bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–02–01
sixty-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. Ginsenoside Rb1 normalizes mitochondrial dynamic homeostasis and alleviates glufosinate-ammonium-induced testicular damage through targeting Drp1.
  2. UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment.
  3. A TFAP4-UBC9-SUMO1 axis orchestrates pathological mitochondrial hyperfission in diabetic complications.
  4. Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
  5. MFN2 interacts with phosphorylated AMPK to mediate mitophagy in MCF-7 cells.
  6. 4-(1-Methylethoxy)-N-(2-methyl-8-quinolinyl)-benzamide (CDN1163) Attenuates Glutamate-Induced Excitotoxicity by Suppressing ER Stress and Restoring Mitochondrial Dynamics in N2a Cells.
  7. PHB2 mitigates intervertebral disc degeneration by modulating mitophagy to inhibit necroptosis in nucleus pulposus cells.
  8. Retraction: Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease.
  9. Retraction: A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
  10. Recent Progress in Hydrogen-mediated Neuroprotection via Modulation of Mitochondrial Quality Control Mechanisms in Brain Injury.
  11. Enriched Environment Ameliorates Cerebral Ischemia-Reperfusion Injury via Dopamine-H2S Axis-Mediated Dual Mitophagy Activation.
  12. Dexmedetomidine Attenuates Hyperoxia-Induced Lung Injury in BPD Mice via Regulation of the Mitophagy-NLRP3-Pyroptosis Pathway.
  13. SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
  14. Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
  15. Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
  16. BAP31 Modulates Mitochondrial Homeostasis Through PINK1/Parkin Pathway in MPTP Parkinsonism Mouse Models.
  17. The Role of Mitochondrial Dynamics in Metabolic Dysfunction-Associated Steatotic Liver Disease and the Regulatory Mechanisms of Exercise Intervention: A Systematic Review of Preclinical Studies.
  18. ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
  19. Microtubule affinity-regulating kinase 4 exacerbates diabetic cardiomyopathy by inhibiting UNC-51-like kinase 1-mediated mitochondrial autophagy.
  20. Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
  21. Mito-nuclear communication: From cellular responses to organismal health.
  22. Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
  23. A Non-Mitophagy Activity of BNIP3L/NIX in Amygdala Glutamatergic Neurons is Essential for Contextual Fear Memory Formation.
  24. Functionalized hydrogels of CeO2 and Urolithin A synergistically scavenge ROS and activate mitophagy for cartilage repair.
  25. Deficiency of FNDC5/Irisin Impairs the Protective Effect of Exercise Against Post-Infarction Myocardial Mitochondrial Injury.
  26. Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis.
  27. Bamboo Rapid Growth: Energy Homoeostasis, Mitochondrial Dynamics and Membrane Crosstalk.
  28. Electroacupuncture pretreatment regulates mitophagy in ULK1 knockout mice subjected to cerebral ischemia-reperfusion injury.
  29. Icaritin alleviates UVB-induced skin damage by inhibiting ferroptosis via modulation of mitochondrial dynamics.
  30. PRKAB2 as a tumor suppressor in renal cell carcinoma: inhibiting mitophagy via the LRPPRC-PRKN/parkin interaction and cardiolipin biosynthesis.
  31. Chronic stress-induced steroids mediate mitochondrial fission and fibrosis in the trabecular meshwork via the MIEF1-MAOA complex.
  32. Rutin Maintains the Thermogenic Phenotype of Beige Adipocytes and Concomitantly Suppresses Mitophagy Against Obesity in HFD Mice.
  33. Deletion of Glaesserella parasuis nanA promotes apoptosis by inhibiting PINK1/Parkin pathway.
  34. Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
  35. NCOR1 alleviates myocardial infarction by improving lipid peroxidation through PPARG/PINK1-mediated mitophagy.
  36. Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
  37. Pinellia pedatisecta Schott-Derived Exosome-Like Nanovesicles Promote Apoptosis in Colorectal Cancer by Regulating the Lysosome-Mediated Mitophagy Pathway.
  38. Zalcitabine induces ferroptosis in multiple myeloma through the TFAM-cGAS-STING-SLC7A11 axis.
  39. Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells.
  40. Association of HIF1α, BNIP3, and BNIP3L with Hypoxia-Related Metabolic Stress in Metabolic Syndrome.
  41. Molecular mechanism of berberine in ameliorating leptin resistance and mitochondrial dysfunction through the TRIB1-C/EBPα axis in obesity.
  42. Investigating the Potential Role of Capsaicin in Facilitating the Spread of Coxsackievirus B3 via Extracellular Vesicles.
  43. A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy.
  44. Gastrodin Ameliorates Pain-Depression Comorbidity through SIRT3-Dependent Alleviation of Oxidative Stress and Promotion of Mitochondrial Biogenesis.
  45. Molecular Subtyping and Prognostic Prediction in Pancreatic Cancer Based on Mitophagy-Related Genes.
  46. Targeting the mitochondrial metabolite-dynamics-MDVs-MitoEVs axis: a new frontier in osteoarthritis management.
  47. Ferroptosis-dependent small extracellular vesicles ULK1 enhances mitophagy and suppresses breast cancer migration.
  48. OPA1 as a Cancer Target: Molecular Mechanisms, Structural Insights, and Strategies for Drug Development.
  49. Correction: Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.
  50. Dapansutrile preserves pancreatic beta-cell function by regulating insulin vesicle membrane fusion and mitochondrial homeostasis.
