bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–03–29
77 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial quality control: a new mechanism for antiviral therapy.
  2. Mitophagy Activation via the YAP/Parkin Pathway Underlies the Neuroprotective Action of Tetramethylpyrazine in Cerebral Ischemia/Reperfusion Injury.
  3. Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease.
  4. Activation of Mitophagy by Kinetin Mitigates Coal-Silica Mixed Dust-Induced Pulmonary Fibrosis via Modulating Macrophage Mitochondrial Function in Mice.
  5. Realgar Transforming Solution as a Novel Arsenic Agent Triggers PINK1/Parkin-Dependent Mitophagy and Apoptosis in the Molm-13 Acute Myeloid Leukemia Cell Line.
  6. Mitochondrial Homeostasis in Diabetic Cardiomyopathy: From Dysfunction to Therapeutic Strategies.
  7. Effect of (-)-Epicatechin on Mitochondrial Homeostasis in Skeletal Muscle of Female Obese Rats.
  8. CAP1 deficiency protects podocytes in diabetic kidney disease by reducing mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial fission.
  9. Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
  10. STOML2 Knockdown Amplifies PINK1/Parkin-Dependent Mitophagy in Colorectal Cancer.
  11. Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
  12. Metformin Attenuates Osteoarthritis Progression by Modulating Mitochondrial Dynamics via Activation of the AMPK/Drp1 Pathway.
  13. c/EBPβ-driven Uchl3-mediated deubiquitination of TRPV1 promotes neuropathic pain by inducing mitochondrial fission in male rats.
  14. The ATF3-DRP1 Axis Coordinates Mitochondrial Homeostasis and Suppresses Early Apoptosis in Zinc-Deficient Cardiomyocytes.
  15. Age-Dependent Decline in Plasmalogen Biosynthesis Impairs Stress-Induced Mitochondrial Fission in Drosophila.
  16. ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertension.
  17. Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.
  18. Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease.
  19. Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism.
  20. Cell biology: Killing the prisoner escaping from mitochondria.
  21. GDF11 activates AMPK-dependent mitophagy to drive osteogenic differentiation of rat bone marrow mesenchymal stem cells.
  22. Melatonin Ameliorates decaBDE-Induced Autism-Relevant Behaviors Through Promoting SIRT1/SIRT3/FOXO3a-Dependent Mitochondrial Quality Control.
  23. Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.
  24. Agomelatine Alleviates Depressive-Like Behaviors in Mice by Promoting Mitophagy in Parvalbumin-Expressing Neurons of the Hippocampal Ventral Dentate Gyrus.
  25. The Effect of Mechanical Loading on Mitophagy in Aged Myoblasts.
  26. Mitochondrial fusion induced by Mdivi-1 and leflunomide alters cell proliferation and viability, steroidogenesis and oxidative stress in chicken ovarian cells.
  27. Mitochondrial stress as a conceptual interface between bacterial infection and post-infectious metabolic disease.
  28. Microsporidian Encephalitozoon hellem inhibits host mitophagy by inducing ERAD to degrade BNIP3L.
  29. Disruption of Mitophagy-Related Gene Expression in Gestational Diabetes Mellitus: A Transcriptomic and Machine Learning Approach.
  30. Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
  31. Activation of mitophagy via miR-223/NLRP3 axis ameliorates dopaminergic neuronal damage in parkinson's disease.
  32. CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.
  33. Astaxanthin protects heart mitochondria from damage caused by chronic alcohol intoxication.
  34. Dual-Targeting Cuproptosis and Mitophagy via a Flavopiridol-Copper Nanoplatform Potentiates Immunotherapy Against Uveal Melanoma.
  35. Trihexyl phosphate exposure disrupts mitophagy and activates mtDNA-cGAS-STING signaling to drive pyroptosis and steroidogenic impairment in Leydig cells.
  36. Macrophage SH3 domain‑containing GRB2‑like protein B1 is required for Rab7‑mediated mitophagy in inflammation during sea water drowning acute lung injury.
  37. Dimeric PKM2 in chondrocytes impairs mitochondrial homeostasis in osteoarthritis.
  38. PM10 Disrupts Mitochondrial Homeostasis in Corneal Epithelial Cells: Protective Effects of SKQ1.
  39. SIRT1 activation restores PINK1-dependent mitophagy to reverse airway barrier dysfunction in Acinetobacter baumannii infection.
  40. Yixinjiedu Formula Attenuates Pressure Overload-Induced Cardiac Dysfunction by Suppressing Ferroptosis and Restoring Mitophagy via the PINK1/Parkin Axis.
  41. Spermine Ameliorates DSS-Induced Ulcerative Colitis in Mice by Improving Mitophagy and Intestinal Microbiota.
  42. SOCS3 suppresses glioblastoma growth via JAK-STAT inhibition and mitochondrial unfolded protein response activation.
  43. SHED-derived exosomes ameliorate age-related osteoporosis by activating mitophagy in senescent bone marrow mesenchymal stem cells.
  44. Mitochondrial Dynamic Proteins MiD49 and MiD51 as Novel Targets of Cardioprotection.
  45. AP39 alleviates HHCY-induced myocardial remodeling by regulating FUNDC1-mediated mitochondrial dynamics via S-sulfhydration of NEDD8/CUL4B.
  46. Lutein attenuates sodium fluoride (NaF) and gamma-irradiation induced hepatotoxicity via AMPK-PGC1α mitochondrial biogenesis induction.
  47. [Akt/SIRT3-dependent mitochondrial autophagy inhibits apoptosis of alveolar epithelial cells and alleviates hyperoxia-induced acute lung injury].
  48. NCBP2 Regulates PGAM5-Mediated Mitophagy Via KIF23 Alternative Splicing To Promote Cervical Cancer ProgressionRun Title: NCBP2 Promotes Cervical Cancer Via Mitophagy.
  49. Quercetin targets the TNF-a/TNF pathway to activate mitochondrial autophagy to improve nucleus pulposus cell function and delay disc degeneration.
  50. Efficacy and Mechanisms of Duhuo Jisheng Decoction in Treating Intervertebral Disc Degeneration: A Network Pharmacology and Experimental Study.
  51. Silicon carbide nanoparticles induce pulmonary fibrosis by promoting macrophage apoptosis through parkin-mediated mitophagy disruption and the intervention effect of emodin.
  52. Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila.
  53. MAP2K6 directly phosphorylates BCL2L13 to mediate mitophagy for suppressing tumorigenicity.
  54. Mitochondrial perspectives on environmental pollutant-induced male reproductive toxicity.
  55. Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
  56. HIF-1α suppresses SNPH expression to facilitate liver metastasis of colorectal cancer through regulating mitochondrial dynamics and filopodia formation.
  57. MSC-derived exosomes ameliorate systemic lupus erythematosus by reprogramming macrophage mitochondrial homeostasis via the CMPK2-cGAS-STING axis.
  58. Mediterranean diet preserves renal mitochondrial homeostasis and attenuates early diabetic kidney injury in db/db mice.
  59. Nature's Bioactives in Cardiorenal Syndrome: Polyphenols at the Crossroads-Preclinical Insights into Redox, Inflammation, and Mitochondrial Protection.
  60. Metformin attenuates HSV-1-induced neuropathic pain by restoring Sirt3-mediated mitophagy.
  61. Abolishing PorB-induced mitophagy enhances gonococcal outer membrane vesicle vaccine efficacy.
  62. Correction: Chen et al. Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics. J. Clin. Med. 2022, 11, 135.
  63. Mitochondrial Ultrastructure, Fission Proteins, Activity, and Motor Dysfunctions in the Innovative Parkinson's Disease Model Induced by Manganese Inhalation.
  64. MFN2-PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs.
  65. The SDF-1α/CXCR4 axis regulates chondrocyte mitochondrial dynamics via the ERK/AMPKα pathway.
  66. ROS-triggered smart nanoplatform promotes osteoarthritis repair by modulating macrophage polarization and mitochondrial homeostasis.
  67. Subcellular photoprotection through precision nutraceuticals: Divergent actions of rutin and punicalagin on redox and mitochondrial homeostasis in human dermal fibroblasts.
  68. Frequency and Hearing Loss Phenotypes of OPA1 Variants in a Cohort of 18,475 Patients with Hearing Impairment.
  69. Identification and Validation of MTFP1 as a Mitochondrial Target Restoring Dynamics and ECM Remodeling in Acute Myocardial Infarction.
  70. Antagonistic effects of selenium on methylmercury-induced toxicity through mitochondrial quality control and enhanced GSH synthesis in Caenorhabditis elegans.
  71. Corrigendum to "DPEP1 mediates regulation of mitochondrial quality control via FOXO1/ALDH1L2 axis to attenuate ferroptosis in pulmonary endothelial cells to alleviate sepsis-associated acute lung injury" [Int. Immunopharmacol. 170 (2026) 116049].
  72. Mitochondria in situ releasing corosolic acid enhanced antitumor effects via activating mitophagy in castration-resistant prostate cancer.
  73. Urolithin A From Gut Metabolite to Therapeutic Agent: Bioavailability, Mechanisms, and Translational Insights.
  74. Self-assembly of glycyrrhizic acid and aconitine alleviates heart failure by inhibiting autophagy and inducing reprogramming of energy metabolism.
  75. Inhalable PD-L1-engineered hybrid cellular vesicles suppress excessive neutrophil activation and restore mitochondrial homeostasis to alleviate ischemia-reperfusion lung injury and pneumonia.
  76. A Ginkgo biloba-derived tRNA-derived fragment attenuates asthma by restoring airway structural cell homeostasis via mitochondrial regulation.
  77. 5'tiRNA-32-LysCTT-11 Alleviates Sepsis-Induced Myocardial Injury by stabilizing Mfn2 and inhibiting mitochondrial dysfunction-mediated necroptosis.
  1. Front Immunol. 2026 ;17 1798516
    Mitochondrial quality control: a new mechanism for antiviral therapy.
    Xujie Duan, Wenjing Lan, Rui Liu, Pei Zhang, Sixu Chen, Yufei Zhang, Liang Zhang, Huiping Li, Shuying Liu.
      Mitochondria are highly dynamic organelles involved in energy production, metabolic regulation, calcium homeostasis, apoptosis, and innate immunity. The mitochondrial network is susceptible to damage from physiological and environmental factors, including viral infections. Mitochondrial quality control (MQC) is the primary pathway that maintains normal physiological functions and mitochondrial homeostasis. Mitochondrial dynamics and mitophagy are complex processes within the MQC mechanism that can be exploited by viruses to modulate mitochondrial morphology, metabolism, and innate immune responses, achieving immune evasion, promoting self-replication, and accelerating infection. Viruses or their proteins target mitochondrial dynamics or mitophagy and regulate these processes via direct or indirect mechanisms. In addition, numerous molecular modulators of MQC have been reported. These findings provide new opportunities to understand the MQC process and have the potential for use as antiviral therapeutic agents. This article reviews the relationships between MQC, viral infection events, and viral pathogenesis, introduces the known molecular pharmacological regulators of MQC, and emphasizes their importance in antiviral drug development.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy; viral infection
    DOI:  https://doi.org/10.3389/fimmu.2026.1798516
  2. Biomolecules. 2026 Mar 13. pii: 429. [Epub ahead of print]16(3):
    Mitophagy Activation via the YAP/Parkin Pathway Underlies the Neuroprotective Action of Tetramethylpyrazine in Cerebral Ischemia/Reperfusion Injury.
    Lanxi Xu, Meiyu Wang, Yan Feng, Sihan Wang, Yihan Qian, Weiru Jiang, Jiadong Xu, Yan Fang, Yani Zhang, Lisheng Chu.
       BACKGROUND: Mitophagy is a critical mitochondrial quality control mechanism that limits neuronal injury following cerebral ischemia/reperfusion injury (CI/RI). Tetramethylpyrazine (TMP), a bioactive alkaloid from Ligusticum chuanxiong Hort., exhibits neuroprotective effects in cerebrovascular disorders. However, whether these effects involve mitophagy regulation remains unclear.
    METHODS: CI/RI was induced using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in HT22 cells. Neurological function, infarct volume, mitochondrial function, and mitophagy-related markers were assessed. Pharmacological inhibitors and genetic manipulation of YAP and Parkin were used to investigate underlying mechanisms.
    RESULTS: TMP treatment significantly reduced infarct volume and improved neurological deficits in MCAO/R mice, accompanied by enhanced mitophagy, as indicated by increased mitochondrial LC3 recruitment and Parkin expression. In OGD/R-injured HT22 cells, TMP promoted mitophagosome and mitolysosome formation, reduced mitochondrial reactive oxygen species, and restored mitochondrial membrane potential. Inhibition of mitophagy with Mdivi-1 attenuated TMP-mediated neuroprotection. Mechanistically, TMP promoted YAP nuclear localization, and inhibition of YAP or silencing of Parkin abolished TMP-induced mitophagy, while Parkin overexpression restored mitophagy under YAP inhibition.
    CONCLUSIONS: TMP alleviates CI/RI by promoting mitophagy through the YAP/Parkin signaling pathway, suggesting mitophagy modulation as a potential therapeutic strategy for ischemic brain injury.
    Keywords:  YAP/Parkin; cerebral ischemia/reperfusion injury; mitophagy; neuroprotection; tetramethylpyrazine
    DOI:  https://doi.org/10.3390/biom16030429
  3. FASEB J. 2026 Mar 31. 40(6): e71692
    Integrative Insights Into Mitochondrial Dysfunction and Organelle Crosstalk in Diabetic Kidney Disease.
    Wanyu Cao, Guoding Cao, Qingtai Meng, Dingfei Li, Jie Zhang, Tianhui Wu, Fengmin Zhang.
      Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease and is driven in large part by early, sustained mitochondrial dysfunction, which promotes metabolic reprogramming, oxidative stress and inflammation that accelerate glomerular and tubular injury. We review recent mechanistic and translational advances linking mitochondrial dysfunction and organelle crosstalk to DKD progression. We synthesize evidence across four interrelated mitochondrial axes-metabolic reprogramming, altered fission-fusion dynamics, defective mitophagy, and mtDNA release-and highlight mitochondria-ER contacts (MAMs) as a nexus integrating redox signaling and calcium homeostasis. Preclinical studies indicate that interventions restoring mitochondrial biogenesis, rebalancing dynamics, enhancing selective mitophagy and preserving mtDNA attenuate glomerular and tubular injury. Clinically, several approved agents (metformin, SGLT2 inhibitors, finerenone, GLP-1RAs) exert renoprotective effects involving mitochondrial pathways; deconvolution of multi-component formulations, targeted antioxidants, metabolic activators and fission inhibitors expand therapeutic options, while organelle-level approaches such as mitochondrial transplantation are emergent. We propose a translational framework that links redox-centered mitochondrial mechanisms to actionable therapeutic strategies for DKD.
    Keywords:  diabetic kidney disease; metabolism reprogramming; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; mtDNA
    DOI:  https://doi.org/10.1096/fj.202504735R
  4. Antioxid Redox Signal. 2026 Apr;44(10-12): 528-549
    Activation of Mitophagy by Kinetin Mitigates Coal-Silica Mixed Dust-Induced Pulmonary Fibrosis via Modulating Macrophage Mitochondrial Function in Mice.
    Meiyu Chang, Qiang Zhou, Yi Guan, Yingzheng Zhao, Shuhan Guo, Qiufang Qu, Le Liu, Zhiheng Li, Xiangwei Zhao, Hong Cao, Sanqiao Yao.
       AIMS: Coal workers' pneumoconiosis (CWP) is an occupational lung disease caused by the inhalation of coal dust. A key underlying pathogenic mechanism is driven by mitochondrial dysfunction and excessive reactive oxygen species (ROS), which trigger macrophage inflammation and cell death. Damaged mitochondria are selectively degraded via mitophagy, a process essential for maintaining mitochondrial homeostasis and promoting cell survival. However, the role of mitophagy dysregulation in dust-induced mitochondrial dysfunction and the underlying treatment with kinetin remain unclear. This study aimed to explore the role of PINK1/Parkin-mediated mitophagy in coal-silica mixed dust (CSD)-induced mitochondrial damage and to investigate the therapeutic potential of kinetin in targeting this pathway.
    RESULTS: In this study, we compared the effects of CSD exposure and kinetin treatment on mitophagy, mitochondrial function, inflammation, and pulmonary fibrosis. We found that CSD exposure triggered ROS accumulation, mitochondrial membrane potential collapse, and impaired oxidative phosphorylation, leading to reduced adenosine triphosphate synthesis. Mechanistically, CSD suppressed PINK1/Parkin signaling and diminished LC3B mitochondrial recruitment, resulting in defective mitophagy. Notably, kinetin treatment and PINK1 overexpression restored PINK1/Parkin activation and LC3II-dependent mitophagy, alleviated mitochondrial dysfunction, and suppressed subsequent macrophage inflammation and pulmonary fibrosis. Genetic knockdown of PINK1 abolished the protective effects of kinetin, confirming a PINK1-dependent mechanism.
    INNOVATION: Our results revealed that kinetin is a PINK1-dependent mitophagy activator, positioning it as a promising therapeutic candidate for CWP by targeting mitochondrial integrity.
    CONCLUSION: Kinetin exerts its antifibrotic effects on CWP by promoting PINK1-mediated mitophagy, improving mitochondrial function, and alleviating macrophage inflammation. Antioxid. Redox Signal. 44, 528-549.
    Keywords:  coal–silica mixed dust; inflammation; kinetin; mitochondrial function; mitophagy; pulmonary fibrosis
    DOI:  https://doi.org/10.1177/15230864251411565
  5. Biol Trace Elem Res. 2026 Mar 27.
    Realgar Transforming Solution as a Novel Arsenic Agent Triggers PINK1/Parkin-Dependent Mitophagy and Apoptosis in the Molm-13 Acute Myeloid Leukemia Cell Line.
    Teng Wang, Chunyi Lyu, Yunxiao Luo, Weilin Liu, Chen Han, Xinyu Tang, Ruirong Xu.
       BACKGROUND: Acute myeloid leukemia (AML) remains challenging to treat due to frequent relapse and therapeutic resistance. Mitochondrial stress responses and mitophagy have emerged as critical regulators of leukemic cell fate. Realgar Transforming Solution (RTS) is a highly soluble arsenic preparation bioleached from realgar via Acidithiobacillus ferrooxidans; however, its impact on mitochondrial quality control in AML is poorly defined.
    METHODS: Human AML cell lines Molm-13 and THP-1, as well as normal human bone marrow stromal cells HS-5, were treated with RTS. Cell viability, apoptosis, oxidative stress, mitochondrial membrane potential, and mitophagy were assessed using CCK-8 assays, Annexin V-FITC/PI flow cytometry, DCFH-DA and JC-1 staining, Western blotting, RT-qPCR, monodansylcadaverine staining, immunofluorescence, and transmission electron microscopy. Mitophagy involvement was evaluated using the Drp1/mitophagy inhibitor Mdivi-1, while mitochondrial ROS contribution was examined using the mitochondrial-targeted antioxidant mitoTEMPO.
    RESULTS: After 24 h treatment, RTS selectively reduced viability and induced apoptosis in Molm-13 and THP-1 cells, while HS-5 cells were less sensitive. RTS provoked mitochondrial ROS accumulation, MMP loss, Bax/Cyt-c upregulation and Bcl-2 downregulation. Concomitantly, markers of PINK1/Parkin-dependent mitophagy (characterized by increased LC3-II/LC3-I ratio, PINK1/Parkin upregulation, and p62 degradation), increased MDC/TEM autophagic structures, and mitochondrial ultrastructural damage were observed. Pharmacologic inhibition with Mdivi-1 or mitochondrial ROS scavenging with mitoTEMPO significantly attenuated RTS-induced ROS, mitophagy activation, mitochondrial dysfunction and apoptosis.
    CONCLUSION: In vitro, RTS induces mitochondrial ROS-dependent activation of PINK1/Parkin-mediated mitophagy that converges on intrinsic mitochondrial apoptosis in AML cells. These data nominate RTS as a mitochondria-targeting candidate for further preclinical evaluation.
