagy, and primary bile acid biosynthesis in Asap3-/- mice. Collectively, these findings demonstrate that ASAP3 is a negative regulator of liver aging, promoting senescence and impairing autophagy and mitochondrial function by disrupting actin cytoskeleton dynamics. Targeting ASAP3 may represent a promising strategy to delay hepatic aging and extend healthspan.
    Keywords:  ASAP3; Actin cytoskeleton; Aging; Autophagy; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.018
  55. Mol Med. 2026 Jul 04.
    Dopamine signaling reprograms macrophage FAO to alleviate acute lung injury by inhibiting NETosis via the CXCL10-CXCR3 axis.
    Ximing Liao, Changwen Deng, Jing Gao, Ziqi Yang, Tian Li, Jialin Yao, Muyun Wang, Fengyang Xie, Zhaoqi Li, Kun Wang, Qiang Li, Di Wu, Wujian Xu, Wei Gao.
       BACKGROUND: Dysregulated innate immunity and oxidative stress drive the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), yet master endogenous regulators that orchestrate inflammation resolution remain elusive.
    METHODS: This study employed public database mining, clinical data investigation, murine disease models, mouse bone marrow-derived macrophages and neutrophils, and human macrophages from healthy donors and ARDS patients, to investigate the dynamic changes of the dopaminergic signaling system in the acute pulmonary inflammatory environment and its role in regulating macrophage metabolism and neutrophil extracellular trap formation (NETosis).
    RESULTS: Public database mining and experimental data reveal accelerated dopamine (DA) turnover during ALI. DA, signaling via D1-like receptors, reprograms macrophage metabolism by enhancing carnitine palmitoyltransferase 1 A (CPT1A)-dependent fatty acid oxidation (FAO) and mitochondrial fitness, which is coupled with the suppression of MAPK/NF-κB and NLRP3 inflammasome activation. These modulated macrophages restrain neutrophilic inflammation by secreting IL-10 to inhibit the CXCL10-CXCR3 axis, thereby curtailing neutrophil hyperactivation and pathogenic NETosis. Crucially, this protective mechanism is conserved in human macrophages from both healthy donors and ARDS patients.
    CONCLUSION: Our findings establish DA as a therapeutic target for recalibrating innate immunity in ALI, providing a mechanistically grounded framework for targeting dopaminergic signaling to resolve dysregulated inflammation, with exploratory preclinical translational implications for ALI/ARDS therapy.
    Keywords:  Acute lung injury; Dopamine; Macrophage metabolism; Mitochondrial homeostasis; Neutrophil extracellular traps
    DOI:  https://doi.org/10.1186/s10020-026-01549-7
  56. Front Immunol. 2026 ;17 1761658
    The role of mitochondrial proteases in inflammation and immunity.
    Anna Rebeka Oliveira Ferreira, Emily A Day.
      The global rise in chronic inflammatory and autoimmune disorders has intensified research to understand cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses. By selectively degrading misfolded or damaged proteins, they maintain mitochondrial function and bioenergetic capacity. Beyond housekeeping roles, mitochondrial proteases also influence immune signaling by modulating mitochondrial stress pathways, reactive oxygen species production, and the release of mitochondrial-derived danger signals. Dysregulation of these proteases has been linked to chronic inflammation and contributes to the pathogenesis of inflammatory diseases. This review summarizes current knowledge on the role of mitochondrial proteases CLPXP, LONP1, i-AAA, m-AAA, as well as processing peptidase OMA1, in immune cells and inflammatory pathologies. We explore the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating the results from immune cells as well as other non-immune cell types, including those involved in cancer, neurodegeneration, renal injury, and other inflammatory pathologies. We explore mitochondrial proteases function as context-dependent regulators of immunometabolic signaling, with effects shaped by cell type, metabolic state, and stress conditions. Finally, we discuss emerging small molecules and drugs targeting mitochondrial proteases to highlight their potential therapeutic role in modulating inflammation. By situating mitochondrial proteases at the crossroads of immunometabolism and therapeutic intervention, this review underscores their untapped potential in the development of innovative anti-inflammatory strategies.
    Keywords:  MAVS; cGAS-STING; immune cells; inflammatory disease; innate immunity; macrophages; mitochondrial dysfunction; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2026.1761658
  57. Osteoarthritis Cartilage. 2026 Jul 07. pii: S1063-4584(26)00955-6. [Epub ahead of print]
    SMSC-EVs restore chondrocyte function through S1PR1-mTORC2-mediated mitochondrial fusion and GPS2-HDAC1-driven epigenetic regulation.
    Zijian Guo, Xingjia Mao, Zehua Wang, Xiaoke Li, Jingkai Di, Changxin Xiang, Shuai Chen, Zehui Yan, Zui Tian, Panfeng Fu, Zigang Ge, Wenxiang Cheng, Wei Zhang, Jiake Xu, Chuan Xiang.
       OBJECTIVE: In osteoarthritis (OA) treatment, synovial mesenchymal stem cell-derived extracellular vesicles (SMSC-EVs) hold therapeutic potential; however, the mechanisms coordinating mitochondrial and epigenetic repair remain unclear.
    DESIGN: Chondrocyte proliferation, apoptosis and migration were assessed in vitro. Mitochondrial function was evaluated via membrane potential, oxygen consumption, ATP and reactive oxygen species (ROS) levels and network morphology. RNA sequencing and proteomics identified altered pathways. Key molecules (MFN2, S1PR1, GPS2, mTOR components) were investigated using siRNA knockdown. Protein localisation and interactions were examined by immunofluorescence, co-immunoprecipitation and in silico modelling. Efficacy was validated in a monosodium iodoacetate-induced rat OA model.