  51. High-protein diet promotes aging by activating the CG6415/AMT gene and disrupting mitochondrial homeostasis.
  52. Transcriptome analysis and RT-qPCR validation of mitophagy-related key genes in the progression of diabetic retinopathy.
  53. Insulin-like Growth Factor 2 mRNA-binding Protein 2 Regulates PINK1 Expression through m6A Pathway to Promote Mitophagy in BMSCs Alleviating Postmenopausal Osteoporosis.
  54. NIPSNAP3B elevates mitochondrial biogenesis to attenuate lipid accumulation in childhood obesity via AMPK pathway.
  55. Lutein Attenuates Parkinson's Disease Progression by Regulating Mitochondrial Function via the TRIM31/Drp1 Signaling Pathway.
  56. Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
  57. Lactylation Reprogramming in the Bone Infection Microenvironment Identifies PGK1 K361 as a Potential Therapeutic Target for Osteogenic Dysfunction.
  58. Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
  59. Autophagy Dysregulation in Crohn's Disease and Colorectal Cancer-An Analysis of BECN1, PINK1, and LAMP2 Gene Expression.
  60. Bidirectional Regulation of NLRP3 Inflammasome and Mitochondrial Quality Control in Sepsis: Mechanisms and Therapeutic Implications.
  61. Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.
  1. Ecotoxicol Environ Saf. 2026 Jan 27. pii: S0147-6513(26)00113-2. [Epub ahead of print]310 119784
    Ginsenoside Rb1 normalizes mitochondrial dynamic homeostasis and alleviates glufosinate-ammonium-induced testicular damage through targeting Drp1.
    Jirong Chen, Fan Yang, Yang Hu, Caiying Zhang, Dianyun Wang, Yi Li, Penghui Liu, Chenghong Xing, Haotang Li, Huabin Cao, Xueyan Dai.
      Glufosinate-ammonium (GLA), a broad-spectrum non-selective herbicide widely used in contemporary agriculture, raises concerns due to its potential reproductive toxicity. Ginsenoside Rb1, a triterpenoid glycoside, exhibits antioxidant and anti-inflammatory activities. Therefore, this study employs network toxicology and pharmacology to comprehensively analyze GLA-induced testicular toxicity mechanisms and the protective mechanism of ginsenoside Rb1. Results show that GLA exposure causes testicular injury accompanied by vacuolization of Sertoli cells, spermatogenic cell detachment and disorganized spermatids, and the action in a dose-dependent manner. Network toxicology and pharmacology identified mitochondrion, autophagy and apoptosis as key target pathways mediating GLA toxicity, while ginsenoside Rb1's protection also occurred mainly by regulating mitophagy. We observed that GLA exposure causes excessive mitochondrial fragmentation and autophagosome. Mechanistically, GLA disturbs mitochondrial dynamical homeostasis via significantly upregulating mitochondrial fission proteins (Drp1/Fis1) and inhibiting mitochondrial fusion proteins (Opa1/Mfn2), eventually causing excessive mitochondrial fission and mitophagy. Inversely, Mdivi-1 (Drp1 inhibitor) reduced GLA-induced mitochondrial fragmentation and mitophagy, while the addition of ginsenoside Rb1 greatly improved GLA-induced testicular damage by suppressing Drp1-mediated excessive mitochondrial fission and mitophagy. These findings provide a first glimpse into the molecular mechanisms of GLA-induced male reproductive toxicity in mice and demonstrate ginsenoside Rb1's potential to protect Sertoli cells from GLA exposure.
    Keywords:  Drp1; Ginsenoside Rb1; Glufosinate-ammonium; Mitochondrial fission; Testicular toxicity
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.119784
  2. Int J Mol Sci. 2026 Jan 22. pii: 1119. [Epub ahead of print]27(2):
    UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment.
    Bo Jin, Junyao Qu, Ke Xu, Yufei Zhang, Peng Xu, Xin Wang, Bo Zhao, Xianting Jiao.
      Mitophagy, as a critical form of selective autophagy, plays a central role in maintaining cellular homeostasis. While the canonical PTEN-Induced Kinase 1 (PINK1)-Parkin pathway is well established, mitophagy can still be effectively induced in Parkin-deficient cells such as HeLa, indicating the existence of Parkin-independent alternative pathways. The mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) acts as a key effector in such pathways, yet its regulatory mechanisms remain incompletely understood. Here, we identify Ubiquitination Factor E4B (UBE4B) as an E3 ubiquitin ligase for NIPSNAP1 and demonstrate that it catalyzes NIPSNAP1 ubiquitination in both Human Embryonic Kidney 293 cells (HEK293T) and HeLa cells. Under mitochondrial depolarization, UBE4B not only promotes NIPSNAP1 ubiquitination and subsequent lysosome-dependent degradation, but also significantly enhances its interaction with the autophagy adaptors Nuclear Dot Protein 52 kDa (NDP52) and Sequestosome 1 (p62/SQSTM1). Notably, while Parkin does not ubiquitinate NIPSNAP1, UBE4B-mediated ubiquitination facilitates mitophagy in Parkin-null HeLa cells by strengthening the binding between NIPSNAP1 and NDP52. Collectively, this study unveils a novel mitophagy pathway regulated by the UBE4B-NIPSNAP1 axis, offering new insights into mitochondrial quality control.