    Keywords:  Acute myeloid leukemia; Apoptosis; Bio-transforming; Mitophagy; Realgar; Realgar transforming solution
    DOI:  https://doi.org/10.1007/s12011-026-05072-y
  6. Antioxidants (Basel). 2026 Mar 22. pii: 399. [Epub ahead of print]15(3):
    Mitochondrial Homeostasis in Diabetic Cardiomyopathy: From Dysfunction to Therapeutic Strategies.
    Yafei Huang, Wenyu Zou, Xindi Jiang, Jing Cheng, Jia Zheng.
      Diabetic cardiomyopathy is a specific form of heart dysfunction that occurs in diabetic patients independent of other cardiomyopathies such as coronary artery disease. It significantly contributes to heart failure and mortality in this population. The pathogenesis of diabetic cardiomyopathy mainly includes oxidative stress, inflammatory response, apoptosis and disrupted mitochondrial homeostasis. Mitochondrial homeostasis, encompassing mitochondrial dynamics, mitochondrial oxidative metabolism and mitophagy, is regulated by a variety of signaling pathways and plays a pivotal role in maintaining the normal function of cardiomyocytes. At present, the exact mechanisms underlying diabetic cardiomyopathy pathogenesis remain unclear, and effective prevention and treatment methods are lacking. This review therefore expounds the pathogenesis of diabetic cardiomyopathy from the perspective of mitochondrial homeostasis, providing new approaches to clinical management.
    Keywords:  diabetic cardiomyopathy; mitochondrial homeostasis; pathogenesis
    DOI:  https://doi.org/10.3390/antiox15030399
  7. Molecules. 2026 Mar 22. pii: 1050. [Epub ahead of print]31(6):
    Effect of (-)-Epicatechin on Mitochondrial Homeostasis in Skeletal Muscle of Female Obese Rats.
    Elena de la C Herrera-Cogco, Socorro Herrera-Meza, Yuridia Martínez-Meza, Javier Pérez-Durán, Guillermo Ceballos, Enrique Méndez-Bolaina, Nayelli Nájera.
       BACKGROUND: Main risk factors associated with the development of sarcopenia (coexistence of muscle mass loss and dysfunction) are a sedentary lifestyle coupled with obesity. Associated mitochondrial dysfunction leads to energy deficits and perturbations in the balance between protein synthesis and degradation, thereby triggering muscle dysfunction or atrophy. Aside from exercise, which is challenging to implement and maintain, particularly in women, treatments for diminishing sarcopenia are scarce. The objective of the present study was to evaluate the effect of the flavanol (-)-epicatechin (EC) in a hypercaloric diet-induced obese female rat model. Muscle strength and endurance, as well as relative mitochondrial DNA content in skeletal muscle, were assessed.
    METHODS: Female rats were fed a hypercaloric diet to induce obesity, as evidenced by increases in body weight, Lee index, and lipid profile alterations, and by abdominal fat accumulation, and to promote a sarcopenic phenotype. Functional tests of grip strength and mobility (treadmill) were performed. Mitochondrial relative content was evaluated by measuring the ratio of mtDNA/nuclear DNA, and the expression of genes related to mitochondrial biogenesis (Pgc1-α, Tfam), fusion (Mfn1 and Opa1), fission (Drp1 and Fis1), and mitophagy (Pink1 and Pkn), and function; citrate synthase and Ucp3 were also evaluated.
    RESULTS: A significant decrease in mobility and strength was observed in obese female rats, accompanied by reduced mitochondrial numbers, activity, and dynamics, but not by changes in muscle size or weight. Treatment with EC induced mitochondrial biogenesis and positive changes in mitochondrial dynamics (fission and fusion) and activity, as measured indirectly by changes in citrate synthase and Ucp3 expression.
    DISCUSSION: Results reinforce the potential of EC as a modulator of mitochondrial function in dysfunctional conditions associated with obesity, thereby attenuating the mechanisms underlying sarcopenia.
    Keywords:  epicatechin; females; obesity; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/molecules31061050
  8. Free Radic Biol Med. 2026 Mar 19. pii: S0891-5849(26)00243-1. [Epub ahead of print]250 116-133
    CAP1 deficiency protects podocytes in diabetic kidney disease by reducing mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial fission.
    Shuang Yao, Zongda Li, Huimin Ma, Xinying Yu, Tingting Hu, Zihan Wang, Rui Zhang, Haihai Liang, Jundong Jiao.
      The mitochondria-associated endoplasmic reticulum membrane (MAM) is crucial for mitochondrial homeostasis. Excessive mitochondrial fission has been recognized as an early pathological event in podocyte injury in diabetic kidney disease (DKD). Cyclase-associated protein 1 (CAP1), an actin-binding protein, has been implicated as a potential regulator of mitochondrial dynamics; however, its role in DKD remains unclear. This study revealed that increased MAM formation is associated with excessive mitochondrial fission in podocytes from DKD patients. Podocyte-specific CAP1 knockdown significantly ameliorated podocyte injury and albuminuria in diabetic mice, with the protective effect attributed to the inhibition of MAM formation and mitochondrial fission. Mechanistically, high glucose triggered the CAP1-induced actin depolymerization, which promoted the enrichment of inverted formin 2 (INF2) from the endoplasmic reticulum (ER) to the MAM. At the MAM interface, the protein interaction between CAP1 and the enriched INF2 was enhanced, thereby exacerbating mitochondrial fission and dysfunction, which ultimately led to podocyte injury. Our findings not only provide the first evidence for the pathogenic role of CAP1 in podocytes during DKD progression, but also elucidate a novel mechanism by which CAP1 modulates mitochondrial fission via the MAM.
    Keywords:  Actin; Cyclase-associated protein 1; Diabetic kidney disease; Mitochondria-associated endoplasmic reticulum membrane; Mitochondrial fission
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.052
  9. Autophagy. 2026 Mar 22. 1-2
    Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
    Julia A Thayer, Derek P Narendra.
      Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
    Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2646238
  10. Biochem Genet. 2026 Mar 27.
    STOML2 Knockdown Amplifies PINK1/Parkin-Dependent Mitophagy in Colorectal Cancer.
    Tingting Cheng, Xin Zhao, Yuelu Ruan.
      
    Keywords:  Colorectal cancer; Invasion; Migration; Mitophagy; PINK1/Parkin; Proliferation; STOML2
    DOI:  https://doi.org/10.1007/s10528-026-11354-w
  11. Cell Death Dis. 2026 Mar 24.
    Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
    Qian Liu, Lei Su, Xiaoyun Wei, Shijie Lin, Lingkai Huang, Lige Hou, Yanhong Wang, Liubing Hu, Junyang Tan, Jing Qiao, Qinghua Zhou, Yi Ma, Wenjun Wang, Jianshuang Li.
      Malic enzyme 2 (ME2), a pivotal enzyme related to the tricarboxylic acid (TCA) cycle, has been implicated in multiple cancers due to its overexpression and metabolic role in regulating the NADP+/NADPH balance. Malic enzyme 2 has been reported to regulate mitochondrial biogenesis and fusion; however, whether malic enzyme 2 participates in mitophagy regulation has remained unclear. Here, we reported that malic enzyme 2 depletion enhances PINK1-Parkin-mediated mitophagy. Mechanistically, ME2 competes with the E3 ubiquitin ligase TRIM25, disrupting its binding with ATPase family AAA domain-containing protein 3 A (ATAD3A), a mitochondrial protein crucial for the degradation of PINK1. Loss of malic enzyme 2 strengthens the TRIM25-ATAD3A interaction, resulting in ATAD3A ubiquitination and proteasomal degradation. The consequent PINK1 accumulation drives mitophagy activation. Hyperactivated mitophagy caused by malic enzyme 2 knockdown disrupts mitochondrial homeostasis, which suppresses the proliferative capacity of hepatoma cells. Moreover, pharmacological inhibition of mitophagy partially rescued the suppressed cell proliferation in the malic enzyme 2-knockdown cells. Our findings reveal a previously unrecognized role of malic enzyme 2 in mitochondrial quality control and highlight the ME2-ATAD3A-PINK1 axis as a potential regulatory node for mitophagy modulation.
    DOI:  https://doi.org/10.1038/s41419-026-08623-2
  12. J Inflamm Res. 2026 ;19 540176
    Metformin Attenuates Osteoarthritis Progression by Modulating Mitochondrial Dynamics via Activation of the AMPK/Drp1 Pathway.
    Yaji Yang, Haotian Zhou, Jianye Yang, Feilong Li, Qianshui Hu, Ying Jia, Wei Huang, Leilei Qin, Yu Zhou.
       Background: Osteoarthritis (OA) is a chronic degenerative disease primarily characterized by articular cartilage degradation and chondrocyte dysfunction. Mitochondrial impairment and oxidative stress in chondrocytes are pivotal contributors to OA pathogenesis. Emerging evidence suggests that metformin, beyond its role in glucose regulation, exhibits antioxidative and anti-inflammatory properties via activation of AMP-activated protein kinase (AMPK). Nonetheless, how metformin regulates mitochondrial dynamics and autophagy in OA remains to be fully elucidated.
    Methods: A mouse anterior cruciate ligament transection (ACLT) model and an IL-1β-induced oxidative stress model in human chondrocytes were established. Following metformin administration, a comprehensive assessment was conducted using histological staining, immunohistochemistry, Western blotting, flow cytometry, confocal microscopy, and AMPK siRNA transfection to evaluate the effects of metformin on mitochondrial function, autophagic activity, and oxidative stress in chondrocytes.
    Results: Metformin markedly improved articular cartilage architecture in ACLT mice and enhanced the stability of the cartilage matrix. It activated AMPK signaling in chondrocytes while suppressing Dynamin-related protein 1 (Drp1) phosphorylation at Ser637, thereby promoting mitochondrial fission and mitophagy. By reducing reactive oxygen species accumulation, restoring mitochondrial membrane potential, and inhibiting NOD-like receptor thermal protein domain associated protein 3 inflammasome activation, metformin effectively mitigated oxidative stress in chondrocytes. AMPK siRNA experiments further demonstrated that the AMPK/Drp1 axis is pivotal for metformin-induced mitochondrial protection and promotion of chondrocyte proliferation.
    Conclusion: This study demonstrates that metformin delays osteoarthritis progression by activating the AMPK/Drp1 pathway to modulate mitochondrial fission and mitophagy, attenuate oxidative stress, and restore chondrocyte function. These findings provide novel mechanistic insight into the therapeutic potential of metformin in osteoarthritis and highlight mitochondrial dynamics as a promising target for future OA interventions.
    Keywords:  AMPK; Drp1; metformin; mitochondrial fission; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.2147/JIR.S540176
  13. Neuropharmacology. 2026 Mar 20. pii: S0028-3908(26)00112-7. [Epub ahead of print]292 110939
    c/EBPβ-driven Uchl3-mediated deubiquitination of TRPV1 promotes neuropathic pain by inducing mitochondrial fission in male rats.
    Ziyun Qiang, Dongxue Sun, Qian Lei, Ruowei Guan, Jinchi Cai, Dongxu Wang, Bo Fang.
      This study investigates the mechanism of the TRPV1 channel in neuropathic pain (NP), focusing on the c/EBPβ/Uchl3/TRPV1 axis and mitochondrial dynamics. Using male rats chronic constriction injury (CCI) model and an LPS-induced dorsal root ganglion (DRG) cell model, we measured paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), assessed expression changes of related molecules via Real-time quantitative reverse transcription PCR (RT-qPCR) and Western blot, observed mitochondrial fission via transmission electron microscopy (TEM) and Tomm20 immunofluorescence, evaluated mitochondrial function via JC-1 and MitoSOX, and examined neuronal excitability via calcium imaging. Co-immunoprecipitation (Co-IP) confirmed Uchl3-TRPV1 binding, and ubiquitination assay combined with Cycloheximide (CHX) chase and proteasome inhibition assays demonstrated that Uchl3 inhibits TRPV1 degradation via deubiquitination. Luciferase and Chromatin immunoprecipitation (ChIP) assays verified c/EBPβ as a transcriptional activator of Uchl3. Results showed that TRPV1 activation promoted mitochondrial fission, dysfunction, and neuronal excitability, driving NP. Uchl3 stabilized TRPV1 by removing its ubiquitination, altering mitochondrial dynamics. c/EBPβ transcriptionally upregulated Uchl3, forming a regulatory cascade. Intrathecal si-c/EBPβ in CCI rats downregulated c/EBPβ, Uchl3, and TRPV1, restored mitochondrial homeostasis, and alleviated pain behavior. In conclusion, the c/EBPβ/Uchl3/TRPV1 pathway regulates NP through mitochondrial dynamics in male rats, presenting a novel therapeutic target for NP treatment.
    Keywords:  Deubiquitination; Mitochondrial dynamics; Neuropathic pain; TRPV1; c/EBPβ
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110939
  14. Biol Trace Elem Res. 2026 Mar 26.
    The ATF3-DRP1 Axis Coordinates Mitochondrial Homeostasis and Suppresses Early Apoptosis in Zinc-Deficient Cardiomyocytes.
    Zhaoyuan Wu, Ziwei Guo, Meng Liu, Wei Liu, Rukun Ou, Juan Wang, Chao Wu, Quangen Ma, Jin Ma, Heng Tang, Kaiquan Chen.
      
    Keywords:  Activating transcription factor 3 (ATF3); Cardiomyocyte apoptosis; Dynamin-related protein 1 (DRP1); Mitochondrial fission; NF-κB signaling; Zinc deficiency
    DOI:  https://doi.org/10.1007/s12011-026-05080-y
  15. Exp Cell Res. 2026 Mar 20. pii: S0014-4827(26)00091-1. [Epub ahead of print] 114974
    Age-Dependent Decline in Plasmalogen Biosynthesis Impairs Stress-Induced Mitochondrial Fission in Drosophila.
    Ankur Kumar, Anurag Das, Tracey Stewart, Fong-Fu Hsu, Ping Kang, Hua Bai.
      Mitochondrial dynamics, maintained by balanced fission and fusion, are essential for organelle quality control and cellular homeostasis, yet this process becomes disrupted during aging. The upstream cues underlying age-associated fission defects remain poorly defined. Here, using Drosophila oenocytes (hepatocyte-like cells), we show that aging drives progressive mitochondrial enlargement and morphological abnormalities. Live-cell imaging analysis demonstrated that young oenocytes rapidly undergo mitochondrial fission in response to paraquat-induced oxidative stress, whereas aged oenocytes fail to fragment, resulting in persistently enlarged mitochondria. This age-dependent fission defect correlates with a marked decline in mitochondrial plasmalogen levels, a class of ether phospholipids enriched in mitochondrial membranes. In addition, genetic disruption of plasmalogen biosynthesis using a hypomorphic mutation in the plasmanylethanolamine desaturase Kua (TMEM189) recapitulated the aging phenotype. These findings establish that an age-dependent decline in plasmalogen biosynthesis impairs mitochondrial fission, leading to persistent mitochondrial enlargement. Thus, loss of plasmalogen-dependent membrane dynamics represents a novel mechanism driving mitochondrial dysfunction during aging in metabolic tissues.
    Keywords:  Aging; Drosophila oenocytes; Drp1; Mitochondrial fission; Plasmalogens
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114974
  16. Commun Biol. 2026 Mar 27.
    ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertension.
    Liu Yi, Wenming He, Changqing He, Xianbao Shi, Xiaodong Deng, Jinyu Chang, Jie Ni, Li Liu, Lina Shan.
      Pulmonary hypertension (PH) is a life-threatening disorder characterized by progressive pulmonary vascular remodeling, occlusive arteriopathy, and right ventricular failure. However, the molecular mechanisms underlying these pathological hallmarks remain elusive. This study aimed to introduce aldolase B (ALDOB)-K87 lactylation as a critical regulator of mitochondrial fission and metabolic reprogramming in PH pathogenesis. Integrated lactylomic profiling in hypoxic human pulmonary artery smooth muscle cells (PASMCs) and validation in rodent PH models revealed that hypoxia-induced ALDOB-K87 lactylation amplified glycolytic flux, fostering lactate accumulation and self-reinforcing lactylation. Mechanistically, ALDOB lactylation recruited dynamin-related protein 1 (DRP1) to mitochondria via sentrin/SUMO-specific peptidase 3-mediated deSUMOylation of DRP1. This facilitated mitochondrial fragmentation, exacerbating PASMC proliferation, migration, and phenotypic switching. Sirtuin 1 serves as a delactylase for ALDOB, and its downregulation in PH sustains lactylation-driven pathology. Genetic or pharmacological suppression of ALDOB lactylation attenuates mitochondrial fission and PH progression in vivo, whereas lactylation-mimetic mutants exacerbate disease phenotypes. This study unveiled a lactate-ALDOB-DRP1 axis that bridged metabolic rewiring with mitochondrial dynamics, offering novel therapeutic targets for PH.
    DOI:  https://doi.org/10.1038/s42003-026-09934-y
  17. Cells. 2026 Mar 13. pii: 517. [Epub ahead of print]15(6):
    Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.
    Yusra Zarlashat, Anna Picca.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC.
    Keywords:  T-cell exhaustion; immune evasion; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15060517
  18. Int J Mol Sci. 2026 Mar 12. pii: 2599. [Epub ahead of print]27(6):
    Restoring Mitochondrial Homeostasis: Therapeutic Strategies for Metabolic Dysfunction-Associated Fatty Liver Disease.
    José S Morgado, Ivo F Machado, Anabela P Rolo, Carlos M Palmeira.
      Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disorder worldwide, driven by metabolic dysfunction, excessive lipid accumulation, and progressive hepatocellular injury. A growing body of evidence identifies mitochondrial impairment as a central contributor to MAFLD pathogenesis and disease progression. Reduced oxidative capacity, elevated reactive oxygen species, and accumulation of dysfunctional mitochondria collectively exacerbate steatosis, inflammation, and metabolic inflexibility. In recent years, therapeutic strategies aimed at restoring mitochondrial homeostasis have gained considerable attention, with particular focus on agents capable of inducing mitochondrial biogenesis through pathways involving PGC-1α, AMPK, SIRT1, and mTOR. This review synthesizes current knowledge on mitochondrial dysfunction in MAFLD and highlights emerging compounds that ameliorate disease phenotypes by enhancing mitochondrial biogenesis. By examining their mechanisms of action and preclinical efficacy, we underscore the therapeutic potential of targeting mitochondrial quality-control pathways, mainly mitochondrial biogenesis, as a promising avenue for mitigating MAFLD progression.
    Keywords:  MAFLD; biogenesis; dynamics; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms27062599
  19. Cells. 2026 Mar 12. pii: 505. [Epub ahead of print]15(6):
    Heart-Specific and Conditional Deletion of the Immt Gene Reveals Its Role in Regulating Mitochondrial Structure and Total Heart Metabolism.
    Yasuhide Kuwabara, Caitlin Keezer, Suh-Chin J Lin, Akanksha Rajput, Jeffery D Molkentin.
      Mitochondria comprise ~1/3rd of the volume of an adult ventricular cardiomyocyte. The gene Immt encodes the Mic60/Mitofilin protein that is hypothesized to organize the mitochondrial contact site and cristae organization system (MICOS) complex that generates mitochondrial cristae junctions between the inner and outer membranes. To investigate the function of the Immt gene in the mouse heart, we generated and characterized mice in which this gene was specifically deleted in the mouse heart using a loxP-targeted allele (Immtfl/fl) and either the constitutive heart-specific Myh6-Cre transgene or the conditional Myh6-MerCreMer transgene, each of which showed lethality in several weeks. Hearts from these mice showed progressive hypertrophic cardiomyopathy and failure with lost contractility and lung edema. At the ultrastructural level, hearts from these mice showed extreme abnormalities in mitochondrial architecture characterized by lost cristae junctions, stacking of the inner mitochondrial membranes, mitophagy and areas with complete absence of mitochondria. Analysis of mitochondria showed loss of the MICOS complex of proteins as well as loss of mitochondrial membrane potential (Δψ) and increased expression of mitophagy proteins and mitochondrial biogenesis transcription factors. Hearts from these mice also showed widespread cardiomyocyte necrosis and induction of the universal mitochondrial stress response at the mRNA level, as well as major alterations in cardiac metabolites, suggesting greater use of glucose, ketones and amino acids. We conclude that the Immt gene is required for cardiac mitochondrial structure and function, although the ensuing mitochondrial stress response provides molecular clues as to how the heart can compensate metabolically and maintain viability for weeks after mitochondria are absent or unfunctional.