    RESULTS: SMSC-EVs enhanced chondrocyte proliferation, reduced apoptosis and restored mitochondrial fusion and bioenergetics through activation of the S1P-S1PR1-mTORC2 axis, leading to MFN2 upregulation (mean difference: 0.676 [95% CI: 0.572-0.778]). EV treatment also induced GPS2 nuclear translocation (mean difference: 0.403 for GPS2/lamin B [0.318-0.489]), facilitating interaction with HDAC1 and increased HDAC1 expression (mean difference: 0.474 [0.398-0.552]). In vivo, SMSC-EVs mitigated cartilage degradation and improved functional outcomes, reflected by decreased OARSI scores (mean difference: -9.000 [-10.518 to -7.482]).
    CONCLUSIONS: SMSC-EVs ameliorate OA through coordinated mitochondrial and epigenetic mechanisms, restoring mitochondrial integrity via the S1P-S1PR1-mTORC2-MFN2 pathway and promoting proliferation through GPS2-HDAC1-mediated epigenetic regulation. These findings highlight a synergistic therapeutic strategy targeting mitochondrial-epigenetic dysfunction in OA.
    Keywords:  Epigenetic regulation; Extracellular vesicle; MTORC2 signalling; Mitochondrial fusion; Mitofusin 2; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.joca.2026.06.013
  58. Food Res Int. 2026 Sep 30. pii: S0963-9969(26)01248-2. [Epub ahead of print]240 119565
    WIPButyrate produced by the Lycium ruthenicum polysaccharide alleviated sleep deprivation-induced chronic fatigue syndrome in mice through promoting microglial autophagy.
    Xinyuan Wang, Yijia Zhang, Huihui Wang, Yujuan Chen, Taiqi Qu, Wenrui Zhang, Xintong Wang, Yixuan Li, Yanan Sun.
      This study explored whether Lycium ruthenicum polysaccharide (LRP) influences gut microbiota-derived short-chain fatty acids (SCFAs) and neuroinflammatory responses in a sleep deprivation-induced CFS-like mouse model. Oral LRP was associated with improved fatigue-related behavioral performance, reduced neuronal injury, and better cognitive and motor outcomes. These changes coincided with an increased abundance of putative butyrate-producing bacteria and higher butyrate levels in serum and brain. To examine a possible downstream link, sodium butyrate was tested in cultured microglia and attenuated inflammatory activation while improving mitochondrial stress and autophagy-related readouts. Overall, the data suggest that microbiota-associated butyrate changes may contribute to the observed benefits of LRP, supporting its potential as a food-derived strategy for fatigue-related neuroinflammation.
    Keywords:  Butyrate; CFS; LRP; Microglia; Mitophagy
    DOI:  https://doi.org/10.1016/j.foodres.2026.119565
  59. Front Aging. 2026 ;7 1830839
    Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
    Nengneng Shi, Xiaojing Li.
      Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology. However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts. In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.
    Keywords:  age-related disease; aging; inflammation; mitochondria; mitochondrial transcription factor A; oxidative stress
    DOI:  https://doi.org/10.3389/fragi.2026.1830839
  60. CNS Neurosci Ther. 2026 Jul;32(7): e71013
    Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.
    Zou Pan, Li Yang, Haiyan Tang, Chen Chen, Qian Yang, Tenghui Wu, Fang He, Zhanwei Zhang, Fangyun Liu, Jing Peng.
       AIM: To delineate the clinical features of AFG3L2-related developmental and epileptic encephalopathy (DEE) and explore its pathogenic mechanisms.
    METHODS: Whole-genome and blood transcriptome sequencing were performed in undiagnosed DEE patients. Patient-derived skin fibroblasts were established for the analysis of RNA and protein expression as well as for mitochondrial functional assays, including OPA1 processing, mtDNA copy number, membrane potential, ATP production, mitochondrial morphology analysis, and mitochondrial stress testing. Additionally, published AFG3L2-related epilepsy cases were systematically reviewed.
    RESULTS: We identified four novel AFG3L2 variants in four DEE patients from two unrelated families, including splice-site/intronic variants in one family and exon-deletion/intronic variants in the other, fitting a recessive model of disease. In these patients, plus six additional previously reported DEE patients, symptoms included severe developmental delay, intractable seizures, microcephaly, generalized spasticity, and progressive cerebral atrophy. Transcriptome and fibroblast functional analyses revealed aberrant splicing, reduced AFG3L2 expression, defective OPA1 processing, decreased mtDNA content, impaired membrane potential and ATP production, fragmented mitochondrial networks, and diminished respiratory capacity, supporting a loss-of-function mechanism. Compared with spastic ataxia 5-usually involving null-missense or missense-missense genotypes-DEE predominantly features null-null combinations.
    SIGNIFICANCE: We implicate AFG3L2 as a novel causative gene for DEE, likely through mitochondrial proteostasis failure and bioenergetic compromise, expanding the phenotypic and genotypic spectrum of AFG3L2-related disorders.
    Keywords:   AFG3L2 ; developmental and epileptic encephalopathy; genomic and transcriptomic sequencing; mitochondrial dysfunction; m‐AAA protease
    DOI:  https://doi.org/10.1002/cns.71013
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