    Keywords:  HeLa cell; NIPSNAP1; UBE4B; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.3390/ijms27021119
  3. Acta Diabetol. 2026 Jan 28.
    A TFAP4-UBC9-SUMO1 axis orchestrates pathological mitochondrial hyperfission in diabetic complications.
    Zhiyu Jin, Ying Jiang, Dayun Tao, Zunyan Li, Xiuling He, Hao Zhou, Hang Zhu, Lina Ren.
       BACKGROUND: Mitochondrial failure is a cornerstone of diabetic organ damage. While it is well understood that shattered mitochondria (excessive fission) and aggressive cleanup (mitophagy) drive this deterioration, the upstream genetic "switches" that trigger these processes remain unclear. This study investigates whether a specific regulatory chain the TFAP4-UBC9-SUMO1 axis orchestrates this mitochondrial breakdown in diabetic tissues.
    METHODS: We analyzed transcriptomic data from four independent cohorts (GEO datasets: GSE1009, GSE4745, GSE6880, and GSE133598) covering diabetic renal and cardiac tissues. By integrating differential expression analysis with functional enrichment tools (GO, KEGG, and GSEA), we mapped the molecular landscape connecting cellular stress to mitochondrial dynamics and metabolic remodeling.
    RESULTS: Our analysis revealed a synchronized stress response across all datasets rather than isolated gene changes. Diabetic tissues exhibited a distinct upregulation of pathways related to protein SUMOylation, mitochondrial organization, and ER stress. Specifically, the data showed a convergence of signals indicating chronic "Protein processing in the endoplasmic reticulum" and sustained "Mitophagy," accompanied by broad shifts in lipid and energy metabolism. These signatures suggest that the machinery responsible for SUMO-modifying proteins is hyperactive and tightly linked to mitochondrial clearance programs.
    CONCLUSION: The transcriptomic evidence supports a model where TFAP4 acts as a transcriptional driver that boosts UBC9 and SUMO1 expression. This upregulation likely fuels the SUMO-dependent modification of DRP1, locking mitochondria in a state of hyper-fission and forcing the cell into excessive self-eating (mitophagy). The TFAP4-UBC9-SUMO1 axis thus represents a critical, yet overlooked, engine of mitochondrial depletion and offers a promising new target for halting diabetic complications.
    Keywords:  DRP1; Diabetic complications; Mitochondrial dysfunction; Mitochondrial fission; Mitophagy; SUMOylation; Transcriptomic analysis
    DOI:  https://doi.org/10.1007/s00592-026-02645-0
  4. J Adv Res. 2026 Jan 26. pii: S2090-1232(26)00090-1. [Epub ahead of print]
    Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
    Dandan Wang, Mei Li, Jun Ma, Guocheng Du, Jingwen Zhou, Jian Chen, Xin Guan.
       INTRODUCTION: Skeletal muscle is a high-energy-consuming tissue whose development and function critically depend on mitochondrial homeostasis. Mitochondrial quality control involves multiple clearance mechanisms, including mitocytosis, mitophagy, and apoptosis. However, how these pathways are coordinated during myogenic differentiation remains systematically unexplained.
    OBJECTIVES: This study aimed to investigate the sequential activation and coordination of mitocytosis, mitophagy, and apoptosis inresponse to gradient mitochondrial damage, and to explore their impact on myogenesis.
    METHODS: We established a gradient mitochondrial damage model in myoblasts using different concentrations of CCCP. Through fluorescence imaging, western blotting, genetic interventions, and small-molecule inhibitors, we investigated the activation sequence and crosstalk among different clearance pathways, and explored their effects on myotube formation and function.
    RESULTS: Escalating mitochondrial damage triggered a sequential activation of clearance mechanisms: KIF5B-mediated mitocytosis was first induced, followed by PINK1-dependent mitophagy, and ultimately Caspase 3-mediated apoptosis. When mitocytosis was inhibited, mitophagy dominated mitochondrial clearance, whereas enhanced mitocytosis suppressed both mitophagy and apoptosis. When mitophagy was impaired, cellular homeostasis could be maintained by upregulating mitocytosis under mild mitochondrial damage, but this led to premature apoptosis under severe mitochondrial damage. Myogenesis was significantly suppressed when either mitocytosis or mitophagy was impaired, whether through small-molecule inhibitors or the genetic knockdown of KIF5B or PINK1. Notably, low-dose CCCP treatment promoted myotube formation and mitochondrial function, and also attenuated the myogenic deficits resulting from KIF5B or PINK1 deficiency. Furthermore, KIF5B overexpression enhanced glycolytic metabolism and accelerated myoblast proliferation, highlighting its role beyond mitochondrial clearance.
    CONCLUSION: These findings provide new insights into the coordinated regulatory network among mitochondrial clearance mechanisms and their roles in myogenic differentiation. These insights advance the understanding of muscle biology and offer potential strategies for enhancing muscle regeneration in biomedical and cellular agriculture applications.
    Keywords:  Apoptosis; Mitochondrial clearance; Mitocytosis; Mitophagy; Myogenic differentiation
    DOI:  https://doi.org/10.1016/j.jare.2026.01.065
  5. Int J Biochem Cell Biol. 2026 Jan 23. pii: S1357-2725(26)00010-5. [Epub ahead of print] 106906
    MFN2 interacts with phosphorylated AMPK to mediate mitophagy in MCF-7 cells.