    Keywords:  cardiac hypertrophy; cardiomyocyte; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/cells15060505
  20. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00166-1. [Epub ahead of print]36(6): R259-R261
    Cell biology: Killing the prisoner escaping from mitochondria.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria contain their own DNA (mtDNA), which can be released via multiple routes and cause inflammation and disease. A recent study revealed the unexpected role of a mitochondrial nuclease, present in the intermembrane space, in preventing mtDNA escape via mitophagy.
    DOI:  https://doi.org/10.1016/j.cub.2026.02.016
  21. Am J Stem Cells. 2026 ;15(1): 1-12
    GDF11 activates AMPK-dependent mitophagy to drive osteogenic differentiation of rat bone marrow mesenchymal stem cells.
    Xinfeng Gao, Qiting He, Junjun Chen, Gen Wu, Shaoqiang Xia, Shuaiwei Shang, Linghang Xue, Xinqiang Bei, Kai Xiao.
       BACKGROUND: Growth differentiation factor 11 (GDF11) has emerged as a potential regulator of bone regeneration; however, the molecular mechanisms through which it influences osteogenic differentiation, particularly in relation to mitochondrial quality control, remain unclear. This study aimed to elucidate the role of adenosine monophosphate-activated protein kinase (AMPK)-dependent mitophagy in GDF11-mediated osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMMSCs).
    METHODS: rBMMSCs were induced toward osteogenic differentiation with or without GDF11 treatment. To specifically inhibit AMPK-dependent mitophagy, Compound C, an AMPK inhibitor, was employed. Osteogenic differentiation was evaluated using alkaline phosphatase (ALP) staining and activity assays, while Alizarin Red S (ARS) staining was performed to assess matrix mineralization. The expression of Mitophagy- and osteogenesis-associated markers was analyzed through immunofluorescence staining, quantitative real-time PCR, and western blotting.
    RESULTS: GDF11 significantly enhanced the osteogenic differentiation of rBMMSCs, as evidenced by increased ALP activity, more intense ALP staining, enhanced calcium nodule formation, and elevated expression of ALP and RUNX2. GDF11 activated mitochondrial function by promoting AMPK phosphorylation and inducing Mitophagy. Inhibition of AMPK significantly impaired Mitophagy, while Compound C-mediated blockade of AMPK-dependent mitophagy not only suppressed basal osteogenic differentiation but also abolished the pro-osteogenic effects of GDF11. This was reflected by a pronounced reduction in GDF11-induced ALP activity, mineralization, and the expression of key osteogenic genes at both the mRNA and protein levels.
    CONCLUSION: GDF11 enhances the osteogenic differentiation of rBMMSCs by activating AMPK-dependent mitophagy. These findings identify AMPK-dependent Mitophagy as a pivotal mechanism mediating the osteogenic actions of GDF11, providing new mechanistic insights that may guide the development of novel strategies for bone regeneration.
    Keywords:  AMPK; Growth differentiation factor 11; bone marrow mesenchymal stem cells; mitophagy; osteogenic differentiation
    DOI:  https://doi.org/10.62347/RLSG3699
  22. Antioxidants (Basel). 2026 Mar 23. pii: 405. [Epub ahead of print]15(3):
    Melatonin Ameliorates decaBDE-Induced Autism-Relevant Behaviors Through Promoting SIRT1/SIRT3/FOXO3a-Dependent Mitochondrial Quality Control.
    Lu Gao, Jinghua Shen, Jingjing Gao, Tian Li, Dongying Yan, Xinning Zeng, Jia Meng, Hong Li, Dawei Chen, Jie Wu.
      The etiology of autism spectrum disorder (ASD) implicates genetic predispositions and environmental chemicals, such as polybrominated diphenyl ethers (PBDEs). We aimed to identify whether mitochondrial quality control (MQC) was involved in ASD-relevant behavioral changes induced by decabromodiphenyl ether (deca-BDE, BDE-209) and the alleviation by melatonin. Pregnant rats exposed to BDE-209 (50 mg/kg i.g.) were administrated melatonin through drinking water (0.2 mg/mL) during gestation and lactation. Behavioral assessments integrated open-field test, three-chamber social test, and Morris water maze; mitochondrial detections took transmission electron microscopy, immunofluorescence, and homeostasis together; hippocampal molecular network was identified through transcriptomics profiles, combining dendritic morphology analysis after Golgi-Cox staining. Melatonin supplementation attenuated BDE-209-reduced social and cognitive ability, accompanied by improvements in hippocampal synaptic plasticity (dendritic spines, PSD95, SNAP25). Mitochondrial dysfunctions, shown as decreases in complex IV activity, ATP content, and mtDNA copies, plus redox imbalance (ROS/SOD2) and resultant mitochondrial membrane potential disruption and apoptosis, together with fusion/fission dynamic (MFN2/DRP1), biogenesis (SIRT1-PGC1α-TFAM), and mitophagy (SIRT3-FOXO3-PINK1) suppression, were reversed by melatonin partially through SIRT1 (Sirtuin-1)-dependent pathways, as these protections were abolished by inhibitor EX527. This study highlighted the SIRT1-SIRT3 axis in MQC and behavioral effects, providing novel intervention for PBDEs' neurodevelopmental impairment.
    Keywords:  autism spectrum disorder; decabromodiphenyl ether; melatonin; mitochondrial quality control; sirtuins
    DOI:  https://doi.org/10.3390/antiox15030405
  23. Front Cell Dev Biol. 2026 ;14 1761278
    Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.
    Qing Chen, Yu-Lun Chang, Miao-Wen Hung, Po-Lin Lee, Chen Hsin, Yi-Fan Lin.
       Introduction: The decline of mitochondrial homeostasis and proteostasis, the two key cell quality control mechanisms, is the hallmark of aging and age-related diseases. One of the most notable examples is the age-related progressive loss of muscle mass, quality, and strength --a condition known as sarcopenia. In atrophic muscle, mitochondrial dysfunction and proteostasis impairment frequently occur together, indicating a potential association between the decline of mitochondrial homeostasis and proteostasis. However, the mechanism by which these two modes of cell quality control are coordinated remains poorly understood.
    Methods: We employed dexamethasone-induced muscle atrophy models in both larval and adult zebrafish to investigate the role of cell stress responses in muscle maintenance. Mitochondrial stress was assessed by measuring the mitochondrial unfolded protein response (UPRmt) activity using qRT-PCR and reporter analyses. Proteostasis impairment was evaluated by detecting insoluble polyubiquitinated protein aggregates via Western blotting. Muscle integrity was examined histologically in larval and adult tissues. We performed these assays in sirt1 loss of function conditions (genetic mutation and pharmacological inhibition). Furthermore, to elucidate the mechanism by which Sirt1 regulates proteostasis and muscle preservation, we inhibited the mitochondrial fatty acid oxidation (mFAO) using etomoxir.
    Results: Inhibition of Sirt1 markedly exacerbated muscle deterioration and proteostasis impairment under dexamethasone-induced muscle atrophy in zebrafish. Mechanistically, Sirt1 is required for activation of the UPRmt, which in turn promotes expression of the mFAO gene cpt1b. Pharmacological inhibition of Cpt1 using etomoxir phenocopied the defects in muscle integrity and proteotoxic stress observed following Sirt1 inhibition. Importantly, enhancement of proteostasis via hormetic heat shock partially rescued the etomoxir-induced muscle defects.
    Discussion: We have demonstrated that muscle atrophic stress induced by dexamethasone treatment activates the UPRmt in zebrafish. The UPRmt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Notably, suppressing the UPRmt via Sirt1 inhibition leads to protein aggregation and the ultimate loss of muscle mass, indicating a link between mitochondrial function and proteostasis. We have further shown that mitochondrial metabolism plays a role in proteostasis regulation, as pharmacological inhibition of the mFAO exacerbates dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking UPRmt signaling to myocellular proteostasis, and highlight the activity of Sirt1, which coordinates these two key cell quality control mechanisms, in muscle preservation during muscle atrophy.
    Keywords:  SIRT1; UPRmt; mitochondrial dysfunction; mitochondrial homeostasis; muscle atrophy; myocellular proteostasis; proteostasis
    DOI:  https://doi.org/10.3389/fcell.2026.1761278
  24. Neuropharmacology. 2026 Mar 24. pii: S0028-3908(26)00118-8. [Epub ahead of print] 110945
    Agomelatine Alleviates Depressive-Like Behaviors in Mice by Promoting Mitophagy in Parvalbumin-Expressing Neurons of the Hippocampal Ventral Dentate Gyrus.
    Suhong Ye, Qiaolu Xu, Ling Bao, Azhar Badry Hussein, Qinglin Lu, Xia Yuan, Nashwa Amin, Marong Fang.
       BACKGROUND: Major depressive disorder (MDD) is highly prevalent, but some patients are refractory to conventional treatments. Mitochondrial dysfunction, impaired mitophagy, and parvalbumin (PV)-expressing hippocampal neuron deficits are linked to MDD pathogenesis, while agomelatine's antidepressant mechanism involving these elements remains unclear.
    AIM: This study aimed to clarify whether agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in PV neurons of the hippocampal ventral dentate gyrus (vDG).
    METHODS: Male C57BL/6J and Pvalb-cre::Ai14 mice underwent chronic unpredictable mild stress (CUMS) for depression modeling. Groups included Control, CUMS, CUMS+Fluoxetine (FLX), CUMS+Agomelatine (AGO), CUMS+AGO+3-Methyladenine (autophagy inhibitor), CUMS+AGO+Rapamycin (an mTORC1 inhibitor that indirectly promotes autophagy in a cell-type-dependent manner), and CUMS with vDG-targeted AAV-Beclin1 overexpression (oeBeclin1)±AGO. Behavioral tests (TST, FST, SPT, OFT, SIT) and molecular/morphological analyses (Western blotting, IF, RT-qPCR, DHE staining, TEM, Golgi staining) were conducted.
    RESULTS: CUMS induced depressive-like behaviors and reduced PV neuron density. AGO's performance is no less effective than FLX. Mechanistically, it upregulated autophagy-related proteins (Beclin1, ATG5, LC3II/I) and downregulated p62. oeBeclin1 synergized with agomelatine to improve mitochondrial morphology, reduce ROS, and inhibit neuroinflammation.
    CONCLUSION: In conclusion, agomelatine alleviates CUMS-induced depressive-like behaviors in mice, which is associated with the promotion of mitophagy in vDG PV neurons of the hippocampus, mitigating mitochondrial damage and neuroinflammation. This uncovers a novel mechanism for its efficacy and highlights targeted mitophagy activation as a promising MDD therapeutic strategy.
    Keywords:  Agomelatine; Ai14 mice; Mitophagy; PV neuron; chronic unpredictable mild stress
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110945
  25. Cells. 2026 Mar 15. pii: 522. [Epub ahead of print]15(6):
    The Effect of Mechanical Loading on Mitophagy in Aged Myoblasts.
    Evangelos Tolis, Eirini Chatzinikita, Athanasios Moustogiannis, Antonios Giannopoulos, Maria Maridaki, Michael Koutsilieris, Anastassios Philippou.
      Background: During aging, skeletal muscle mass constantly diminishes and myogenic potential declines. At the cellular level, a decline in mitochondrial function is a hallmark of the aging process and the deficiency of the mitochondrial network contributes to a progressive reduction in muscle mass. Autophagic clearance of mitochondria through the process of mitophagy is required to remove impaired or damaged mitochondria, while mitophagy is a key regulator of muscle maintenance. Dysfunctional degradation of mitochondria is increasingly associated with aging (mitophaging), while mechanical stimuli have been shown to ameliorate the aging-induced impaired muscle mass and function; however, less is known about the potential effects of mechanical loading on mitophaging. The aim of the present study was to investigate the effect of mechanical stretching on mitophagy in aged myoblasts, in vitro. Methods: Cell senescence was replicated using a multiple cell division model of C2C12 myoblasts. The control and aged cells were cultured on elastic membranes and underwent passive stretching using a mechanical loading protocol of 15% elongation for 12 h at a frequency of 1 Hz. Cell signaling and gene expression responses of mitophagy-associated and myogenic regulatory factors (MRFs) were assessed through immunoblotting and qRT-PCR of the cell lysates derived from stretched and non-stretched control and aged myoblasts. Results: Mitophagy factor AMP-activated protein kinase (AMPK), mitochondrial biogenesis stimulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a), and mitophagy/mitochondrial biogenesis factor Parkin were downregulated in control stretched myoblasts compared to non-stretched cells, while the specific mechanical loading protocol used also reduced the phosphorylation of unc-51-like autophagy-activating kinase 1 (p-ULK1) (p < 0.05), as well as the expression of myogenic factor 5 (Myf5) and myogenic factor 4 (myogenin) (p < 0.001). Interestingly, this mechanical loading resulted in increased PGC-1a and Parkin expression (p < 0.05) and induced the previously undetected BCL2 interacting protein 3-like (BNIP3L/NIX) and AMPK expression and p-ULK1 activation in the aged myoblasts. In addition, mechanical stretching differentially affected the expression of MRFs in aged cells, upregulating the early differentiation factor, Myf5 (p < 0.01), while downregulating the late differentiation factor myogenin (p < 0.001). Conclusions: These findings suggest the beneficial effects of mechanical loading on the impaired mitophagy and early differentiation in aged myoblasts, as indicated by the mitophagy initiation and the promotion of mitochondrial biogenesis in these cells. The mechanical loading-induced downregulation of mitophagy and myogenesis in the control myoblasts might indicate their loading-specific differential responses compared to the aged cells.
    Keywords:  mechanical loading; mitophagy; senescence
    DOI:  https://doi.org/10.3390/cells15060522
  26. Poult Sci. 2026 Mar 21. pii: S0032-5791(26)00479-7. [Epub ahead of print]105(6): 106850
    Mitochondrial fusion induced by Mdivi-1 and leflunomide alters cell proliferation and viability, steroidogenesis and oxidative stress in chicken ovarian cells.
    Noemie Couty, Christelle Rame, Lucille Berthet, Claire Chevaleyre, Christine Péchoux, Pascal Froment, Joelle Dupont.
      Mitochondria are key organelles that regulate energy production, oxidative stress, and steroidogenesis. They are highly dynamic, continuously undergoing fusion and fission. While disruptions in these processes affect follicular development and fertility in mammals, little is known about their role in avian species. This study investigated the expression and functional roles of mitochondrial fusion in hen granulosa and theca cells isolated from dominant (F1) and smaller (F3/F4) follicles. Gene expression analysis revealed that fusion-related genes (MFN1, MFN2, and OMA1) are more highly expressed in theca cells than in granulosa cells. Furthermore, MFN1 and MFN2 levels significantly increase as follicles mature from the F3/F4 to the F1 stage, suggesting that mitochondrial fusion is closely linked to follicular development. To explore the functional impact, cells were treated with Mdivi-1 and leflunomide; both compounds successfully promoted mitochondrial fusion, as evidenced by elongated mitochondrial morphologies. However, their effects on mitochondrial homeostasis differed: leflunomide, but not Mdivi-1, significantly increased fusion gene expression and reduced mitochondrial DNA (mtDNA) copy number (ND4, ND6, ATP6). Inducing mitochondrial hyperfusion generally impaired cell viability and proliferation. High doses of both inhibitors suppressed proliferation across both cell types, molecularly confirmed by the downregulation of the pro-proliferative gene CCND1 and the upregulation of the cell cycle inhibitor P21. Regarding steroidogenesis, mitochondrial fusion exerted cell-specific effects. In granulosa cells, both treatments enhanced progesterone secretion, supported by increased expression of STAR, 3BHSD, and CYP11A1. Conversely, in theca cells, fusion led to decreased testosterone secretion and reduced expression of CYP11A1 and CYP19A1. Finally, while Mdivi-1 did not alter reactive oxygen species (ROS) or ATP levels, leflunomide significantly reduced oxidative stress and increased ATP production. In conclusion, mitochondrial dynamics play a critical, cell-specific role in regulating hen ovarian physiology, influencing the balance between proliferation, metabolism, and steroidogenesis.
    Keywords:  Fusion; Granulosa; Hen; Mitochondria; Theca
    DOI:  https://doi.org/10.1016/j.psj.2026.106850
  27. Front Cell Infect Microbiol. 2026 ;16 1795935
    Mitochondrial stress as a conceptual interface between bacterial infection and post-infectious metabolic disease.
    Nicolás Plaza, Diliana Pérez-Reytor, Gino Corsini, Katherine García, Ítalo M Urrutia.
      Mitochondria are central hubs integrating cellular bioenergetics, redox balance, innate immune signaling, and metabolic homeostasis. During bacterial infections, these organelles are recurrent targets of pathogen-derived toxins, secreted effectors, and host inflammatory mediators, leading to a state broadly defined as mitochondrial stress. This stress encompasses alterations in oxidative phosphorylation, mitochondrial dynamics, calcium handling, reactive oxygen species (ROS) production, and activation or disruption of mitochondrial quality control pathways such as mitophagy. In this perspective, we propose mitochondrial stress as a conceptual framework linking bacterial infection and post-infectious metabolic disease. Using enteric bacterial pathogens such as Salmonella enterica serovars Typhimurium and Typhi, together with Vibrio parahaemolyticus, as conceptual models, we synthesize current evidence showing how distinct bacterial strategies converge on mitochondrial dysfunction and immunometabolic reprogramming of host cells. We argue that, while mitochondrial stress responses may initially support antimicrobial defense, their incomplete resolution may contribute to long-lasting metabolic and inflammatory alterations in epithelial, immune, and metabolic tissues. Persistent mitochondrial dysfunction may contribute to insulin resistance, chronic inflammation, and increased susceptibility to metabolic disease after infection. By framing mitochondrial stress as a central integrator of infection and metabolism, this perspective highlights key knowledge gaps and identifies mitochondria-centered pathways as potential targets to prevent or mitigate post-infectious metabolic sequelae.
    Keywords:  Salmonella enterica; Vibrio parahaemolyticus; bacterial infection; immunometabolism; mitochondrial stress; post-infectious metabolic disease
    DOI:  https://doi.org/10.3389/fcimb.2026.1795935
  28. PLoS Pathog. 2026 Mar;22(3): e1014078
    Microsporidian Encephalitozoon hellem inhibits host mitophagy by inducing ERAD to degrade BNIP3L.
    Ziyun Zou, Yibo Hu, Zhongxia Guan, Jiajing Chen, Qingyao Zhang, Yinze Han, Junyu Zhu, Chunxia Wang, Bing Han, Tian Li, Zeyang Zhou.
      Microsporidia are known intracellular pathogens that infect nearly all animals and deeply manipulate host mitochondrial homeostasis for survival. Here, we report a novel mechanism by which the human-pathogenic Encephalitozoon hellem modulates the mitophagy machinery of its host. We identified the secreted protein EhPTP4 as a key effector in disrupting selective degradation processes in the infected cells. EhPTP4 is found to localize within the nucleus of infected cells, where it induces increased expression of endoplasmic reticulum-associated degradation (ERAD) pathway components, including HSPA5, HERPUD1, and PDIA4. This induction enhances protein ubiquitination in host cells and leads to the degradation of BNIP3L, a critical regulator of mitophagy. Investigation into the molecular interaction network revealed that EhPTP4 interacts with host corepressor RCOR1 and histone H3. This interaction modulates histone acetylation, specifically at H3K14ac sites, thereby further influencing the expression of a key ERAD gene, HERPUD1. This study uncovers a sophisticated strategy by which microsporidia manipulates both ER stress response and the histone acetylation to suppress mitophagy. These findings provide new insights into the mechanisms of microsporidian pathogenesis.