    Shixian Zhai, Zihong Huang, Chunchun An, Lu Gao, Tongsheng Chen.
      Mitofusin 2 (MFN2) has been reported to play an important role in mitophagy, but how MFN2 mediates mitophagy remains incompletely understood. Here, we establish that MFN2 upregulation is a key driver of mitophagy in MCF-7 cells. MFN2 overexpression triggers mitochondrial degradation, as verified by multiple mitophagy markers, whereas MFN2 knockdown abolishes the mitophagic response induced by Leflunomide (Lef), a compound that promotes mitophagy by upregulating MFN2. To elucidate the underlying mechanism, fluorescence imaging and subcellular fractionation reveal that MFN2 promotes AMP-activated protein kinase (AMPK) phosphorylation at Thr172 and facilitates translocation of AMPK from the cytoplasm to mitochondria. Quantitative Förster resonance energy transfer (FRET) analysis supports phosphorylation-dependent formation of an MFN2-AMPK complex in cells, and site-directed mutagenesis supports Thr172 phosphorylation dependence, as the phosphomimetic AMPK (T172D) mutant exhibits enhanced complex formation with MFN2, while the phosphodeficient AMPK (T172A) mutant shows little or no complex formation with MFN2. Co-immunoprecipitation further supports an MFN2-AMPK complex in cells. The MFN2-AMPK complex is essential for mitophagy: Compound C, a pharmacological inhibitor of AMPK, prevents both MFN2-AMPK complex formation and mitophagy, even in cells overexpressing MFN2. Notably, AMPK activation through Acadesine (AICAR) treatment is insufficient to induce mitophagy, but it markedly enhances mitophagy markers when combined with MFN2 overexpression. In conclusion, MFN2 mediates efficient mitophagy by recruiting Thr172-phosphorylated AMPK to mitochondria through a phosphorylation-dependent MFN2-AMPK complex.
    Keywords:  AMPK phosphorylation; Autophagy; FRET; Interaction; Leflunomide; MFN2; Mitochondrial
    DOI:  https://doi.org/10.1016/j.biocel.2026.106906
  6. ACS Chem Neurosci. 2026 Jan 28.
    4-(1-Methylethoxy)-N-(2-methyl-8-quinolinyl)-benzamide (CDN1163) Attenuates Glutamate-Induced Excitotoxicity by Suppressing ER Stress and Restoring Mitochondrial Dynamics in N2a Cells.
    Vikrant Rahi, Swapnil Sharma, Ravinder K Kaundal.
      Excessive glutamate release during excitotoxic events such as stroke and neurodegeneration leads to elevated mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane depolarization, contributing to dysfunction of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and subsequent endoplasmic reticulum (ER) stress. SERCA is critical for maintaining ER Ca2+ homeostasis, and its impairment exacerbates ER stress and neuronal excitotoxicity. In this study, we investigated the neuroprotective potential of CDN1163 (4-(1-methylethoxy)-N-(2-methyl-8-quinolinyl)-benzamide), a small-molecule SERCA activator, in an in vitro model of glutamate-induced toxicity using N2a cells. Glutamate exposure markedly reduced cell viability and induced apoptosis, as evidenced by increased caspase-3 and Bax expression along with suppression of the antiapoptotic protein Bcl-2. These cytotoxic effects were accompanied by excessive intracellular and mitochondrial ROS generation and dissipation of the mitochondrial membrane potential (ΔΨm), indicating mitochondrial dysfunction. Glutamate further disrupted mitochondrial quality control by impairing mitophagy initiation, reflected by reduced PINK1 and Parkin expression and altered LC3-II and phospho-p62 levels. This mitochondrial impairment coincided with pronounced ER stress, characterized by activation of unfolded protein response signaling pathways, including increased expression of BiP, p-IRE1α, XBP 1s, p-PERK, p-eIF2α, ATF4, CHOP, and ATF6, together with downregulation of SERCA1a and SERCA2b, leading to ER Ca2+ dyshomeostasis. Treatment with CDN1163 significantly reversed glutamate-induced cytotoxicity by restoring cell viability, suppressing apoptosis, reducing mitochondrial and cellular ROS, stabilizing mitochondrial membrane potential, reactivating mitophagy, and alleviating ER stress through restoration of SERCA expression and ER Ca2+ homeostasis. Collectively, these findings demonstrate that CDN1163 confers neuroprotection against glutamate-induced excitotoxic injury by targeting interconnected mitochondrial and ER stress pathways, highlighting its therapeutic potential in excitotoxic neurodegenerative conditions.
    Keywords:  endoplasmic reticulum stress; excitotoxicity; mitochondrial dynamics; mitophagy; neuronal apoptosis; sarco-endoplasmic reticulum Ca2+-ATPase
    DOI:  https://doi.org/10.1021/acschemneuro.5c00863
  7. iScience. 2026 Feb 20. 29(2): 114365
    PHB2 mitigates intervertebral disc degeneration by modulating mitophagy to inhibit necroptosis in nucleus pulposus cells.
    Zhenyu Zhu, Yongcheng Liang, Xiaowen Liu, Fanqi Kong, Kaiqiang Sun, Ximing Xu, Jiangang Shi.