    DOI:  https://doi.org/10.1371/journal.ppat.1014078
  29. J Diabetes Res. 2026 ;2026(1): e7913374
    Disruption of Mitophagy-Related Gene Expression in Gestational Diabetes Mellitus: A Transcriptomic and Machine Learning Approach.
    Souhaib Bouati, Shaima Ameen, Nour Al Dain Marzouka, Fadwah Alhantoobi, Emad Masuadi, Ghada Mohammed, Noha Ahmed Mousa, Shahad Mahmoud, Muhieddine Seoud, Hisham Mirghani, Halima Alnaqbi, Ayman Pathan, Maha Saber-Ayad, Wael Osman.
       BACKGROUND: Gestational diabetes mellitus (GDM) is a pregnancy-associated metabolic disorder linked to adverse maternal and fetal outcomes. Mitochondrial dysfunction is a recognized feature of GDM, yet the role of mitophagy-the selective degradation of damaged mitochondria-remains insufficiently understood.
    OBJECTIVE: This study examined the expression and regulatory patterns of mitophagy-related genes (MRGs) in GDM using publicly available transcriptomic datasets.
    METHODS: Transcriptomic datasets available in public repositories were analyzed to explore MRG expression and regulatory dynamics in GDM. RNA-seq data from two datasets: GSE203346 (placental and cord blood samples) and GSE154414 (placental samples) were analyzed to identify differentially expressed mitophagy genes. Additionally, maternal circulating blood RNA-seq data from GSE154377 were included for machine learning analysis. These datasets, which encompassed samples collected across multiple trimesters, facilitated a comparative evaluation of MRG expression dynamics in both placental tissue and maternal blood throughout pregnancy. A curated list of 65 MRGs was evaluated using edgeR and DESeq2 for differential expressions (DEs). Temporal expression dynamics were modeled with the multiclassPairs package in R using GSE154377.
    RESULTS: Consistent downregulation of four critical MRGs-MUL1, PINK1, TOMM7, and ATF4-was observed in GDM placental tissue (GSE154414) and in both placental tissue and fetal umbilical cord blood (GSE203346) but not in maternal peripheral blood. In healthy pregnancies, these genes exhibited distinct temporal regulation across gestation, a pattern disrupted in GDM. Classifier models based on MRG expression accurately predicted gestational stage in controls (accuracy > 85%) but performed poorly in GDM (accuracy < 50%). Functional enrichment analyses revealed impaired mitochondrial protein import, autophagy, and oxidative stress responses.
    CONCLUSION: These findings suggest that mitophagy dysregulation is an early and persistent defect in GDM, with MUL1, PINK1, TOMM7, and ATF4 emerging as potential biomarkers and therapeutic targets. The results support the hypothesis that mitochondrial quality control failure contributes to the pathogenesis of GDM with similar patterns shown in both placental and cord blood tissues. However, these genes were not significantly altered in plasma, highlighting tissue context as a critical factor in detecting mitophagy-related dysregulation.
    Keywords:  ATF4; GDM; MUL1; PINK1; TOMM7; gene expression; mitophagy; placenta
    DOI:  https://doi.org/10.1155/jdr/7913374
  30. Biomolecules. 2026 03 16. pii: 445. [Epub ahead of print]16(3):
    Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
    Snježana Kaštelan, Antonela Gverović Antunica, Suzana Konjevoda, Zora Tomić, Ana Sarić, Marjan Kulaš, Lorena Kulaš, Emina Kujundžić Begović, Samir Čanović, Petra Kovačević, Mira Ivanković.
      Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification.
    Keywords:  mitochondria-targeted intervention; mitochondrial quality control; mitochondrial reactive oxygen species (mtROS); mitophagy; precision medicine; redox signalling; retinal ganglion cells; retinal neurodegeneration; reverse electron transport
    DOI:  https://doi.org/10.3390/biom16030445
  31. Metab Brain Dis. 2026 Mar 23. pii: 65. [Epub ahead of print]41(1):
    Activation of mitophagy via miR-223/NLRP3 axis ameliorates dopaminergic neuronal damage in parkinson's disease.
    Yan Wu, Xuemei Fan, Dewei Wang, Hui Yang.
      
    Keywords:  Dopamine neuronal damage; MiR-223; Mitophagy; NLRP3; Parkinson's disease
    DOI:  https://doi.org/10.1007/s11011-026-01805-z
  32. Redox Biol. 2026 Mar 19. pii: S2213-2317(26)00130-8. [Epub ahead of print]92 104132
    CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.
    Chunyu Shang, Kaixin Du, Yixin Zou, Yixuan Han, Yuanli Gong, Ziwen Duan, Yifan Wu, Li Wang, Jianyong Li, Rui Gao, Wei Xu, Jinhua Liang.
      Despite effective first-line regimens, some patients with diffuse large B-cell lymphoma (DLBCL) still experience relapse or resistance, emphasizing the urgent need for innovative treatment approaches. Cytidine triphosphate synthase 1 (CTPS1) is a key regulatory and rate-limiting enzyme for de novo nucleotide synthesis pathway. However, the role of CTPS1 in DLBCL and its potential therapeutic value remain unknown. We found that high levels of CTPS1 were associated with poor prognosis in patients with DLBCL. The single-cell RNA sequencing (scRNA-seq) revealed that phospholipid metabolism and mitophagy-related pathways were activated in DLBCL cells with high CTPS1 expression. Mechanistically, CTPS1 up-regulated the expression of choline/ethanolamine phosphotransferase 1 (CEPT1) by increasing CTP availability, thereby reprogramming glycerophospholipid metabolism. The glycerophospholipids synthesized by CEPT1 maintained mitochondrial homeostasis and promoted BCL2 interacting protein 3 (BNIP3)-mediated mitophagy, ultimately driving the DLBCL progression. Moreover, highly selective CTPS1 inhibitor R80 could reduce the viability of DLBCL cells.
    Keywords:  CEPT1; CTPS1; Diffuse large B-Cell lymphoma; Mitophagy; Phospholipid metabolism
    DOI:  https://doi.org/10.1016/j.redox.2026.104132
  33. Biomed Khim. 2026 Feb;72(1): 28-41
    Astaxanthin protects heart mitochondria from damage caused by chronic alcohol intoxication.
    O V Krestinina, I V Odinokova, A I Zvyagina, R R Sotnikov, L D Sotnikova, Yu L Baburina.
      The natural antioxidant astaxanthin (AST) demonstrates the cardioprotective effect on cardiac mitochondria in rats subjected to chronic alcohol intoxication. Particularly, AST restored cardiac mitochondrial respiratory activity and Ca2+ capacity of rats exposed to chronic alcohol intoxication; it also had a positive impact on the balance of functionally important processes of mitochondrial fission/fusion, as well as mitophagy. In addition, AST prevented alcohol-induced morphological damage to cardiac tissue. Overall, the results demonstrate that AST promotes normalization of cardiac mitochondrial function, protecting these organelles from degenerative changes caused by alcohol intoxication and improving cardiac energy metabolism. Thus, AST helps to compensate the cardiac mitochondrial damage caused by chronic alcohol intake by restoring their functional activity and stress resistance.
    Keywords:  astaxanthin; cardiac mitochondria; chronic alcohol intoxication; mitochondrial dysfunction; mitochondrial fission/fusion; mitophagy
    DOI:  https://doi.org/10.18097/PBMCR1617
  34. Adv Sci (Weinh). 2026 Mar 27. e21183
    Dual-Targeting Cuproptosis and Mitophagy via a Flavopiridol-Copper Nanoplatform Potentiates Immunotherapy Against Uveal Melanoma.
    Hong Ren, Zhihong Deng, Sheng Lu, Jing Zhang, Wenbin Liu, Jia Tan.
      Uveal melanoma (UM) is a highly therapy-resistant ocular malignancy with an immunosuppressive tumor microenvironment (TME) and low tumor mutational burden. Here, we developed NP@Fla-Cu, a glutathione (GSH)-responsive nanoparticle designed to co-induce cuproptosis and mitophagy dysregulation. Cuproptosis, a copper-dependent mitochondrial cell death pathway, is amplified by NP@Fla-Cu's dual functionality: its GSH-degradable shell depletes copper-chelating GSH, while its core delivers a flavopiridol-copper complex (Fla-Cu). Flavopiridol acts as a copper ionophore, driving mitochondrial copper overload to trigger cuproptosis, while hyperactivating mitophagy, causing organelle depletion and metabolic collapse. In UM intraocular orthotopic xenograft models, NP@Fla-Cu exhibited tumor-specific accumulation and potent antitumor activity. Immunological evaluation in a B16F10 murine melanoma model further demonstrated that NP@Fla-Cu effectively remodeled the tumor immune microenvironment, as evidenced by enhanced CD8+ T cell infiltration. By synergizing copper cytotoxicity with immunomodulation, this nanoplatform sensitizes immune-cold UM to immunotherapy. This work establishes cuproptosis induction via NP@Fla-Cu as a transformative strategy against UM, effectively addressing challenges in tumor selectivity and off-target toxicity. The dual functionality of flavopiridol as a copper ionophore and mitophagy activator provides a promising combinatorial approach to overcome therapy resistance in immunosuppressive malignancies.
    Keywords:  cuproptosis; flavopiridol; immunotherapy; mitophagy; uveal melanoma
    DOI:  https://doi.org/10.1002/advs.202521183
  35. J Hazard Mater. 2026 Mar 20. pii: S0304-3894(26)00805-8. [Epub ahead of print]507 141827
    Trihexyl phosphate exposure disrupts mitophagy and activates mtDNA-cGAS-STING signaling to drive pyroptosis and steroidogenic impairment in Leydig cells.
    Yinwei Dai, Zhuoqi Chen, Weijian Zhu, Shaowei Wang, Xiya Ren, Yuli Yang, Ren-Shan Ge.
      Trihexyl phosphate (THP), a widely detected organophosphate flame retardant, poses emerging concerns due to its potential male reproductive toxicity, though mechanistic insights remain limited. Here, we delineate a downstream cascade linking THP exposure to testosterone suppression through mitochondrial dysfunction and cytosolic DNA-sensing pathways in adult Leydig cells (LCs). In vivo, oral THP exposure (0, 12.5, 25, 50 mg/kg/day, 14 days) in adult male C57BL/6 mice reduced serum testosterone without altering LH/FSH levels, accompanied by downregulated steroidogenic genes/proteins (NR5A1, SCARB1, STAR) at low-medium doses and diminished CYP11A1 + LC populations at the highest dose. In vitro, THP impaired MA-10 LC viability and steroidogenesis. Mechanistically, THP disrupted PINK1/Parkin-mediated mitophagy, increased mitochondrial ROS, and triggered mtDNA leakage, thereby activating the cGAS-STING-TBK1-IRF3 axis. This was accompanied by enhanced NLRP3 inflammasome signaling and pyroptotic responses. Pharmacological and genetic interventions supported pathway dependence: urolithin A restored mitochondrial homeostasis and attenuated cGAS-STING activation, while RU.521 and STING knockdown preserved testosterone output by suppressing NLRP3-associated signaling. Structural and transcriptomic analyses further supported STING-NLRP3 association and linked elevated cGAS-STING activity with mitophagy suppression and pyroptosis in LCs. Our findings provide evidence that THP disrupts testosterone synthesis via a mitophagy-mtDNA-cGAS-STING-pyroptosis axis, highlighting mitophagy enhancement and cGAS-STING inhibition as potential intervention strategies. The primary chemical initiating event and direct molecular target(s) of THP remain to be defined.
    Keywords:  CGAS-STING pathway; Leydig cell dysfunction; Mitochondrial quality control; Pyroptosis; Trihexyl phosphate (THP)
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141827
  36. Int J Mol Med. 2026 May;pii: 138. [Epub ahead of print]57(5):
    Macrophage SH3 domain‑containing GRB2‑like protein B1 is required for Rab7‑mediated mitophagy in inflammation during sea water drowning acute lung injury.
    Hongjuan Ning, Jingyu Deng, Yongheng Gao, Wei Zhang, Jian Chen, Xian Guo, Faguang Jin.
      Acute lung injury (ALI) accompanied by an inflammatory response is an important complication after drowning. Macrophage activation and polarization are implicated in the inflammatory process of lipopolysaccharide (LPS)‑induced ALI (LPS‑ALI), but little is known about drowning‑induced ALI (drowning‑ALI). SH3 domain‑containing GRB2‑like protein B1 (SH3GLB1) is a member of the endophilin family and has been shown to be involved in mitochondrial morphological changes and autophagy. However, its role in ALI remains unclear. Thus, the present study aimed to examine the effects of macrophages in drowning‑ALI and to elucidate the underlying molecular mechanism involved. In the present study, single‑cell RNA‑sequencing indicated that the regulation of macrophages in drowning‑ALI was similar to that in LPS‑ALI by single‑cell profiling of lung immune cells isolated from the lungs. Specifically, SH3GLB1 was highly expressed in macrophages of drowning‑ALI mouse models and was related to inflammation. Furthermore, SH3GLB1 deletion ameliorated LPS‑ALI or drowning‑ALI. By contrast, the restoration of SH3GLB1 expression provoked LPS‑ALI and drowning‑ALI. Mechanistically, SH3GLB1 was shown to interact with Rab7 to contribute to mitophagy, which resulted in mitochondrial dysfunction. Overall, these findings indicated that SH3GLB1 is required for Rab7‑mediated mitophagy in inflammation during ALI and could be a novel target for lung protection.
    Keywords:  Rab7; SH3 domain‑containing GRB2‑like protein B1; acute lung injury; macrophage; mitophagy
    DOI:  https://doi.org/10.3892/ijmm.2026.5809
  37. Cell Death Dis. 2026 Mar 25.
    Dimeric PKM2 in chondrocytes impairs mitochondrial homeostasis in osteoarthritis.
    Bo Liu, Yun Liang, Chenzhong Wang, Ziyu Weng, Yi Yang, Yi Shi, Chi Zhang.
      Cartilage degradation is considered a hallmark of end-stage osteoarthritis (OA), characterized by significant alterations in the extracellular matrix (ECM). This study examines the role of pyruvate kinase muscle type 2 (PKM2) dimerization in cartilage degradation and ECM homeostasis in OA. Bioinformatic analyses identified an upregulation of PKM in OA cartilage, particularly within fibrocartilage subpopulations. Elevated expression and dimerization of PKM2 were observed in both human and murine OA cartilage. Chondrocyte-specific PKM2 deficiency, along with treatment using TEPP-46, a PKM2 tetramer stabilizer, reduced OA progression and promoted cartilage matrix production in a murine OA model with destabilization of the medial meniscus (DMM). Mechanistically, PKM2 deficiency or tetramer stabilization promoted mitochondrial fusion and preserved mitochondrial function via disruption of PKM2-ERK interaction, resulting in ERK-dependent upregulation of mitofusin 1 (MFN1), but not mitofusin 2 (MFN2). Notably, AAV-mediated MFN1 knockdown abrogated the chondroprotective effects of PKM2 deficiency. These findings indicate that targeting PKM2 dimerization may represent a promising therapeutic strategy for mitigating OA.Increased PKM2 dimerization in osteoarthritic cartilage plays a pivotal role in extracellular matrix (ECM) degradation during osteoarthritis progression. Stabilization of PKM2 tetramers by TEPP-46 or genetic deletion of PKM2 disrupts PKM2-ERK interaction, promotes upregulation of the mitochondrial fusion protein MFN1, preserves mitochondrial function, and restores ECM homeostasis.
    DOI:  https://doi.org/10.1038/s41419-026-08621-4
  38. Antioxidants (Basel). 2026 Feb 25. pii: 284. [Epub ahead of print]15(3):
    PM10 Disrupts Mitochondrial Homeostasis in Corneal Epithelial Cells: Protective Effects of SKQ1.
    Mallika Somayajulu, Robert Wright, Farooq S Muhammed, Sharon A McClellan, Ahmed S Ibrahim, Linda D Hazlett.
      Airborne particulate matter with a diameter of <10 μm (PM10) can damage the corneal epithelium by inducing oxidative stress, disrupting the NRF2 antioxidant pathway, and triggering epithelial barrier dysfunction and inflammation. However, the role of mitochondria in mediating PM10-induced damage remains unexplored. This study investigated the impact of PM10 on mitochondrial homeostasis in both immortalized human corneal epithelial cells (HCE-2) and the mouse corneal epithelium, as well as the protective effects of SKQ1. For in vivo assessment, female C57BL/6 mice were exposed to either control air or PM10 (±SKQ1) in a whole-body exposure chamber for 2 weeks (3 h/day, 5 days/week, with weekends off). In vitro, HCE-2 cells were exposed to 100 μg/mL PM10 (±SKQ1) for 24 h, and mitochondrial function and morphology were evaluated. In vitro, PM10 significantly impaired mitochondrial function by reducing basal, maximal, and ATP-linked respiration; reserve capacity; and coupling efficiency compared to the control and SKQ1 groups. PM10 also downregulated mitofusin1 (MFN1) and optic atrophy1 (OPA1) and upregulated dynamin-related protein1 (DRP1) and mitochondrial fission protein1 (FIS1) in HCE-2 cells. In addition, PM10 exposure significantly decreased the mitochondrial membrane potential; mitochondrial DNA copy number; and cytochrome c oxidase subunit 4 isoform 1 (COX4i1), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels. SKQ1 pre-treatment significantly attenuated these effects. In vivo, PM10 exposure significantly decreased the levels of MFN1, TFAM, COX4i1, and superoxide dismutase (SOD2), whereas SKQ1 treatment significantly reversed these effects. Overall, these findings demonstrate that PM10 exposure induces mitochondrial fragmentation, disrupts mitochondrial biogenesis and quality control, and reduces mitochondrial respiration, resulting in mitochondrial dysfunction. SKQ1 effectively reversed these changes, suggesting its potential as a therapeutic strategy to protect corneal epithelial cells from PM10-induced mitochondrial damage.
    Keywords:  PM10; SKQ1; corneal epithelium; mitochondria
    DOI:  https://doi.org/10.3390/antiox15030284
  39. Free Radic Biol Med. 2026 Mar 25. pii: S0891-5849(26)00253-4. [Epub ahead of print]
    SIRT1 activation restores PINK1-dependent mitophagy to reverse airway barrier dysfunction in Acinetobacter baumannii infection.
    Jianxia Zhou, Fujian Zhou, Chunyan He, Jiemei Cen, Dingyun Feng, Yajun Xiong, Yanbing Sheng, Long Zhang, Xiaonan Zhang, Yuying Feng, Aiguo Xu.
      A. baumannii is one of the most widespread extensively drug-resistant pathogens in hospital environments. It exhibits robust resistance to a variety of adverse conditions and enables prolonged survival in clinical settings. However, the molecular pathogenesis and regulatory mechanisms of highly virulent A. baumannii strains remain incompletely elucidated. Here, novel evidence is presented indicating that A. baumannii induces mitochondrial damage while concurrently suppressing mitophagy. This suppression results in the accumulation of dysfunctional mitochondria, ultimately causing cellular barrier dysfunction and cell death. Furthermore, based on a mouse pneumonia model infected with A. baumannii, it is demonstrated that the pathogen impairs PINK1-dependent mitophagy in vivo. This impairment significantly increases inflammatory cell infiltration in the lungs and elevates the levels of inflammatory factors in peripheral blood and bronchoalveolar lavage fluid, thereby markedly increasing mortality rates. Importantly, the activation of SIRT1 partially restores cellular and airway barrier functions by up-regulating PINK1-dependent mitophagy, consequently attenuating the virulence and pathogenicity of A. baumannii. Our findings reveal that the maintenance of barrier integrity mediated by mitophagy plays a critical role in regulating the virulence of this pathogen. This discovery may contribute to the development of innovative therapeutic strategies targeting mitochondrial pathways to combat infections caused by A. baumannii strains.