      Intervertebral disc degeneration involves loss of nucleus pulposus (NP) cells driven by inflammatory and mitochondrial stress-related death pathways. Because mitophagy maintains mitochondrial quality, its disruption may influence cell fate during degeneration. Using human tissues, a mouse lumbar instability model, a rat disc puncture model, and human NP cells stimulated with TNF-α, SM-164, and Z-VAD-FMK (TSZ), we examined how mitochondrial quality control shapes necroptotic signaling. Necroptotic cells displayed mitochondrial damage and reduced mitophagy, while mitophagy activation limited necroptosis and preserved extracellular matrix components. We identified the mitochondrial protein PHB2 as a key regulator linking mitophagy to suppression of necroptosis. PHB2 loss impaired mitophagy, disrupted mitochondrial function, and intensified necroptotic death, whereas PHB2 overexpression restored mitophagy, maintained mitochondrial membrane potential, and reduced degeneration. In vivo PHB2 delivery mitigated necroptosis and protected disc structure. These findings highlight a mitochondria-centered mechanism that shapes cell survival during disc degeneration.
    Keywords:  Biological sciences; Cell biology; Health sciences; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.114365
  8. Hum Mol Genet. 2026 Jan 26. pii: ddaf187. [Epub ahead of print]
    Retraction: Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddaf187
  9. Hum Mol Genet. 2026 Jan 26. pii: ddaf188. [Epub ahead of print]
    Retraction: A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddaf188
  10. Curr Neurovasc Res. 2026 Jan 19.
    Recent Progress in Hydrogen-mediated Neuroprotection via Modulation of Mitochondrial Quality Control Mechanisms in Brain Injury.
    Xue Jiang, Chao Xia, Ruping Zhao, Chenlu Xiong, Xinyuan Duan, Fei Xie.
      Brain injury is a leading cause of mortality and long-term disability worldwide, characterized by energy metabolism dysfunction, oxidative stress, inflammatory responses, and programmed cell death, with mitochondrial dysfunction serving as a central pathological nexus. In recent years, hydrogen, as an emerging gaseous signaling molecule, has demonstrated remarkable neuroprotective effects in various experimental models of brain injury owing to its unique biological properties, including selective antioxidant, anti-inflammatory, anti-apoptotic, and mitochondrial- protective activities. This review comprehensively summarizes the protective effects and underlying molecular mechanisms of hydrogen in ischemic stroke, traumatic brain injury, hypoxic-ischemic encephalopathy, intracerebral hemorrhage, subarachnoid hemorrhage, chronic cerebral hypoperfusion, and toxic encephalopathy. Special emphasis is placed on hydrogen's ability to modulate mitochondrial quality control networks, encompassing antioxidative membrane protection, precise regulation of mitophagy, remodeling of mitochondrial dynamics, and metabolic reprogramming, thereby improving neuronal survival and functional recovery. Moreover, this review has discussed current limitations, unresolved scientific questions, and major challenges, while proposing future directions, such as multi-omics integration, advanced structural biology investigations, innovative experimental model optimization, and systematic clinical translational research. Collectively, hydrogen holds great promise as a novel mitochondriatargeted neuroprotective strategy for brain injury, offering not only a solid theoretical foundation but also a potential personalized and precise therapeutic avenue for future clinical applications in neurological disorders.
    Keywords:  Hydrogen; brain injury; mitochondrial dynamics.; mitochondrial quality control; mitophagy; neuroprotection
    DOI:  https://doi.org/10.2174/0115672026430179251224095358
  11. Antioxidants (Basel). 2025 Dec 30. pii: 52. [Epub ahead of print]15(1):
    Enriched Environment Ameliorates Cerebral Ischemia-Reperfusion Injury via Dopamine-H2S Axis-Mediated Dual Mitophagy Activation.
    Bao Zhou, Haocheng Qin, Pengkun Yang, Na Ren, Lu Sun, Zhengran Ding, Zhong He, Shuai Zhang, Zijian Hua, Ya Zheng, Ce Li, Shenyi Kuang, Yulian Zhu, Kewei Yu.
      Cerebral ischemia-reperfusion injury triggers mitochondrial dysfunction and oxidative stress, exacerbating neuronal apoptosis. Emerging evidence highlights hydrogen sulfide (H2S) as a gasotransmitter modulating redox balance, autophagy, and apoptosis. This study investigates the neuroprotective mechanisms of Enriched Environment (EE) against ischemic injury, focusing on mitochondrial dynamics and H2S-mediated pathways. Using MCAO mice and OGD/R-treated SH-SY5Y neurons, interventions targeting H2S synthesis, hypoxia-inducible factor 1-alpha (HIF-1α), and mitophagy were implemented. Behavioral, histological, and molecular analyses demonstrated EE significantly improved neurological outcomes, suppressed apoptosis, and attenuated oxidative damage (reduced MDA, elevated MnSOD/glutathione). Mechanistically, EE enhanced mitophagy via dual pathways: canonical PINK1/parkin-mediated mitochondrial clearance, corroborated by transmission electron microscope and LC3B/parkin colocalization, and non-canonical HIF-1α/BNIP3L axis activation. Transcriptomic and Co-immunoprecipitation (Co-IP) data revealed EE upregulated endogenous H2S biosynthesis post-injury by promoting dopamine-induced calcium influx, which activated calmodulin-dependent signaling to stimulate cystathionine β-synthase/γ-lyase expression. Pharmacological blockade of H2S synthesis or HIF-1α abolished mitochondrial protection, confirming H2S as a central mediator. Notably, H2S exerted antiapoptotic effects by restoring mitochondrial integrity through synergistic mitophagy activation and oxidative stress mitigation. These findings propose a novel neuroprotective cascade: EE-induced dopaminergic signaling potentiates H2S production, which coordinates PINK1/parkin and HIF-1α/BNIP3L pathways to eliminate dysfunctional mitochondria, thereby preserving neuronal homeostasis. This study elucidates therapeutic potential of EE via H2S-driven mitochondrial quality control, offering insights for ischemic brain injury intervention.