    Keywords:  Acinetobacter baumannii; Mitophagy; PINK1; SIRT1; airway barrier
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.062
  40. Pharmaceuticals (Basel). 2026 Feb 25. pii: 360. [Epub ahead of print]19(3):
    Yixinjiedu Formula Attenuates Pressure Overload-Induced Cardiac Dysfunction by Suppressing Ferroptosis and Restoring Mitophagy via the PINK1/Parkin Axis.
    Kang Xie, Haowen Zhuang, Xin Dong, Yulin Ouyang, Xin Liu, Zhongzheng Zhang, Mengyuan Wang, Jinhong Chen, Xinmeng Teng, Wei Wang, Chun Li, Junyan Wang.
      Background: Pressure overload-induced heart failure (HF) involves cardiac remodeling, ferroptosis, and impaired mitophagy. Yixinjiedu formula (YXJDF), a traditional Chinese medicine, shows cardiovascular protective effects, but its underlying mechanisms remain largely unclear. This study aims to evaluate the cardioprotective effect of YXJDF in pressure overload-induced HF and explore its regulatory role in ferroptosis and mitophagy. Methods: A transverse aortic constriction (TAC) mouse model and angiotensin II-induced HL-1 cardiomyocytes were used to assess the therapeutic effects of YXJDF. Cardiac function, ferroptosis, and mitophagy were evaluated using histological, biochemical, molecular, and imaging analyses. Autophagic flux was assessed using lysosomal inhibition. Network pharmacology was applied to identify potential targets, while LC-MS/MS profiling and molecular docking were used to characterize major constituents of YXJDF and predict target interactions. Results: In TAC mice, YXJDF significantly improved cardiac function and attenuated myocardial hypertrophy and fibrosis. YXJDF suppressed ferroptotic injury, as evidenced by reduced lipid peroxidation, restoration of GPX4 and FTH1 expression, and normalization of antioxidant capacity. Mitophagy was restored, as indicated by increased PINK1 and Parkin expression, enhanced LC3-II accumulation, and reduced p62 and TOM20 levels, and as confirmed by autophagic flux analysis. Consistent protective effects on ferroptosis and mitophagy were observed in angiotensin II-induced cardiomyocytes. Network pharmacology analysis identified PINK1 as a key target, which was validated by in vivo and in vitro experiments. LC-MS/MS identified 20 major chemical constituents in YXJDF, and molecular docking showed strong binding affinity between several compounds (e.g., calycosin, salvianolic acid A) and PINK1. Conclusions: YXJDF ameliorates pressure overload-induced cardiac injury by restoring PINK1/Parkin-mediated mitophagy and suppressing ferroptosis. These findings reveal a multi-target mechanism underlying the therapeutic potential of YXJDF in HF.
    Keywords:  PINK1/Parkin pathway; Yixinjiedu formula; ferroptosis; heart failure; mitophagy
    DOI:  https://doi.org/10.3390/ph19030360
  41. Life (Basel). 2026 Mar 04. pii: 417. [Epub ahead of print]16(3):
    Spermine Ameliorates DSS-Induced Ulcerative Colitis in Mice by Improving Mitophagy and Intestinal Microbiota.
    Ran Yu, Yamei Liu, Yating Zheng, Saisai Chen, Ling Tong, Jichun Wang, Chengmin Li, Chuanjian Zhang.
      Spermine (Spe) plays a critical role in maintaining the integrity of the intestinal barrier and promoting intestinal development. However, the therapeutic role of Spe on ulcerative colitis (UC) remains unclear. This study aims to research the impact and mechanism of Spe on dextran sulfate sodium (DSS)-induced colitis in mice. Twenty-eight C57BL/6 mice were orally administered Spe before and during DSS treatment to evaluate its protective effects. Lipopolysaccharides (LPSs) were used to construct an in vitro UC model in IEC-6 cells. The study indicates that Spe treatment upregulated the expression of tight junction protein occludin and inhibited NLRP3 mediated inflammatory response by downregulating the levels of NLRP3, Caspase-1, IL-1β, IL-18 and TNF-α in the colon of DSS-treated mice. In addition, Spe enhanced mitophagy in colitis mice by increasing expressions of mitophagy factors (PINK1, Parkin, LC3-II) in DSS-treated mice. PINK1-mediated mitophagy helps alleviate LPS-induced mitochondrial damage in IEC-6 cells. Furthermore, Spe regulates the gut microbiota composition in mice with colitis by increasing the abundance of unclassified Muribaculaceae, reducing the levels of Firmicutes and Blautia, and lowering the Firmicutes/Bacteroidetes ratio. In conclusion, spermine exhibited treatment efficacy on DSS-induced colitis by inhibiting NLRP3-mediated inflammatory response, promoting mitophagy and improving intestinal microbial dysbiosis.
    Keywords:  NLRP3; mice; microbiota; mitophagy; spermine; ulcerative colitis
    DOI:  https://doi.org/10.3390/life16030417
  42. Cell Div. 2026 Mar 25.
    SOCS3 suppresses glioblastoma growth via JAK-STAT inhibition and mitochondrial unfolded protein response activation.
    Gaolei Hou, Zhaofei Song, Jingtao Wang, Junmei Wang, Hongbin Wang, Tao Li.
       INTRODUCTION: Glioblastoma (GBM) represents one of the most aggressive brain malignancies, characterized by rapid proliferation and pronounced resistance to apoptosis, resulting in poor therapeutic outcomes. Suppressor of cytokine signaling 3 (SOCS3), a crucial negative regulator of the JAK-STAT pathway, frequently undergoes epigenetic silencing in GBM. However, the tumor-suppressive functions of SOCS3 remain inadequately defined. The present study explores the role of SOCS3 in regulating mitochondrial stress responses and evaluates its therapeutic potential in GBM.
    METHODS: SOCS3 was overexpressed in GBM cell lines, and its effects on cell viability and apoptosis were assessed using MTT assays, TUNEL staining, and Western blotting. Proteomic profiling was performed to identify SOCS3-regulated pathways. A xenograft mouse model was used to validate tumor-suppressive effects in vivo. The impact of IL-6 (JAK-STAT activator) and Nicotinamide Riboside (NR, a mitochondrial stress inducer) was also examined.
    RESULTS: SOCS3 overexpression significantly suppressed GBM cell proliferation and induced apoptosis. Proteomic analysis revealed upregulation of mitochondrial unfolded protein response (UPRmt) and mitophagy-related proteins. In vivo, SOCS3 reduced tumor growth and enhanced apoptotic signaling. IL-6 treatment restored JAK-STAT activity and reversed SOCS3-mediated tumor suppression. In contrast, NR treatment synergistically augmented SOCS3-induced mitochondrial stress and apoptosis, suggesting that mitochondrial dysfunction contributes to enhanced cell death.
    CONCLUSION: SOCS3 exerts dual tumor-suppressive effects in GBM by inhibiting JAK-STAT signaling and activating mitochondrial stress pathways. These findings provide mechanistic insights into the function of SOCS3 and support its potential as a therapeutic target in GBM by promoting UPRmt-driven apoptosis.
    Keywords:  Apoptosis; Glioblastoma; JAK-STAT signaling; Mitochondrial unfolded protein response (UPRmt); Nicotinamide riboside (NR); SOCS3
    DOI:  https://doi.org/10.1186/s13008-026-00178-0
  43. Nanomedicine (Lond). 2026 Mar 23. 1-15
    SHED-derived exosomes ameliorate age-related osteoporosis by activating mitophagy in senescent bone marrow mesenchymal stem cells.
    Kuan Yang, Baize Zhang, Yingyue Zhang, Xiaojing Wang, Xiao Yuan.
       AIM: This study aims to explore the therapeutic efficacy of stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-Exo) in age-related osteoporosis (OP) and clarify its mechanism via mitophagy activation in senescent bone marrow mesenchymal stem cells (BMSCs).
    METHODS: SHED-Exo were isolated, characterized and proteomically profiled. In vitro, H2O2-induced senescent bone marrow mesenchymal stem cells (BMSCs) were treated with SHED-Exo, with mitophagy modulators used for mechanistic validation. In vivo, SHED-Exo were systemically administered to aged osteoporotic mice, assessing biodistribution, safety and therapeutic effects via micro-computed tomography, and molecular analyses of bone tissue/BMSCs.
    RESULTS: SHED-Exo possessed canonical exosomal properties and were enriched in osteogenic/mitophagic proteins. In vitro, SHED-Exo restored mitochondrial function, activated mitophagy and enhanced osteogenic differentiation of senescent BMSCs. In vivo, SHED-Exo showed no organ toxicity and effectively ameliorated bone loss by upregulating mitophagic/osteogenic markers in aged osteoporotic mice.
    CONCLUSION: SHED-Exo ameliorate age-related OP by activating mitophagy in senescent BMSCs, serving as a novel translational nanotherapeutic for age-related bone disorders.
    Keywords:  SHED-derived exosomes; age-related osteoporosis; bone marrow mesenchymal stem cells; mitophagy; osteogenic differentiation
    DOI:  https://doi.org/10.1080/17435889.2026.2645397
  44. Cells. 2026 Mar 20. pii: 559. [Epub ahead of print]15(6):
    Mitochondrial Dynamic Proteins MiD49 and MiD51 as Novel Targets of Cardioprotection.
    Parisa Samangouei, Gustavo E Crespo-Avilan, Andrew R Hall, Sauri Hernandez-Resendiz, J Maeve Elder, Laura D Osellame, Nicole G Z Tee, Khairunnisa Katwadi, Sang-Bing Ong, Xiu-Yi Kwek, Siavash Beikoghli Kalkhoran, Niall Burke, Derek M Yellon, Derek J Hausenloy.
      Novel therapeutic strategies are required to protect the heart from acute ischaemia-reperfusion injury (IRI) and improve outcomes in patients with acute myocardial infarction (AMI). Mitochondria play a critical role in determining cardiomyocyte fate following acute IRI, with genetic and pharmacological inhibition of Drp1-mediated mitochondrial fission limiting cardiomyocyte death. We investigated the role of the mitochondrial Drp1 receptors, MiD49 and MiD51, as novel targets for cardioprotection. In cardiac cell lines subjected to simulated IRI, dual genetic knockdown of both MiD49 and MiD51 reduced cell death, inhibited mitochondrial fission, prevented mitochondrial permeability transition pore opening, and attenuated mitochondrial calcium overload compared with wild-type cells. However, individual knockdown of either MiD49 or MiD51 did not induce mitochondrial elongation or inhibit MPTP opening. Whole-body genetic ablation of MiD49 in adult mice modestly altered mitochondrial morphology but did not affect myocardial infarct size or cardiac function following AMI. Together with the in vitro protection seen with dual MiD49/51 knockdown, these findings suggest that MiD49 deficiency alone is insufficient and that coordinated inhibition of MiD49 and MiD51 may be required for cardioprotection.
    Keywords:  MiD49; MiD51; cardioprotection; ischaemia-reperfusion injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial permeability transition pore
    DOI:  https://doi.org/10.3390/cells15060559
  45. Front Pharmacol. 2026 ;17 1729145
    AP39 alleviates HHCY-induced myocardial remodeling by regulating FUNDC1-mediated mitochondrial dynamics via S-sulfhydration of NEDD8/CUL4B.
    Yaling Li, Jianghe Jiang, Yingchun Song, Ting Yang, Xinghua Yuan, Xuan Li, Chenlong Luo, Yan Shi, Shengquan Liu, Chun Chu, Jun Yang.
       Introduction: Hyperhomocysteinemia (HHCY) is a well-recognized risk factor for cardiovascular diseases; however, the molecular mechanisms underlying HHCY-induced myocardial remodeling remain unclear. This study aimed to investigate the role of mitochondrial dysfunction and cardiomyocyte senescence in HHCY-associated myocardial remodeling and to explore the potential protective effects of AP39, a mitochondria-targeted hydrogen sulfide (H2S) donor.
    Methods: An integrated approach combining retrospective clinical analysis, animal models, and cellular experiments was employed. Associations between homocysteine (HCY) levels and left ventricular hypertrophy were analyzed in hypertensive patients. In vivo and in vitro models of HHCY were used to assess cardiac function, myocardial fibrosis, cellular senescence, mitochondrial dynamics, and underlying molecular mechanisms, with or without AP39 intervention.
    Results: Clinical analysis demonstrated that HHCY was significantly associated with left ventricular hypertrophy, and elevated HCY levels increased the risk of ventricular hypertrophy. In animal models, HHCY resulted in impaired cardiac function, evidenced by reduced left ventricular fractional shortening and increased left ventricular end-systolic diameter, accompanied by myocardial fibrosis and cardiomyocyte senescence. AP39 treatment markedly ameliorated these pathological changes. Mechanistically, AP39-derived H2S promoted S-sulfhydration of the NEDD8/CUL4B complex, thereby reducing ubiquitin-dependent degradation of FUNDC1. Upregulation of FUNDC1 restored mitochondrial dynamic homeostasis by weakening its interaction with DRP1, ultimately suppressing cardiomyocyte senescence.
    Discussion: These findings uncover a previously unrecognized mechanism by which AP39 preserves mitochondrial homeostasis through regulation of the FUNDC1-DRP1 axis via NEDD8/CUL4B-dependent S-sulfhydration. This study identifies a novel therapeutic target and provides mechanistic insight into HHCY-associated myocardial remodeling.
    Keywords:  AP39; NEDD8/CUL4B pathway; hyperhomocysteinemia; mitochondrial dynamics; myocardial remodeling
    DOI:  https://doi.org/10.3389/fphar.2026.1729145
  46. Mol Biol Rep. 2026 Mar 25. pii: 543. [Epub ahead of print]53(1):
    Lutein attenuates sodium fluoride (NaF) and gamma-irradiation induced hepatotoxicity via AMPK-PGC1α mitochondrial biogenesis induction.
    Amira Abd-ElRaouf, Fatma Y Abdou, Maha M Ali, Mahmoud E Habieb.
       BACKGROUND: Mitochondrial biogenesis is an adaptive reaction that restores metabolic equilibrium following mitochondrial malfunction. Lutein has been studied for its ability to inhibit hepatotoxicity caused by sodium fluoride (NaF) or irradiation by inducing mitochondrial biogenesis through AMPK-PGC1α signaling.
    METHODS AND RESULTS: Animals were randomized to six groups: Group I (vehicle) received sunflower oil; group II (Lutein) received Lutein (40 mg/kg) for two weeks; group III (NaF) received sodium fluoride (48 mg/kg) for two weeks; group IV (NaF + Lutein) received NaF and 1 h later received Lutein; group V (IRR) was exposed to 7 Gy single dose of gamma rays, and group VI (IRR + Lutein) was provided Lutein for two weeks together with a single irradiation dose. Hepatotoxicity was reported following NaF or irradiation exposure, as increased serum ALT, AST, MDA, and 3-nitrotyrosine levels were detected, paired with decrease in albumin, total protein, GSH and Nrf2 expression. Both NaF and irradiation caused a decline in the mitochondrial biogenesis pathway PGC1α/TFAM, as well as a significant decrease in AMPK, ATP, complex I, and complex II levels as compared to control. In contrast, lutein improved the levels of these biomarkers, implying that it helped lessen hepatotoxicity caused by irradiation or NaF, by enhancing mitochondrial biogenesis and conserving energy metabolism.
    CONCLUSION: The findings suggests that lutein plays a preventive role against NaF or gamma-radiation by activating AMPK-PGC1α mitochondrial biogenesis.
    Keywords:  Hepatotoxicity; Lutein; Mitochondrial biogenesis; Sodium fluoride; γ-irradiation
    DOI:  https://doi.org/10.1007/s11033-026-11634-z
  47. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2026 Jan;38(1): 138-145
    [Akt/SIRT3-dependent mitochondrial autophagy inhibits apoptosis of alveolar epithelial cells and alleviates hyperoxia-induced acute lung injury].
    De Su, Yu Hong, Jie Zheng, Junya Liu, Hong Mei, Xinxin Liu, Kun Yu, Banghai Feng, Liting Cheng, Song Qin.
       OBJECTIVE: To investigate the role and underlying mechanism of the protein kinase B (Akt)/sirtuin 3 (SIRT3) signaling pathway in hyperoxia-induced acute lung injury (HALI).
    METHODS: 1) In vivo experiments: C57BL/6J mice were randomly assigned to a control group (normoxia) or a HALI group (≥95% oxygen), with six mice in each group. After 24 hours of exposure, lung histopathological changes were evaluated by hematoxylin-eosin (HE) staining, and the lung wet/dry weight (W/D) ratio was calculated. Apoptosis-related proteins in total lung lysates (cleaved caspase-3, Bax, and Bcl-2) and mitophagy-related proteins in mitochondrial fractions [p62, Beclin-1, and microtubule-associated protein light chain 3-II/I (LC3-II/I)] were measured by Western blotting. 2) In vitro experiments: Mouse type II alveolar epithelial cells (AEC II) MLE-12 in the logarithmic growth phase were used. Cells were divided into control group, H2O2 group (500 μmol/L H2O2 to mimic the HALI), and H2O2+3-methyladenine (3-MA) group. After 24 hours, cell viability was assessed by cell counting kit-8 (CCK-8), apoptosis was quantified by flow cytometry, and related proteins were detected by Western blotting. To explore the role of mitophagy in H2O2-induced apoptosis, cells were pretreated 2 hours before modeling with 10 μmol/L 3-MA, a mitophagy inhibitor. In additional experiments, cells were divided into control, H2O2, H2O2+Ly294002, and H2O2+SC-79 groups; 10 μmol/L Ly294002 (Akt inhibitor) or SC-79 (Akt activator) was added 2 hours before modeling to investigate the involvement of Akt signaling in mitophagy-mediated protection against H2O2-induced apoptosis. SIRT3 was further knocked down to determine whether it functions downstream of Akt in this protective pathway.
    RESULTS: 1) In vivo results: Under light microscopy, the control group exhibited clear and regularly arranged alveolar structures, whereas the HALI group showed marked inflammatory cell infiltration, edema, and thickened alveolar walls. The lung W/D ratio was higher in the HALI group than that in the control group (11.5±1.1 vs. 5.4±0.8, P < 0.05). Compared with the control group, the HALI group showed increased expression of pro-apoptotic proteins Bax, cleaved caspase-3 [Bax (Bax/GAPDH): 0.49±0.06 vs. 0.18±0.05, cleaved caspase-3 (cleaved caspase-3/GAPDH): 1.71±0.07 vs. 0.63±0.06, both P<0.05], and decreased expression of anti-apoptotic protein Bcl-2 (Bcl-2/GAPDH: 0.39±0.05 vs. 1.03±0.08, P<0.05). Mitophagy-related markers were also altered, with increased LC3-II/I ratio and Beclin-1 [LC3-II/I ratio: 2.16±0.06 vs. 1.10±0.10, Beclin-1 (Beclin-1/GAPDH): 1.04±0.08 vs. 0.42±0.04, both P<0.05], and decreased p62 (p62/GAPDH: 0.41±0.04 vs. 0.99±0.08, P<0.05), suggesting that apoptosis and mitophagy may be involved in HALI progression. 2) In vitro results: Compared with the control group, H2O2 treatment reduced cell viability, Bcl-2, and p62 [cell viability: (48.45±6.48)% vs. (96.80±2.27)%, Bcl-2 (Bcl-2/GAPDH): 0.57±0.07 vs. 0.82±0.05, p62 (p62/GAPDH): 0.39±0.06 vs. 1.03±0.07, all P<0.05], while increasing apoptosis rate, LC3-II/I ratio, Beclin-1, Bax, and cleaved caspase-3 [apoptosis rate: (16.12±1.76)% vs. (6.54±0.75)%, LC3-II/I ratio: 2.05±0.12 vs. 0.97±0.07, Beclin-1 (Beclin-1/GAPDH): 0.69±0.05 vs. 0.18±0.03, Bax (Bax/GAPDH): 0.53±0.07 vs. 0.29±0.04, cleaved caspase-3 (cleaved caspase-3/GAPDH): 0.63±0.04 vs. 0.19±0.04, all P<0.05]. Compared with the H2O2 group, 3-MA pretreatment further aggravated apoptosis [cell viability: (34.00±5.05)% vs. (48.45±6.48)%, apoptosis rate: (22.21±3.05)% vs. (16.12±1.76)%, cleaved caspase-3 (cleaved caspase-3/GAPDH): 1.03±0.09 vs. 0.63±0.04, Bax (Bax/GAPDH): 0.69±0.07 vs. 0.53±0.07, Bcl-2 (Bcl-2/GAPDH): 0.30±0.04 vs. 0.57±0.07, p62 (p62/GAPDH): 0.64±0.05 vs. 0.39±0.06, Beclin-1 (Beclin-1/GAPDH): 0.34±0.04 vs. 0.69±0.05, LC3-II/I ratio: 1.64±0.05 vs. 2.05±0.12, all P<0.05], indicating that inhibition of mitophagy promotes MLE-12 apoptosis. Similar changes were observed after adding the Akt inhibitor Ly294002, whereas the Akt activator SC-79 produced effects opposite to those of 3-MA, suggesting that Akt activation promotes mitophagy and thereby suppresses apoptosis. Compared with the H2O2+SC-79 group, SIRT3 knockdown (H2O2+SC-79+siSIRT3) increased apoptosis rate, cleaved caspase-3, Bax, and p62 [apoptosis rate: (10.30±0.96)% vs. (8.82±0.95)%, cleaved caspase-3 (cleaved caspase-3/GAPDH): 0.69±0.05 vs. 0.44±0.05, Bax (Bax/GAPDH): 0.99±0.06 vs. 0.49±0.04, p62 (p62/GAPDH): 0.59±0.06 vs. 0.38±0.04, all P<0.05], and decreased SIRT3, Bcl-2, and Beclin-1 [SIRT3 (SIRT3/GAPDH): 0.48±0.05 vs. 0.68±0.04, Bcl-2 (Bcl-2/GAPDH): 0.64±0.05 vs. 0.78±0.05, Beclin-1 (Beclin-1/GAPDH): 0.68±0.04 vs. 0.79±0.04, all P<0.05]. These findings indicate that SIRT3 knockdown attenuates SC-79-induced mitophagy and enhances apoptosis, supporting SIRT3 as an important downstream effector of the Akt pathway.
    CONCLUSIONS: Activation of the Akt/SIRT3 signaling pathway promotes mitophagy to inhibit alveolar epithelial cell apoptosis, thereby attenuating HALI.
    DOI:  https://doi.org/10.3760/cma.j.cn121430-20241230-01074
  48. Appl Biochem Biotechnol. 2026 Mar 24.
    NCBP2 Regulates PGAM5-Mediated Mitophagy Via KIF23 Alternative Splicing To Promote Cervical Cancer ProgressionRun Title: NCBP2 Promotes Cervical Cancer Via Mitophagy.
    Ying Su, Juxin Zhang, Henghui Wu, Yu Zhang, Wenlei Zhou.
      Cervical cancer is one of the major threats to women's health worldwide. Nuclear Cap Binding Protein 2(NCBP2) plays a significant role in various cancers, and mitophagy, as a cellular homeostasis regulation mechanism, is closely related to tumorigenesis and development. However, the specific mechanisms by which NCBP2 regulates mitophagy in cervical cancer remain unclear. Bioinformatics was used to screen cervical cancer-related genes and mechanisms. The effects of NCBP2 on the viability, migration, and mitochondrial function of cervical cancer cells were investigated using CCK-8, EdU, and Transwell assays. Comprehensive experimental methods, including RT-qPCR and Western blot, were employed to elucidate the potential mechanisms of NCBP2. NCBP2 was found to be significantly upregulated in cervical cancer and promoted the in vitro proliferation, migration, and invasion of cervical cancer cells. Mechanistically, NCBP2 regulated the alternative splicing of KIF23 to facilitate cervical cancer progression. NCBP2 also regulated mitophagy in cervical cancer cells via the KIF23-PGAM5 axis. Moreover, FBXW8 inhibited the overactivation of mitophagy and exerted tumor-suppressive effects by ubiquitinating and degrading NCBP2. This study reveals that NCBP2 regulates alternative splicing and mitophagy to influence cervical cancer progression, providing new potential therapeutic targets and strategies for cervical cancer treatment.
    Keywords:  Alternative splicing; Cervical cancer; Mitophagy; NCBP2; Ubiquitination
    DOI:  https://doi.org/10.1007/s12010-026-05607-y
  49. Tissue Cell. 2026 Mar 22. pii: S0040-8166(26)00161-8. [Epub ahead of print]101 103468
    Quercetin targets the TNF-a/TNF pathway to activate mitochondrial autophagy to improve nucleus pulposus cell function and delay disc degeneration.
    Xiaofei Wu, Lei Yang, Chaoqi Chen, Fei Liu, Feng Chen, Chao Song, Xinjian Feng.
       BACKGROUND: The primary pathogenic mechanism of lower back pain is intervertebral disc degeneration (IVDD), and the phenotypic change of nucleus pulposus cells and matrix degradation are caused by an imbalance in the "inflammation - autophagy - fibrosis" axis. Despite Tong'an decoction's obvious therapeutic benefits, it is unclear if its principal ingredient, quercetin, controls mitochondrial autophagy and postpones IVDD by interfering with TNF signaling.
    METHODS: Tong'an decoction's various components were screened using the traditional Chinese medicine database, and quercetin's main targets were found. By combining transcriptome differential analysis and module analysis, IVDD core genes may be identified. These genes can then be intersected with the autophagy genes to identify autophagy-associated IVDD genes. Joint validation of core genes, additional single-cell sequencing study of cell subpopulation dynamics, and external data validation of core genes expression. The in vivo effectiveness of quercetin was confirmed by imaging and pathological tissue staining, acupuncture rat models, the identification of inflammatory markers, and the RNA detection of important genes. The mechanism of action of quercetin was anticipated using a quercetin target interaction network. Finally, the lipopolysaccharide induced nucleus pulposus cells model was used for molecular mechanism and functional validation.
    RESULTS: 677 IVDD related autophagy genes (such as HIF1A, TNF, BCL2, and LC3) were screened. Functional enrichment shows that these genes are significantly involved in mitochondrial autophagy, apoptosis, ferroptosis, and inflammatory signaling pathways such as TNF, MAPK, and NF-KB. External verification found that the levels of inflammatory factors IL-1 β and TNF - α were elevated in IVDD tissues, and key genes for autophagy and apoptosis were expressed. Single cell sequencing detected different states of nucleus pulposus cells, among which fibrous nucleus pulposus cells are an important pathological type in IVDD. Trajectory analysis reveals the transition of nucleus pulposus cells from steady state to fibrotic phenotype, accompanied by the secretion of inflammatory factors by macrophages. The animal model showed that the collagen arrangement in the nucleus pulposus tissue of the model group was disordered, fibrosis occurred, and the expression of inflammation, autophagy, apoptosis hub genes HIF1A, MAPK1, NFKB, CASP3, etc. was upregulated, while BCL2 was downregulated. Cell experiments have confirmed that inflammatory stimulation leads to depolarization of mitochondrial membrane potential, elevation of autophagy markers, and swelling of mitochondrial structure, which were alleviated by quercetin intervention.
    CONCLUSION: The study found that TNF/IL-1β driven macrophage infiltration stimulates the NF-κB/MAPK pathway, increasing inflammation-induced mitochondrial autophagy dysregulation. Additionally, HIF-1α hypoxic stress accelerates the transition of nucleus pulposus cells into fibroNPCs. Quercetin treatment can drastically reduce TNF signaling, restore mitochondrial autophagy equilibrium, and reverse fibrosis transformation. This study provides a complete proof chain of "components targets phenotype" for treating IVDD with Tong'an Tang, establishing the groundwork for clinical translation.
    Keywords:  Intervertebral disc degeneration; Mitochondrial autophagy; Multi omics techniques; Nucleus pulposus cells; Quercetin; TNF signaling pathway
    DOI:  https://doi.org/10.1016/j.tice.2026.103468
  50. Curr Med Sci. 2026 Mar 23.
    Efficacy and Mechanisms of Duhuo Jisheng Decoction in Treating Intervertebral Disc Degeneration: A Network Pharmacology and Experimental Study.
    Jing Feng, Lei Xu, Hong-Yan Miao, Shi-Yang Du, Jun-Hui Wang, Xin Cao, Wei Liu, Yun-Tao Wang.
       OBJECTIVE: Intervertebral disc degeneration (IDD) is the main cause of low back pain, which is closely related to an imbalance in extracellular matrix decomposition-anabolism mediated by immune inflammation. Duhuo Jisheng decoction (DHJSD) is effective in treating IDD, but its specific mechanism of action remains unclear and warrants further study. This study aimed to investigate the role of DHJSD in IDD treatment and its underlying mechanisms of action, providing potential therapeutic targets for IDD.
    METHODS: High-performance liquid chromatography‒mass spectrometry (HPLC‒MS/MS) was employed to characterize the chemical composition of DHJSD. A Cell Counting Kit-8 (CCK-8) was used to detect the effects of DHJSD on the viability of pressure-treated nucleus pulposus (NP) cells. NP cells were randomly divided into three groups: control, pressure, and DHJSD groups. Western blotting was used to detect the expression of NLRP3, ASC, caspase-1, IL-1β, collagen II, aggrecan, Sox-9, MMP-3, MMP-13, and Adamts-4 in the aforementioned three groups of cells. An immunofluorescence assay was used to detect NLRP3 expression. Additional groups included the DHJSD + dimethyl sulfoxide (DMSO) and DHJSD + cyclosporine A groups. The expression of mitophagy-related factors, the NLRP3 inflammasome, and subsequent inflammatory reactions were detected by Western blotting and immunofluorescence. Network pharmacology and molecular docking were used to explore the key components and key genes of DHJSD involved in treating IDD. Finally, we verified the bioinformatics results using a rat tail acupuncture model of IDD.
    RESULTS: DHJSD-containing serum improved NP cell viability; the optimal intervention concentration was 20% by volume, and the optimal intervention time was 24 h. Compared with the pressure group, the DHJSD group presented significantly decreased expression of NLRP3, ASC, caspase-1, IL-1β, MMP-3, MMP-13, Adamts-4, and p62, and significantly increased expression of collagen II, aggrecan, Sox-9, PINK1, Parkin, and LC3. However, upon the addition of a mitophagy inhibitor, the protective effect of DHJSD on NP cells was diminished. Network pharmacology and molecular docking studies revealed that HIF-1α may be the key target of DHJSD in the treatment of IDD. Imaging and histopathological results confirmed that DHJSD delayed IDD progression. Western blotting and immunohistochemistry revealed that DHJSD increased HIF-1α expression, regulated mitochondrial division and fusion, and inhibited the activation of the NLRP3 inflammasome and subsequent inflammatory reactions.
    CONCLUSION: DHJSD exerts a protective effect on NP cells by suppressing the activation of the NLRP3 inflammasome and subsequent imbalance in the extracellular matrix via mitophagy, which is potentially associated with the activation of the HIF-1α signaling pathway and the preservation of the metabolic balance of the mitochondria.
    Keywords:  Duhuo Jisheng decoction; Intervertebral disc degeneration; HIF-1alpha; Network pharmacology; Mitophagy; NLRP3; Inflammasome
    DOI:  https://doi.org/10.1007/s11596-026-00184-x
  51. J Hazard Mater. 2026 Mar 17. pii: S0304-3894(26)00743-0. [Epub ahead of print]507 141765
    Silicon carbide nanoparticles induce pulmonary fibrosis by promoting macrophage apoptosis through parkin-mediated mitophagy disruption and the intervention effect of emodin.
    Sufang Wu, Xianglong Wu, Nuo Xu, Ze Li, Yang Dong, Chenxing Zhang, Qian Liu, Huang Chen, Lele Liu, Yanxin Hu, Gancen Zhang, Yunru Liu, Jin Xu, Aihua Gu.
      Silicon carbide nanoparticles (SiC-NPs), an emerging class of nanomaterials, have garnered extensive applications in industrial and biomedical fields. The escalating use of SiC-NPs engenders substantial concerns regarding the potential biosafety implications. Previous studies indicate the association between silicon carbide exposure and elevated incidence of pulmonary fibrosis. However, the underlying mechanisms remain insufficiently elucidated. In this study, we investigated the role of SiC-NPs in pulmonary fibrosis development, employing THP-1-derived macrophages (THP-M) for in vitro experimentation and C57BL/6 mice for in vivo analyses. Our study demonstrated that exposure to SiC-NPs led to the production of reactive oxygen species (ROS) and mitochondrial damage in macrophages. This sequence of events impaired mitophagy and subsequently triggered macrophage apoptosis, ultimately contributing to the pathogenesis of pulmonary fibrosis. Mechanistically, we elucidated that SiC-NPs promoted the ubiquitin-mediated degradation of Parkin, resulting in dysregulated mitophagy. Furthermore, we revealed that emodin treatment mitigated SiC-NPs-induced pulmonary fibrosis by restoring Parkin expression. Our study provides novel insights into the detrimental effects and underlying mechanisms of SiC-NPs in pulmonary fibrosis, as well as highlighting the therapeutic potential of emodin.
    Keywords:  Emodin; Macrophage; Mitophagy; Pulmonary fibrosis; Silicon carbide nanoparticles
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141765
  52. Elife. 2026 Mar 26. pii: e103118. [Epub ahead of print]15
    Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila.
    Francisco Muñoz-Carvajal, Nicole Sanhueza, Mario Sanhueza, Felipe A Court.
      Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPRMT), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPRMT is the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPRMT response can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. Using Drosophila, we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPRMT in olfactory projection neurons leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPRMT activation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This in turn prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPRMT, impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPRMT regulators in age-related neurodegeneration and loss of olfactory function.
    Keywords:  D. melanogaster; cell biology; neuroscience
    DOI:  https://doi.org/10.7554/eLife.103118
  53. Cell Rep. 2026 Mar 24. pii: S2211-1247(26)00255-X. [Epub ahead of print]45(4): 117177
    MAP2K6 directly phosphorylates BCL2L13 to mediate mitophagy for suppressing tumorigenicity.
    Guangsuo Xing, Yile Huang, Xiwen Liu, Linpeng Li, Zichao Liu, Yi Wu, Yanshuang Zhou, Yingzhe Ding, Baodan Chen, Guanru Xue, Zijing Li, Zhihong Hao, Yang Liu, Wenhui Fan, Haolin Ding, Shan Liang, Jingcai He, Junwei Wang, Jian Zhang, Dajiang Qin, Wuming Wang, Gang Lu, Wai-Yee Chan, Pixin Ran, Huaiqiang Ju, Ming Dong, Wenhua Liang, Xingguo Liu, Keshi Chen.
      The mitogen-activated protein kinase (MAPK) pathway widely regulates development and cancer. However, the subcellular localization and function of the secondary kinases in the MAPK pathway remain unclear. Here, we identified mitogen-activated protein kinase kinase 6 or 3 (MKK6/MKK3) as tumor suppressors that could significantly activate mitophagy and suppress tumor growth in lung adenocarcinoma (LUAD). Mechanistically, among MKK1-7, only MKK6/MKK3 exhibited subcellular organellar localization in mitochondria and autophagosome interaction site. The function of MKK6 in mitophagy and tumorigenicity was dependent on its kinase activity, but not through p38. MKK6 directly phosphorylated BCL2L13 at serine 426, enhancing the interaction between BCL2L13 and LC3B, which, in turn, promoted mitophagy, inhibited oxidative phosphorylation (OXPHOS), and prevented tumor growth. Our studies not only revealed that MKK6-BCL2L13 phosphorylation at the interorganellar site can affect mitochondrial quality in tumorigenicity but also might provide a potential therapeutic strategy for LUAD treatment.
    Keywords:  CP: cancer; CP: metabolism; OXPHOS; autophagy; cancer metabolism; metabolism; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117177
  54. Toxicology. 2026 Mar 24. pii: S0300-483X(26)00061-2. [Epub ahead of print] 154454
    Mitochondrial perspectives on environmental pollutant-induced male reproductive toxicity.
    Qiujian Feng, Zhuozhi Gong, Bin Yan, Boda Guo, Jun Guo, Shengjing Liu.
      With rapid industrialization and urbanization, environmental pollutants have emerged as a major threat to male reproductive health, and declining semen quality together with rising rates of male infertility has now become a global public health concern. Owing to its high energetic demand and specialized cellular organization, the testis is especially vulnerable to pollutants, with mitochondria serving as a principal target because they coordinate energy metabolism and apoptotic control. Here we synthesize evidence on how heavy metals, air pollutants, organic pollutants, endocrine disrupting chemicals, micro(nanoplastics), pesticides, and mycotoxins injure testicular mitochondria and the mechanisms involved. Current evidence indicates that these pollutants compromise spermatogenesis and androgen production via convergent mitochondrial pathways, including oxidative stress, metabolic disruption, mitochondria dependent apoptosis, imbalance of mitochondrial dynamics, suppressed biogenesis, and dysregulated mitophagy. Importantly, these mechanisms are not independent, since individual pathways may dominate under specific exposure scenarios, yet they can also intersect and mutually reinforce one another to generate a multistep cascading network that culminates in reproductive injury. Therefore, mitochondrial dysfunction represents a central convergent node through which pollutants drive male reproductive toxicity. Future work should prioritize low dose, long term, and mixture exposure models, integrate multi omics approaches with testicular organoid platforms, define key regulatory pathways, identify early biomarkers, and evaluate mitochondria targeted interventions to support environmental risk assessment and prevention of male reproductive injury.
    Keywords:  disordered energy metabolism; environmental pollutants; mitochondrial quality control; oxidative stress; reproductive toxicity; testicular mitochondria
    DOI:  https://doi.org/10.1016/j.tox.2026.154454
  55. EMBO J. 2026 Mar 24.
    Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
    Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.
      Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.
    Keywords:  AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis
    DOI:  https://doi.org/10.1038/s44318-026-00734-y
  56. Cell Death Dis. 2026 Mar 26.
    HIF-1α suppresses SNPH expression to facilitate liver metastasis of colorectal cancer through regulating mitochondrial dynamics and filopodia formation.
    Lei Zhan, Xiaoxi Li, Xiaoyan Li, Qian Fei, Yue Jin, Jiaxing Yu, Luyao Tian, Feifei Li, Chunning Li, Qian Dong, Yong Zhang, Shulan Sun, Jingdong Zhang.
      Colorectal cancer (CRC) is a leading cause of cancer-associated deaths, with liver metastases developing in about 50% of patients. Mitochondrial dynamics play critical roles in a diverse range of cellular functions, including cell migration and cancer metastasis. However, the influence of mitochondrial dynamics deregulation in CRC liver metastasis is incompletely understood. Through multiple transcriptomic data analysis and validation, we found that low expression of SNPH significantly correlated with poor prognosis of CRC patients. SNPH knockdown altered mitochondrial dynamics to increase cell migration and invasion by promoting filopodia formation. Moreover, the reduced levels of SNPH were linked to HIF-1α expression. Luciferase reporter assay revealed that HIF-1α transcriptionally activated miR-130a-3p expression, which targeted SNPH mRNA to inhibit its protein levels. Furthermore, miR-130a-3p inhibitor suppressed SNPH downregulation, filopodia formation, and CRC cells metastasis under hypoxic conditions. Mechanistically, SNPH downregulation promoted ROS production, resulting in the activation of the AKT/cdc42 pathway and downstream PAK1/Cofilin cascade. The overexpression of SNPH increased mitochondrial fusion and deterred the liver metastasis ability of CRC cells in vivo. Together, our results suggest that SNPH suppression imposed by the HIF-1α/miRNA-130a-3p axis under hypoxia conditions promotes the liver metastasis of CRC cells by activating the AKT/cdc42-PAK1/Cofilin cascade through mitochondrial dynamics-mediated ROS production.