    Keywords:  apoptosis; cerebral ischemia/reperfusion injury; enriched environment; hydrogen sulfide; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15010052
  12. Arch Biochem Biophys. 2026 Jan 23. pii: S0003-9861(26)00019-6. [Epub ahead of print] 110748
    Dexmedetomidine Attenuates Hyperoxia-Induced Lung Injury in BPD Mice via Regulation of the Mitophagy-NLRP3-Pyroptosis Pathway.
    Yue Feng, Dong-Zhui Chen, Heng Cai, Qiu-Yue Zhang.
       OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in preterm infants. Although dexmedetomidine (Dex) has been shown to exert lung-protective effects in experimental BPD models, the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether Dex confers protection against hyperoxia-induced lung injury through regulation of the mitophagy-NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-pyroptosis axis.
    METHODS: A neonatal mouse model of BPD and a hyperoxia-induced injury model in primary alveolar type II epithelial (AECII) cells were established. Gain- and loss-of-function approaches targeting PINK1/Parkin-mediated mitophagy and NLRP3 were applied. Mitophagy, inflammasome activation, mitochondrial integrity, inflammatory responses, and cell injury were evaluated using molecular, imaging, and functional assays.
    RESULTS: Dex significantly alleviated hyperoxia-induced lung injury in neonatal mice and improved the survival of AECII cells under oxidative stress. Dex treatment enhanced PINK1/Parkin-mediated mitophagy, preserved mitochondrial structure and function, suppressed NLRP3 inflammasome activation, reduced inflammatory cytokine release, and attenuated pyroptosis-related protein expression. Notably, genetic silencing of PINK1 abolished the protective effects of Dex, while NLRP3 overexpression partially reversed Dex-mediated anti-inflammatory and cytoprotective effects, indicating a mechanistic link between mitophagy activation and inflammasome inhibition.
    CONCLUSION: Dex protects against hyperoxia-induced lung injury by activating PINK1/Parkin-dependent mitophagy, maintaining mitochondrial homeostasis, inhibiting NLRP3 inflammasome activation, and suppressing pyroptosis. These findings provide mechanistic insight into the therapeutic potential of Dex for the prevention and treatment of BPD.
    Keywords:  NLRP3; bronchopulmonary dysplasia; dexmedetomidine; mitophagy; pyroptosis
    DOI:  https://doi.org/10.1016/j.abb.2026.110748
  13. Sci Rep. 2026 Jan 27.
    SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Age-related hearing loss is characterized by the progressive degeneration of cochlear hair cells and neurons, with mitochondrial dysfunction and impaired mitophagy implicated as molecular mechanisms. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, plays a critical role in the regulation of mitochondrial quality control and mitophagy. SRT2104, a synthetic SIRT1 activator with improved bioavailability compared to resveratrol, has shown neuroprotective effects in age-related neurodegeneration. However, the role of SIRT1 in auditory cell senescence remains unclear. In this study, we investigated the effects of SRT2104 on cellular senescence and mitophagy in HEI-OC1 auditory cells and organotypic cochlear explants. Senescence was induced using low-dose H₂O₂, and SRT2104 was used as a pre-treatment. SRT2104 significantly enhanced SIRT1 activity, upregulated mitophagy-related proteins (PINK1, Parkin, BNIP3, and LC3-II), and downregulated senescence markers (p53 and p21) in cellular and explant models. β-galactosidase staining confirmed reduced senescence in SRT2104-treated groups. Pre-treatment with SRT2104 preserved mitochondrial function, as indicated by enhanced mitochondrial membrane potential, improved mitochondrial DNA integrity, and increased ATP production. SIRT1 knockdown abolished these protective effects, confirming that SRT2104 mediated its anti-senescence and pro-mitophagy activities via SIRT1. Our findings demonstrated that SRT2104 alleviates premature senescence and promotes mitophagy in auditory cells via SIRT1 activation. The pharmacological activation of SIRT1 may represent a promising therapeutic strategy to counteract age-related degeneration in the auditory system.
    DOI:  https://doi.org/10.1038/s41598-026-37606-8
  14. Autophagy. 2026 Jan 28.
    Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
    Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.
      Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.
    Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2026.2623988
  15. Acta Pharm Sin B. 2026 Jan;16(1): 1-12
    Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
    Joshua Kramer, Eric Rohwer, Palaniappan Sethu, Min Xie, Timmy Lee, Victor Darley-Usmar, Jianhua Zhang.
      Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia-reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell-cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.
    Keywords:  Cardiomyocytes; Exophers; Fibroblasts; Macrophages; Migrasomes; Mitophagy; TNTs; Transmitophagy
    DOI:  https://doi.org/10.1016/j.apsb.2025.11.030
  16. Cells. 2026 Jan 12. pii: 137. [Epub ahead of print]15(2):
    BAP31 Modulates Mitochondrial Homeostasis Through PINK1/Parkin Pathway in MPTP Parkinsonism Mouse Models.
    Wanting Zhang, Shihao Meng, Zhenzhen Hao, Xiaoshuang Zhu, Lingwei Cao, Qing Yuan, Bing Wang.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31-an endoplasmic reticulum protein critical for protein trafficking and degradation-has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31fl/fl controls, Slc6a3cre-BAP31fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1-Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders.
    Keywords:  BAP31; EN1; PINK1–Parkin pathway; Parkinson’s disease; mitochondrial homeostasis
    DOI:  https://doi.org/10.3390/cells15020137
  17. Metabolites. 2025 Dec 23. pii: 11. [Epub ahead of print]16(1):
    The Role of Mitochondrial Dynamics in Metabolic Dysfunction-Associated Steatotic Liver Disease and the Regulatory Mechanisms of Exercise Intervention: A Systematic Review of Preclinical Studies.
    Haonan Tian, Aozhe Wang, Haoran Wu, Lin Yan, Jun Wang.
      Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) involves dysregulated mitochondrial dynamics. This review systematically integrates the specific mechanisms by which exercise modulates mitochondrial fusion, fission, and mass control in the liver within MASLD and metabolic dysfunction-associated steatohepatitis (MASH) models. Methods: A comprehensive search of PubMed and Web of Science identified 11 animal studies investigating exercise and mitochondrial dynamics markers. Results: MASLD generally exhibited a "pro-fission" phenotype. Exercise, particularly moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT), reversed these alterations via "pro-fusion, anti-fission" effects and restored biogenesis and mitophagy. Crucially, effects appeared to be "modality-specific" and "intensity-dependent." Current evidence suggests that reversing severe fission and restoring inner-membrane may require a specific "intensity threshold," with voluntary wheel running showing limited efficacy in steatohepatitis. Notably, resistance exercise seemed to display a distinct profile, effectively curbing fission but diverging in fusion/biogenesis regulation. Conclusions: Synthesizing preclinical evidence, this review suggests that exercise ameliorates hepatic mitochondrial dysregulation in MASLD and appears to exhibit characteristics of "modality specificity" and "intensity dependence." Specifically, an "intensity threshold" may be critical for profound structural remodeling, while resistance exercise exhibits a distinct regulatory profile. Future long-term clinical trials are warranted to validate these animal-derived findings and develop stage-specific "precision exercise prescriptions" for patients.
    Keywords:  MASLD; exercise; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/metabo16010011
  18. Nat Commun. 2026 Jan 29.
    ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
    Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.
      Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.
    DOI:  https://doi.org/10.1038/s41467-026-68813-6
  19. World J Diabetes. 2026 Jan 15. 17(1): 112027
    Microtubule affinity-regulating kinase 4 exacerbates diabetic cardiomyopathy by inhibiting UNC-51-like kinase 1-mediated mitochondrial autophagy.
    Yi Wu, Wei-Yi Wang, Jing-Qi Zhang, Sai Wang, Zhi Zeng, Lu Fu, Bin Li.
       BACKGROUND: The incidence of diabetic cardiomyopathy (DCM) is increasing significantly as the population ages. DCM is one of the main causes of heart failure and mortality among patients with diabetes. Impaired mitophagy leads to mitochondrial dysfunction, which in turn aggravates DCM progression. Microtubule affinity-regulating kinase 4 (MARK4) is a key regulator of autophagy in adipocytes.
    AIM: To investigate the role of MARK4 in mitophagy in DCM.
    METHODS: A mouse model of type 2 DCM was developed by administration of low-dose streptozotocin (50 mg/kg) combined with a high-fat diet. After 12 weeks MARK4 expression was knocked down in the mice by injection of the adeno-associated virus AAV9 into the tail vein. Four weeks later, cardiac function and structure were evaluated by echocardiography, and blood glucose levels and body weights were recorded. Mitochondrial ultrastructure and autophagosomes were assessed using electron microscopy. Mitochondrial membrane potentials were examined using fluorescence microscopy while the MARK4 and mitophagy-associated protein levels were investigated using western blotting. The downstream factors of MARK4 were identified using RNA-seq sequencing and bioinformatics with empirical confirmation.
    RESULTS: MARK4 levels were markedly increased in the DCM animal and cardiomyocyte models. Downregulation of MARK4 in DCM mice reduced myocardial tissue injury, increased mitophagy, and mitigated damage to cardiac function. RNA-seq indicated that MARK4 downregulation promoted mitophagy via upregulation of UNC-51-like kinase 1, alleviating myocardial injury in mice. This was confirmed in cell rescue experiments. Bioinformatics predicted interaction between MARK4 and the autophagy marker protein microtubule-associated protein 1 light chain 3B. This was verified using co-immunoprecipitation.
    CONCLUSION: Downregulation of MARK4 in DCM mice can reduce myocardial injury, protect mitochondrial function, and promote mitophagy by upregulating UNC-51-like kinase 1, protecting against cardiac damage.