    DOI:  https://doi.org/10.1038/s41419-026-08551-1
  57. J Nanobiotechnology. 2026 Mar 27.
    MSC-derived exosomes ameliorate systemic lupus erythematosus by reprogramming macrophage mitochondrial homeostasis via the CMPK2-cGAS-STING axis.
    Jie Zang, Jinjin Chu, Wenchang Sun, Chunjuan Yang, Zhuojian Qu, Huaiyu Bie, Yujie Wang, Jintao Guo, Donghua Xu.
      
    Keywords:  Cytidine/uridine monophosphate kinase 2; Macrophage polarization; Mesenchymal stem cell-derived exosomes; Mitochondrial reprogramming; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1186/s12951-026-04320-6
  58. Exp Gerontol. 2026 Mar 19. pii: S0531-5565(26)00085-9. [Epub ahead of print]217 113107
    Mediterranean diet preserves renal mitochondrial homeostasis and attenuates early diabetic kidney injury in db/db mice.
    Giovanna Mercurio, Antonia Giacco, Nicla Scopigno, Michela Vigliotti, Vittorio Maria Mandrone, Matteo Mazzola, Ettore Varricchio, Alberto Fiore, Giuseppe Riccio, Maria Moreno, Federica Cioffi, Elena Silvestri.
       BACKGROUND: Chronic hyperglycemia, oxidative stress, and mitochondrial dysfunction are central drivers of renal structural and functional alterations associated with metabolic disease and accelerated tissue aging. In type 2 diabetes mellitus (T2DM), these mechanisms contribute to early kidney injury and progressive decline in renal resilience. Dietary interventions, including the Mediterranean diet (MD), have been proposed as complementary strategies to counteract metabolic stress, yet mechanistic evidence at the renal mitochondrial level remains limited.
    METHODS: Male db/db mice, a model of obesity- and diabetes-associated metabolic stress, were fed for 8 weeks a standard diet (SD), a Western diet (WD), or a lab-designed MD-based food mix. Db/m littermates on SD served as controls. Renal function, morphology, and molecular pathways related to mitochondrial homeostasis, oxidative stress, and tissue remodeling were assessed through metabolic profiling, histological evaluation, and protein expression analyses.
    RESULTS: Db/db mice displayed overt metabolic dysfunction with increased glucosuria, polyuria, and water intake. SD- and WD-fed db/db animals showed a significant increase in urinary albumin-to-creatinine ratio (uACR), whereas MD-fed db/db mice maintained uACR at control levels, together with preserved serum creatinine and potassium. Histological analyses revealed attenuation of tubular hydropic changes and prevention of glomerular hypertrophy and hypercellularity under MD. At the molecular level, MD preserved nephrin expression, prevented diabetes-induced increases in NOX2, RAGE, and nitrotyrosine, and maintained mitochondrial dynamics by preserving the fission/fusion balance. Moreover, MD limited alterations in autophagy/mitophagy markers and reduced profibrotic (MT-MMP1, TIMP2) and hypoxia-related (HIF1α, VEGF) signaling.
    CONCLUSIONS: A balanced MD-based dietary mix preserves renal structure and function in db/db mice by counteracting oxidative stress, mitochondrial dysfunction, and early fibrotic remodeling. These findings support the MD as a potential nutritional strategy to enhance renal resilience and mitigate metabolic stress-induced kidney aging in the context of diabetes and obesity.
    Keywords:  Fibrosis; Metabolic stress; Mitochondrial homeostasis; Nutritional therapy; Renal aging
    DOI:  https://doi.org/10.1016/j.exger.2026.113107
  59. Nutrients. 2026 Mar 18. pii: 955. [Epub ahead of print]18(6):
    Nature's Bioactives in Cardiorenal Syndrome: Polyphenols at the Crossroads-Preclinical Insights into Redox, Inflammation, and Mitochondrial Protection.
    Caterina Carollo, Maria Elena Ciuppa, Alessandra Sorce, Salvatore Evola, Emanuele Cirafici, Maria Giovanna Vario, Roberta Scimeca, Rosalia Lo Presti, Giuseppe Mulè, Gregorio Caimi.
       BACKGROUND: Cardiorenal syndrome (CRS) represents a complex clinical entity characterized by the bidirectional dysfunction of the heart and kidneys. Despite advances in pharmacological therapy, CRS remains associated with high morbidity and mortality. Pathophysiological drivers, including oxidative stress, chronic inflammation, and mitochondrial derangements, create a self-perpetuating cycle of organ damage that necessitates multitarget therapeutic approaches.
    OBJECTIVE: This review synthesizes current preclinical evidence regarding the protective roles of plant-derived polyphenols-specifically bergamot, curcumin, quercetin, catechins, and resveratrol-in mitigating the cardiorenal continuum.
    METHODS: An analysis of recent literature was conducted, focusing on the molecular mechanisms by which these bioactives modulate redox balance, inflammatory signaling, and mitochondrial homeostasis in experimental models of CRS.
    RESULTS: Polyphenols act at the crossroads of several stress-response pathways. Key mechanisms include the activation of the Nrf2/HO-1 axis to enhance endogenous antioxidant defenses, the suppression of the NLRP3 inflammasome to attenuate systemic "inflammaging", and the preservation of mitochondrial quality through SIRT1/PINK1/Parkin-mediated mitophagy. Furthermore, emerging evidence highlights the role of polyphenols in modulating the gut-kidney-heart axis by reducing microbiota-derived uremic toxins.
    CONCLUSIONS: Preclinical data suggest that polyphenols are potent multifunctional agents capable of breaking the feedback loops of cardiorenal injury. While bioavailability remains a significant translational challenge, novel nano-delivery systems and synthetic analogs offer promising strategies for clinical application. Integrating these bioactives into CRS management could provide a decisive adjunctive strategy to improve metabolic homeostasis and prevent end-stage organ failure.
    Keywords:  NLRP3 inflammasome; Nrf2; cardiorenal syndrome; mitophagy; oxidative stress; polyphenols
    DOI:  https://doi.org/10.3390/nu18060955
  60. Cell Commun Signal. 2026 Mar 28.
    Metformin attenuates HSV-1-induced neuropathic pain by restoring Sirt3-mediated mitophagy.
    Yuanyuan Fang, Mengqiu Deng, Kesheng Huang, Honghao Song, Yan Chu, Huawei Wei, Dashuang Chen, Yutong Yang, Chaofeng Han, Hongbin Yuan.
      
    Keywords:  HSV-1-induced neuropathic pain; Metformin; Microglia; Neuroinflammation; Sirt3
    DOI:  https://doi.org/10.1186/s12964-026-02841-z
  61. Emerg Microbes Infect. 2026 Mar 26. 2651468
    Abolishing PorB-induced mitophagy enhances gonococcal outer membrane vesicle vaccine efficacy.
    Haoyu Ge, Yuling Qin, Shuaijie Song, Dailin Yuan, Shuai Gao, Xu'ai Lin, Stijn van der Veen.
      AbstractThe emergence and global spread of ceftriaxone-resistant Neisseria gonorrhoeae underscores the urgent need for an effective vaccine. Gonococcal outer membrane vesicles (OMVs) are promising as vaccine platform, but their efficacy is potentially compromised by the immunomodulatory properties of gonococcal surface-expressed proteins, particularly the essential outer membrane porin PorB. Our previous work identified that gonococcal OMVs induce epithelial cell mitophagy via PorB, dependent on lysine residues 117 and 171. Given the critical role of dendritic cells (DCs) in initiating adaptive immunity, this study investigated whether PorB-mediated mitophagy in DCs impacts OMV vaccine efficacy. Here, we demonstrated that gonococcal OMVs induce DC mitophagy in a PorB-dependent manner, a process abolished in OMVs expressing the mitophagy-deficient PorB mutant PorBK117Q/K171Q. OMVs expressing PorBK117Q/K171Q demonstrated significantly enhanced DC activation, as shown by increased CD86 and MHC-II expression, and promoted a Th1-skewed T cell response with elevated IFN-γ and TNF-α secretion. In immunized mice, OMVs containing PorBK117Q/K171Q elicited significantly higher total IgG and IgG2a antibody titers against PorB compared with OMVs expressing wild-type PorB, with antibodies displaying enhanced bactericidal activity, including against a strain associated with the high-level ceftriaxone-resistant FC428 clone. Importantly, the OMV PorBK117Q/K171Q vaccine provided enhanced protection in a mouse vaginal colonization model, accelerating bacterial clearance and reducing overall bacterial burden. Therefore, our results identify PorB-induced mitophagy in DCs as a potential immune evasion mechanism that may dampen adaptive immunity. Engineering OMV vaccines to circumvent this process represents a rational strategy to explore for enhancing gonococcal vaccine efficacy.
    Keywords:  Neisseria gonorrhoeae; OMV; dendritic cells; mitophagy; vaccine
    DOI:  https://doi.org/10.1080/22221751.2026.2651468
  62. J Clin Med. 2026 Mar 20. pii: 2381. [Epub ahead of print]15(6):
    Correction: Chen et al. Bicalutamide Exhibits Potential to Damage Kidney via Destroying Complex I and Affecting Mitochondrial Dynamics. J. Clin. Med. 2022, 11, 135.
    Kuan-Chou Chen, Chang-Rong Chen, Chang-Yu Chen, Chiung-Chi Peng, Robert Y Peng.
      In the original publication [...].
    DOI:  https://doi.org/10.3390/jcm15062381
  63. Toxics. 2026 Feb 28. pii: 208. [Epub ahead of print]14(3):
    Mitochondrial Ultrastructure, Fission Proteins, Activity, and Motor Dysfunctions in the Innovative Parkinson's Disease Model Induced by Manganese Inhalation.
    Cesar Alfonso Garcia-Caballero, Jose Luis Ordoñez-Librado, Avril De Alba-Ríos, Enrique Montiel-Flores, Omar Emiliano Aparicio-Trejo, Fernando García-Arroyo, Belén Cuevas-Lopez, José Pedraza-Chaverri, Vianey Rodríguez-Lara, Rocío Tron-Alvarez, Ana Luisa Gutierréz-Valdez, Javier Sánchez-Betancourt, Leonardo Reynoso-Erazo, Maria Rosa Avila-Costa.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet its pathogenic mechanisms remain incompletely understood, highlighting the need for reliable experimental models. We previously developed a murine model based on inhalation of a manganese mixture (MnCl2 and Mn(OAc)3), which reproduces dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and motor impairment. However, its capacity to mimic mitochondrial dysfunction, a key mechanism in PD, had not been explored. This study evaluated mitochondrial ultrastructure, fission and fusion proteins, and the activity of electron transport chain complexes I and IV, alongside fine motor performance. Forty male CD1 mice were divided into control (deionized water) and manganese-exposed groups (0.04 M MnCl2 + 0.02 M Mn(OAc)3), inhaled for 1 h twice weekly over five months. Manganese inhalation induced significant fine motor deficits, increased mitochondrial number with reduced area and circularity, and disorganized cristae. Drp1 and Fis1 levels were elevated, accompanied by decreased activity of complexes I and IV, predominantly in the SNc. These findings demonstrate that this progressive, bilateral model reproduces mitochondrial and motor alterations resembling those observed in PD, supporting its utility for testing mitochondria-targeted therapeutic strategies.
    Keywords:  Drp1; Fis1; Parkinson’s disease; animal model; manganese; mitochondria; mitochondrial activity; ultrastructure
    DOI:  https://doi.org/10.3390/toxics14030208
  64. J Dent Res. 2026 Mar 28. 220345261427294
    MFN2-PERK Axis Regulates ER Stress in Parotid Glands of Aged Mice via MAMs.
    Y Chen, Y M Xu, L L Zhu, Z Y Shan, Z G Yao, H Zhao.
      With aging, the morphology and function of the parotid glands are impaired, and the current mechanism is unknown. The integrity of mitochondria-associated membranes (MAMs), the structure connecting mitochondria and the endoplasmic reticulum (ER), is compromised during aging. This study investigated the effects of aging on MAMs and ER stress in the parotid glands of mice. Here, aged mice presented abnormalities in gland morphology and mitochondrial morphology and reduced MAMs integrity. Protein kinase R-like endoplasmic reticulum kinase (PERK) signaling is the primary mediator of ER stress, which is activated in the parotid glands of aged mice. Furthermore, aging-induced MFN2 downregulation disrupts mitochondrial dynamics. In addition, aging reduces MAMs function by blocking the MFN2-PERK interaction. Treatment with 4-phenylbutyric acid (4-PBA) improved MAMs integrity, inhibited the PERK pathway, and reduced apoptosis. Like 4-PBA, GSK2606414, a pharmacological antagonist of PERK, regulates ER stress and MAMs. Collectively, our data highlight disruption of the MFN2-PERK axis-mediated ER-mitochondrion connection as a cause of aging-induced parotid gland dysfunction.
    Keywords:  aging; endoplasmic reticulum stress; mitochondria-associated membranes; mitofusin 2; oxidative stress; protein kinase R-like endoplasmic reticulum kinase
    DOI:  https://doi.org/10.1177/00220345261427294
  65. Cell Commun Signal. 2026 Mar 26.
    The SDF-1α/CXCR4 axis regulates chondrocyte mitochondrial dynamics via the ERK/AMPKα pathway.
    Jiazhou Li, Hao Chen, Mengmeng Duan, Sijun Liu, Shasha Tu, Li Zhang, Xuedong Zhou, Jing Xie.
      
    Keywords:  CXCR4; Chondrocyte; ERK/MAPK signalling; Mitochondrial dynamics; SDF-1α
    DOI:  https://doi.org/10.1186/s12964-026-02827-x
  66. Colloids Surf B Biointerfaces. 2026 Mar 24. pii: S0927-7765(26)00226-2. [Epub ahead of print]264 115638
    ROS-triggered smart nanoplatform promotes osteoarthritis repair by modulating macrophage polarization and mitochondrial homeostasis.
    Weijian Chen, Jifeng Zhao, Jiasheng Tao, Xiaodong Lin, Yizhe Song, Wenxiang Weiyang, Chao Lu, Peng Peng, Tao Jiang, Chuanxi Zhao, Wengang Liu.
      Oxidative stress and inflammation intertwine to form a self-amplifying "vicious cycle", posing the core factor driving the progression of osteoarthritis (OA). Disrupting this cycle by regulating macrophage polarization, reducing oxidative stress, and maintaining mitochondrial homeostasis is a key strategy to fundamentally halt OA progression. In this study, a ROS-triggered intelligent nanodelivery system (CS@mPDA@Res) was developed to effectively promote OA repair. The system employs mesoporous polydopamine (mPDA) loaded with resveratrol (Res) as the core. By leveraging the high specific surface area and acid resistance of mPDA, this system enables sustained drug release within the OA joint microenvironment. Subsequently, the mPDA@Res nanoparticles were further coated with thioketal (TK)-modified chitosan (CS) as an outer shell. The CS shell disassembles upon ROS stimulation, enabling on-demand release of Res to efficiently promote OA repair through its anti-inflammatory and antioxidant activities. The results demonstrated that CS@mPDA@Res exhibits ROS-triggered intelligent drug release properties and excellent free radical scavenging capacity. In vitro cellular experiments showed that CS@mPDA@Res effectively modulates macrophage polarization, and alleviate oxidative stress-induced mitochondrial dysfunction and cartilage matrix degradation in chondrocytes. In vivo studies further revealed that CS@mPDA@Res treatment significantly alleviates OA joint damage. On day 28 of treatment, OA rats in the CS@mPDA@Res group exhibited 74.1% and 68.69% reductions in Mankin score and International Cartilage Repair Society (ICRS) score, respectively, compared to the model group. In summary, CS@mPDA@Res offers a novel and highly promising therapeutic approach for OA treatment.
    Keywords:  Macrophage polarization; Mitochondrial homeostasis; Osteoarthritis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.colsurfb.2026.115638
  67. J Photochem Photobiol B. 2026 Mar 21. pii: S1011-1344(26)00076-X. [Epub ahead of print]278 113429
    Subcellular photoprotection through precision nutraceuticals: Divergent actions of rutin and punicalagin on redox and mitochondrial homeostasis in human dermal fibroblasts.
    Alessia Riente, Flavio Di Giacinto, Michele Maria De Giulio, Benedetta Niccolini, Elisabetta Tabolacci, Maria Elisabetta Clementi, Marco De Spirito, Giuseppe Maulucci.
      Excessive ultraviolet A (UVA) exposure is a major environmental factor contributing to skin photoaging and oxidative damage. Identifying natural compounds that can counteract these effects is increasingly relevant for preventive and personalized healthcare. Precision nutrition uses diet-derived bioactives to modulate molecular pathways in defined cellular contexts. Polyphenols are promising for sustaining redox and metabolic balance under stress. This study examined the photoprotective actions of rutin (buckwheat, citrus peel) and punicalagin (pomegranate) in human dermal fibroblasts exposed to UVA radiation. Phasor-based fluorescence lifetime imaging microscopy (FLIM) quantified lipid peroxidation-related oxidative stress (Fox) and oxidative phosphorylation activity (Foxphos). Mitochondrial morphology was assessed via fission (Fis1) and fusion (MFN2) markers. Though UVA exposure tended to increase oxidative stress, the observed variation is not significant. Rutin provided superior antioxidant protection under UVA stress, substantially reducing Fox to 0.129 ± 0.02 with a near-significant trend, while punicalagin demonstrated stronger baseline antioxidant activity. Both compounds enhanced oxidative phosphorylation under stress: punicalagin increased Foxphos to 0.823 ± 0.02 (p = 0.004 vs UVA) and rutin to 0.789 ± 0.02 (p = 0.023 vs UVA). UVA disrupted mitochondrial networks, elevating fission and reducing fusion. Rutin reversed these effects, restoring fusion and reducing fission, whereas punicalagin provided partial recovery. In summary, rutin offered broader cytoprotection by mitigating oxidative stress and preserving mitochondrial integrity, while punicalagin mainly supported metabolic activity. These distinct responses highlight polyphenol-based nutraceuticals as precision tools for targeted skin photoprotection, suggesting their potential use in dietary or topical formulations to counteract everyday UVA exposure and photoaging.
    Keywords:  Fluorescence lifetime imaging microscopy; Oxidative stress; Phasor analysis; Polyphenols; UVA photoprotection
    DOI:  https://doi.org/10.1016/j.jphotobiol.2026.113429
  68. Genes (Basel). 2026 Mar 19. pii: 341. [Epub ahead of print]17(3):
    Frequency and Hearing Loss Phenotypes of OPA1 Variants in a Cohort of 18,475 Patients with Hearing Impairment.
    Masayuki Kawakita, Hideaki Moteki, Shin-Ya Nishio, Yumiko Kobayashi, Mika Adachi, Takayuki Okano, Hiroshi Yamazaki, Jun Nakayama, Shinya Ohira, Takashi Ishino, Yutaka Takumi, Shin-Ichi Usami.
       BACKGROUND/OBJECTIVES: The OPA1 gene encodes a dynamin-related GTPase essential for mitochondrial fusion. Variants in OPA1 are a major cause of autosomal dominant optic atrophy (DOA). A subset of DOA patients exhibits hearing loss, often manifesting as auditory neuropathy spectrum disorder (ANSD). In this study, we aimed to describe the frequency of OPA1-related hearing loss in a large cohort of patients with hearing loss and to explore the genotype-phenotype correlations and appropriate interventions.
    METHODS: A total of 18,475 Japanese patients with hearing loss were recruited. Targeted massively parallel sequencing of 158 deafness-related genes was performed, and individuals with OPA1 variants were identified. Clinical data, including age of onset, audiological findings, and systemic features, were retrospectively reviewed.
    RESULTS: Ten individuals from eight independent families carrying OPA1 variants were identified. Three variants were classified as pathogenic or likely pathogenic, while five were variants of uncertain significance. Hearing loss was typically post-lingual in onset and progressive, with predominantly mild-to-moderate severity. Missense variants tended to be associated with DOA-plus phenotypes and ANSD. Five patients obtained only limited benefit from hearing aids, whereas one patient who received a cochlear implant achieved good speech perception.
    CONCLUSIONS: OPA1 is a rare causative gene for hearing loss and is frequently associated with the ANSD phenotype. Affected individuals exhibited phenotypic heterogeneity, which may reflect incomplete penetrance or the influence of mitochondrial DNA-related factors.
    Keywords:  OPA1; auditory neuropathy spectrum disorder; cochlear implant; dominant optic atrophy; syndromic hearing loss
    DOI:  https://doi.org/10.3390/genes17030341
  69. Curr Issues Mol Biol. 2026 Mar 09. pii: 293. [Epub ahead of print]48(3):
    Identification and Validation of MTFP1 as a Mitochondrial Target Restoring Dynamics and ECM Remodeling in Acute Myocardial Infarction.
    Xi Hu, Hailong Bao, Yue Huang, Zhaoxing Cao, Wei Yang, Cheng Huang, Xin Chen, Yanbing Chen, Bingxiu Chen, Guiling Xia, Xiao Yang, Runze Huang, Zhangrong Chen.
      Background: Mitochondrial dysfunction is central to the pathogenesis of acute myocardial infarction (AMI), but mitochondria-related molecular biomarkers and mechanisms remain incompletely defined. This study aimed to identify mitochondria-associated biomarkers in AMI and elucidate their functional roles in mitochondrial dynamics, extracellular matrix (ECM) remodeling, and cardiac protection. Methods: Two GEO datasets (GSE19322, GSE71906) were analyzed to identify mitochondria-related differentially expressed genes (DE-MRGs) by intersecting DEGs with MitoCarta3.0 genes. Functional enrichment (GO/KEGG), LASSO regression, ROC curves, and nomogram modeling were employed to screen biomarkers. Immune infiltration profiling, GeneMANIA, GSEA, TF-mRNA and ceRNA network construction, and drug prediction analyses were performed. Expression validation was conducted via RT-qPCR, Western blot (WB), and immunohistochemistry (IHC) in murine AMI models and hypoxia-induced cardiomyocytes. Functional assays assessed cardiac performance (echocardiography), infarct size (TTC staining), fibrosis (Masson/Sirius red), oxidative stress (ROS), and ECM remodeling (MMP9/TIMP1 axis). Results: We identified 295 DE-MRGs, enriched in oxidative phosphorylation and mitochondrial metabolic pathways. Machine learning and validation analyses pinpointed MTFP1 and DNAJC28 as AMI biomarkers with strong diagnostic accuracy. In vivo and in vitro studies confirmed marked downregulation of MTFP1 post-AMI and under hypoxia. AAV9-mediated MTFP1 overexpression improved cardiac function, reduced infarct size, attenuated fibrosis, and decreased ROS levels. Mechanistically, MTFP1 upregulated phosphorylated DRP1 (Ser616) without altering total DRP1, balanced MMP9/TIMP1 activity, and suppressed fibrosis markers (COL1A1, α-SMA). Gelatin zymography indicated that MMP9 activation remained restrained despite elevated pro-MMP9, consistent with TIMP1-mediated regulation. Hypoxia-induced cardiomyocytes showed similar antifibrotic and antioxidative responses following MTFP1 overexpression. Conclusions: Our study identified MTFP1 as a novel mitochondria-related biomarker and therapeutic modulator in AMI. MTFP1 exerts cardioprotective effects by restoring mitochondrial fission balance and ECM remodeling through the p-DRP1/MMP9/TIMP1 signaling axis, attenuating fibrosis and oxidative stress. These findings provide mechanistic insight into mitochondria-targeted cardioprotection and highlight MTFP1 as a promising diagnostic and therapeutic target for AMI.
    Keywords:  DRP1/MMP9/TIMP1 axis; ECM remodeling; MTFP1; acute myocardial infarction; biomarkers; mitochondria
    DOI:  https://doi.org/10.3390/cimb48030293
  70. J Environ Sci (China). 2026 May;pii: S1001-0742(25)00463-2. [Epub ahead of print]163 252-261
    Antagonistic effects of selenium on methylmercury-induced toxicity through mitochondrial quality control and enhanced GSH synthesis in Caenorhabditis elegans.
    Yanan Zhao, Yuting Ding, Ruoyun Dong, Yuanyuan Wu, Chenxi Zhou, Yaguang Nie, Guoping Zhao, An Xu, Yun Liu.
      Selenium (Se), an essential trace element, plays a critical role in protecting the toxicity of methylmercury (MeHg). However, its detoxification mechanism for alleviating MeHg-induced damage remains largely unexplored. This study focused on the antagonistic effects of Se supplementation on the toxic responses induced by MeHg pretreatment in Caenorhabditis elegans. Our results showed that following a 20 h pre-exposure to MeHg, 4 h exposure to Se effectively and rapidly antagonized the reproductive and neurological impairments induced by MeHg. Meanwhile, we found that the total Hg content decreased from 166 ± 46.0 to 109 ± 18.7 µg/g after the addition of Se. Apart from inhibiting the bioaccumulation of Hg, Se supplementation reduced MeHg-induced reactive oxygen species (ROS) and promoted mitochondrial fusion to improve mitochondrial quality. In addition, MeHg-induced autophagy could be alleviated by increasing lysosome activity after the addition of Se. Further studies revealed that Se supplementation modulated the expression of gss-1 and gst-4, regulating glutathione (GSH) synthesis and elevated MeHg-decreased GSH content from 45.5 % to 79.7 %. These findings suggested that Se recovered MeHg-induced reproductive and neurological damage by modulating mitochondrial function and GSH synthesis, providing valuable insights for developing novel therapeutic strategies against MeHg toxicity.
    Keywords:  Detoxification; Glutathione; Mercury; Mitochondrial; Selenium
    DOI:  https://doi.org/10.1016/j.jes.2025.07.036
  71. Int Immunopharmacol. 2026 Mar 26. pii: S1567-5769(26)00397-8. [Epub ahead of print] 116552
    Corrigendum to "DPEP1 mediates regulation of mitochondrial quality control via FOXO1/ALDH1L2 axis to attenuate ferroptosis in pulmonary endothelial cells to alleviate sepsis-associated acute lung injury" [Int. Immunopharmacol. 170 (2026) 116049].
    Xin Yao, Ziang Wen, Junjie Liao, Yaling Meng, Peng Lu, Xiaopei Li, Zihao Shen, Ao Wang, Minchao Wu, Xiangyu Li, Wanjun Jin, Xiao Zhang, Yuanpu Qi, Jia Feng, Mingyu Chu, Jialin Zhang, Yixuan Dai, Xiaotian Qin, Faliang Zhan, Xiaowei Wang, Meijuan Song.
      
    DOI:  https://doi.org/10.1016/j.intimp.2026.116552
  72. J Transl Med. 2026 Mar 25.
    Mitochondria in situ releasing corosolic acid enhanced antitumor effects via activating mitophagy in castration-resistant prostate cancer.
    Jiaxin Zhang, Hang Zhang, Bin Fang, Haoqin Li, Limin Wang, Yi Liu, Tao Shao, Haixiao Fang, Bo Peng, Wei Zhang, Hua Bai, Bo Ma, Lin Li.
      
    Keywords:  In situ releasing; Mitochondria-targeted; Mitophagy; Organelle-targeted drug delivery; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s12967-026-08057-6
  73. J Food Sci. 2026 Mar;91(3): e70988
    Urolithin A From Gut Metabolite to Therapeutic Agent: Bioavailability, Mechanisms, and Translational Insights.
    Huidong Yuan, Wenjie Xie, Wen Tan, Changqing Wei, Wei Qin, Masatsugu Tamura, Xingqian Ye, Jinhu Tian.
      Accumulating evidences have demonstrated that urolithin A (UroA) exerted a wide range of bioactivities, including antioxidant, anti-inflammatory, and mitochondrial function-enhancing effects, thereby highlighting its potential as a therapeutic agent for various diseases. Preclinical studies have shown that UroA induced mitophagy both in vitro and in vivo, preventing age-associated mitochondrial dysfunction and improving lifespan and muscle function as well as enhancing exercise capacity. However, its clinical application is limited by poor oral bioavailability and considerable interindividual variability in microbial conversion, as pharmacokinetic studies indicated low plasma exposure under standard administration. Moreover, approximately 10% of individuals are classified as urolithin nonproducers, independent of age, posing an additional challenge for clinical translation. To overcome those limitations, formulation strategies such as nanoparticles and liposomes have been developed, resulting in several-fold increases in systemic bioavailability compared with unformulated UroA. This review would provide a comprehensive overview of recent advances in the metabolism of UroA, current approaches to improve its bioavailability, safety evaluations, and elucidated the underlying mechanisms of its bioactivities. Furthermore, recent progresses in chemical and biotechnological synthesis strategies of UroA are also summarized. These insights will provide a scientific foundation for further utilization of UroA for human health.
    Keywords:  bioavailability enhancement; gut microbiota metabolism; microbial fermentation; mitophagy; urolithin A
    DOI:  https://doi.org/10.1111/1750-3841.70988
  74. Phytomedicine. 2026 Mar 19. pii: S0944-7113(26)00329-6. [Epub ahead of print]155 158094
    Self-assembly of glycyrrhizic acid and aconitine alleviates heart failure by inhibiting autophagy and inducing reprogramming of energy metabolism.
    Yixin Liu, Zongjin Pu, Xiaonan Chen, Ying Peng, Chongsheng Peng, Xiaobo Li.
       BACKGROUND: Herb pairs are the fundamental basis of Traditional Chinese Medicine (TCM) prescriptions. The Aconitum carmichaelii Debx-Glycyrrhiza uralensis Fisch herb pair has superior anti-heart failure efficacy compared with the separate use of these two herbs. However, the active substances in this herb pair that protect against heart failure, and their interactions during decoction, are poorly understood.
    PURPOSE: To elucidate how aconitine (A) and glycyrrhizic acid (G), the active substances in this herb pair, react during decoction and the mechanism by which the reaction products alleviate heart failure.
    METHODS: A and G were decocted and formed a self-assembled complex (GA). We characterized the structure of GA and investigated its self-assembly mechanism. An in vivo and in vitro heart failure model was employed to investigate the mechanism by which GA alleviated heart failure.
    RESULTS: The self-assembly of A and G was driven by electrostatic interaction, intermolecular hydrogen bonds, and the hydrophilic/hydrophobic effects. GA alleviated heart failure in vivo and in vitro by inhibiting the overactivation of the MAPK-ERK pathways, restoring calcium homeostasis, and activating the lipoic acid metabolism pathway. Valosin-containing protein was identified as the target protein of GA by DARTS assays, and GA was proven to inhibit autophagy and prevent remodeling of mitochondria to inhibit mitophagy. GA-induced reprogramming of energy metabolism ultimately decelerated the progression of heart failure.
    CONCLUSION: We proposed that GA differs from G and A because only GA can bind the specific protein target and, by affecting different pathways, alleviate heart failure synergistically. Our research raised a new strategy for discovering the scientific explanation of TCM compatibility.
    Keywords:  Energy metabolism reprogramming; Heart failure; Mitophagy; Self-assembly of glycyrrhizic acid and aconitine
    DOI:  https://doi.org/10.1016/j.phymed.2026.158094
  75. Bioact Mater. 2026 Aug;62 319-341
    Inhalable PD-L1-engineered hybrid cellular vesicles suppress excessive neutrophil activation and restore mitochondrial homeostasis to alleviate ischemia-reperfusion lung injury and pneumonia.
    Haoxiang Yuan, Wei Wang, Jian Ma, Huafu Li, Rui Luís Reis, Ying Chen, Xin Xu, Yingying Yuan, Yiwen Li, Leping Yan, Zhijin Fan, Yuhui Liao, Jianxing He.
      Lung ischemia-reperfusion injury and severe pneumonia represent major clinical challenges with high mortality rates and a lack of effective targeted therapies after lung transplant. Their pathogenesis involves multiple factors, including immune dysregulation, oxidative stress, and mitochondrial dysfunction, which limit the efficacy of single-target treatment strategies. This study developed a novel biohybrid nanovesicle system (Res-PD-L1@nmEVs) that integrates the inflammatory targeting capability of neutrophil membrane-derived vesicles, the tissue repair and immunomodulatory functions of PD-L1-overexpressing mesenchymal stem cell extracellular vesicles, and the mitochondrial protective effects of resveratrol. Following nebulized administration, the system demonstrated enhanced pulmonary accumulation and efficient uptake by injured epithelial cells. In vitro experiments confirmed that Res-PD-L1@nmEVs inhibited inflammation and oxidative stress, reduced apoptosis, and restored mitochondrial integrity by activating PINK1-mediated mitophagy and promoting mitochondrial repair, thereby mitigating hypoxia-reoxygenation-induced injury in lung epithelial cells. The delivery of PD-L1 via Res-PD-L1@nmEVs binding to PD-1 on neutrophil membranes suppressed neutrophil activation and alleviated the release of inflammatory factors. In rat models of lung ischemia-reperfusion injury and methicillin-resistant Staphylococcus aureus-induced pneumonia, nebulized administration of Res-PD-L1@nmEVs significantly attenuated lung tissue damage, inhibited neutrophil activation, reduced inflammatory cytokine release, improved alveolar barrier integrity, promoted the recovery of pulmonary function, and alleviated hypoxemia. Transcriptomic analysis revealed that the treatment synergistically enhanced energy metabolism and biosynthetic processes while suppressing inflammatory pathways. This study presents a comprehensive targeted strategy that simultaneously addresses immune dysregulation, oxidative damage, and metabolic dysfunction in inflammatory lung diseases, demonstrating significant potential for clinical translation.
    Keywords:  Lung ischemia-reperfusion injury; Mesenchymal stem cell extracellular vesicles; PD-L1; Pneumonia; Resveratrol
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.03.024
  76. Phytomedicine. 2026 Mar 12. pii: S0944-7113(26)00303-X. [Epub ahead of print]155 158067
    A Ginkgo biloba-derived tRNA-derived fragment attenuates asthma by restoring airway structural cell homeostasis via mitochondrial regulation.
    Ling Feng, Tongmeng Yan, Tingting Xu, Xijing Yuan, Zhitong Mai, Xin Yao, Mao Huang, Zhihong Jiang, Yuan Ma.
       BACKGROUND: Airway remodeling is a critical driver of asthma progression and therapeutic resistance; however, treatment strategies that directly target and reverse this process are still lacking. There is growing evidence that tRNA-derived fragments (tRFs) sourced from Traditional Chinese Medicine (TCM) can modulate disease-associated genes and exert therapeutic effects. We specifically focused on Ginkgo biloba (G. biloba) because of its documented use in traditional practices for respiratory ailments and the reported lung-protective activities of its key bioactive components, such as ginkgolides and flavonoids. Yet, the function of G. biloba-derived tRFs in chronic respiratory conditions like asthma remains elusive, presenting a significant knowledge gap.
    PURPOSE: This study aimed to investigate the therapeutic potential of tRFs from G. biloba in asthma and to elucidate their underlying mechanisms of action.
    STUDY DESIGN: Key targets involved in airway remodeling were systematically identified and mapped to G. biloba-derived tRFs. Functional validation was subsequently performed using both asthmatic mouse models and airway structural cells.
    METHODS: We employed an integrated approach combining multi-sample sequencing, bioinformatics analysis, and experimental validation to identify central mediators of airway remodeling and to pinpoint a core G. biloba-derived tRF. The therapeutic efficacy and mechanistic basis of this tRF were further evaluated in house dust mite (HDM)-induced asthmatic mice, as well as in transforming growth factor beta 1 (TGF-β1)-stimulated bronchial epithelial cells (BECs) and airway smooth muscle cells (ASMCs), with or without tRF treatment.
    RESULTS: Integrated analysis of human clinical samples, public transcriptomic datasets, and an original TCM RNA database identified prostate transmembrane protein, androgen induced 1 (PMEPA1) as a critical regulator of airway remodeling. PMEPA1 was found to exacerbate mitochondrial dysfunction and dysregulate mitophagy in BECs and ASMCs, thereby promoting their transition to pathological phenotypes and perpetuating chronic airway inflammation. A specific G. biloba-derived tRNA fragment, NO.6-tRF-5-1 (abbreviated as tRF_G6), was identified as a potent regulator of PMEPA1. Treatment with tRF_G6 mimics effectively suppressed PMEPA1 expression, which in turn alleviated airway remodeling and inflammation. By attenuating mitochondrial damage and preventing pathological phenotype shifts in airway structural cells, tRF_G6 disrupts the self-sustaining cycle of airway remodeling in asthma.
    CONCLUSION: Our study reveals that a G. biloba-derived tRNA fragment attenuates asthma by targeting PMEPA1 and restoring mitochondrial function, thereby inhibiting airway remodeling. These results pinpoint PMEPA1 as a novel target and underscore the therapeutic potential of specifically targeting it with G. biloba-derived nucleic acids.
    Keywords:  Airway remodeling; Asthma; Mitochondrial damage; Mitophagy; PMEPA1; Traditional chinese medicine; tRNA-derived fragments
    DOI:  https://doi.org/10.1016/j.phymed.2026.158067
  77. Shock. 2026 Mar 16.
    5'tiRNA-32-LysCTT-11 Alleviates Sepsis-Induced Myocardial Injury by stabilizing Mfn2 and inhibiting mitochondrial dysfunction-mediated necroptosis.
    Jing Li, Ludong Yuan, Xiaofang Lin, Dan Ni, Chuanhuan Deng, Yuxuan Liu, Manqing Luo, Pengfei Liang, Bimei Jiang.
       BACKGROUND: Transfer RNA-derived small RNAs (tsRNAs) represent a novel class of non-coding RNAs increasingly implicated in cardiovascular regulation. However, their roles in sepsis-induced cardiomyopathy (SICM) remain largely undefined. This study aimed to investigate the function and underlying mechanism of 5'tiRNA-32-LysCTT-11-a highly upregulated tsRNA in SICM-in modulating myocardial injury.
    METHODS: A murine model of sepsis was established via cecal ligation and puncture (CLP), and myocardial injury was assessed by serum CK-MB/LDH levels, histology, and cardiac function via echocardiography. In vitro, H9C2 cardiomyocytes were exposed to conditioned media (CM) from lipopolysaccharide (LPS)-stimulated macrophages. The expression of 5'tiRNA-32-LysCTT-11 was measured by qRT-PCR. Functional assays including CCK-8, LDH release, PI staining, JC-1, ATP, ROS detection, and MitoTracker staining were performed. Necroptosis was evaluated via MLKL phosphorylation; Mitochondria-associated endoplasmic reticulum membranes (MAMs) formation was assessed by dual-label immunofluorescence and Pacs2 expression. Bioinformatics analysis identified Mitofusin 2 (Mfn2) as a putative target, validated by Western blot, mRNA stability assay (Actinomycin D), and rescue experiments.
    FINDINGS: 5'tiRNA-32-LysCTT-11 was significantly upregulated in SICM. In vivo, its overexpression improved cardiac function and reduced injury biomarkers. In vitro, 5'tiRNA-32-LysCTT-11 mimics preserved mitochondrial integrity, reduced ROS and ATP depletion, suppressed MAM formation and necroptosis. Inhibitor transfection produced opposite effects. Mechanistically, 5'tiRNA-32-LysCTT-11 enhanced Mfn2 mRNA stability and protein expression. Silencing Mfn2 abrogated the protective effects, confirming its central role in the tsRNA's action.
    INTERPRETATION: 5'tiRNA-32-LysCTT-11 exerts cardioprotective effects during sepsis by stabilizing Mfn2 mRNA, preserving mitochondrial function, limiting MAMs formation, and suppressing necroptosis. These findings uncover a novel regulatory mechanism and suggest 5'tiRNA-32-LysCTT-11 as a promising therapeutic target in SICM.
    Keywords:  5’tiRNA-32-LysCTT-11; Cardiomyocytes; Mfn2; Mitochondria; Necroptosis; Sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.1097/SHK.0000000000002821
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