    Keywords:  Diabetic cardiomyopathy; Microtubule affinity-regulating kinase 4; Microtubule-associated protein 1 light chain 3B; Mitochondrial autophagy; UNC-51-like kinase 1
    DOI:  https://doi.org/10.4239/wjd.v17.i1.112027
  20. Autophagy. 2026 Jan 29.
    Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
    Yang Qu, Shanhui Ren, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Chan Ding.
      Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy.
    Keywords:  Amino acid metabolism; MAVS; NDV, PINK1-PRKN; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2624746
  21. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00021-3. [Epub ahead of print]
    Mito-nuclear communication: From cellular responses to organismal health.
    Guanyu Chen, Hangyu Dong, Ye Tian.
      The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations activate retrograde pathways such as the mitochondrial unfolded protein response (UPRmt) and the mitochondrial integrated stress response (ISRmt), which couple organelle dysfunction to nuclear transcriptional programs, thereby promoting mitochondrial function and preserving cellular integrity. Importantly, this communication is not confined to individual cells but extends across tissues to coordinate systemic adaptations. Stress signals can be sensed, broadcasted through secreted mitokines and neural circuits, and then interpreted by distal organs to coordinate systemic adaptations. These systemic responses integrate metabolism, immunity, and behavior, conferring resilience to stress and shaping the trajectory of aging. Understanding this multi-layered communication, from the organelle to the organism and its microbial ecosystem, promises new therapeutic strategies to enhance mitochondrial function, promote resilience, and extend healthspan.
    Keywords:  ISRmt; UPRmt; aging; mito-nuclear communication; mitokine; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.001
  22. Biology (Basel). 2026 Jan 20. pii: 189. [Epub ahead of print]15(2):
    Melatonin as a Guardian of Mitochondria: Mechanisms and Therapeutic Potential in Neurodegenerative Diseases.
    Yanyu Bao, Guoying Miao, Nannan He, Xingting Bao, Zheng Shi, Cuilan Hu, Xiongxiong Liu, Bing Wang, Chao Sun.
      Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer's disease, Parkinson's disease, and Huntington's disease-the major protagonists of NDs-while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials.
    Keywords:  melatonin; mitochondrial dysfunction; mitochondrial quality control; neurodegenerative diseases; oxidative stress
    DOI:  https://doi.org/10.3390/biology15020189
  23. Adv Sci (Weinh). 2026 Jan 25. e17585
    A Non-Mitophagy Activity of BNIP3L/NIX in Amygdala Glutamatergic Neurons is Essential for Contextual Fear Memory Formation.
    Xingxian Zhang, Xinlei Mo, Xinyu Zhou, Xiaoliang Liu, Guizhi Li, Songhui Hu, Yangyang Lu, Chenze Zhu, Jinxi Feng, Zhitong Chen, Weiwei Hu, Yihui Cui, Zhong Chen, Xiangnan Zhang.
      Mitochondrial quality is crucial for maintaining brain homeostasis. BNIP3L/NIX, a mitophagy receptor, has been linked to neurological disorders, yet its specific function in the brain remains unclear. We found BNIP3L highly expressed in basolateral amygdala (BLA) neurons. Selective deletion of bnip3l in BLA glutamatergic neurons (BLAGLU) impaired contextual fear memory, accompanied by reduced neuronal excitation and mitochondrial respiration. Notably, fear conditioning did not invariably activate mitophagy in BLAGLU neurons. Overexpression of both wild-type and a mitophagy-deficient mutant (BNIP3LΔLIR) in BLAGLU neurons was sufficient to rescue the contextual fear memory deficits in bnip3l-/- mice, suggesting a non-mitophagy role. Instead, we detected a prompt mitochondrial fission in BLAGLU neurons after foot-shock conditioning, an effect abolished by bnip3l deletion. Inhibition of Drp1 with Mdivi-1 disrupted memory formation, whereas optogenetic activation of Drp1 restored neuronal excitation and rescued memory deficits in bnip3l-/- mice. These data indicated an essential role of BNIP3L-mediated mitochondrial fission in modulating contextual fear memory. Mechanistically, BNIP3L and Drp1 competitively interact with AMPK, leading to reduced Drp1 phosphorylation and increased Drp1 accumulation on mitochondria, thereby promoting mitochondrial fission. Taken together, the present study revealed a previously uncharacterized, non-mitophagy-dependent role for BNIP3L in contextual fear memory conditioning.
    Keywords:  AMPK‐Drp1; BNIP3L/NIX; basolateral amygdala; contextual fear memory; mitochondrial fission
    DOI:  https://doi.org/10.1002/advs.202517585
  24. Mater Today Bio. 2026 Apr;37 102785
    Functionalized hydrogels of CeO2 and Urolithin A synergistically scavenge ROS and activate mitophagy for cartilage repair.
    Chunhui Ma, Bingxuan Hua, Houlei Wang, Tianle Ma, Qi Lv, Zuoqin Yan.
      In recent years, CeO2 nanoparticles are promising biomaterials due to their excellent biocompatibility and antioxidant properties. This study utilizes a methacrylated gelatin (GelMA) hydrogel platform to construct a dual-functional composite material, CeUA@GelMA, by co-loading CeO2 nanoparticles with urolithin A (UA). This material possesses both reactive oxygen species (ROS) scavenging and mitophagy activation capabilities, aiming to overcome the bottleneck in cartilage regeneration by regulating mitochondrial homeostasis. In vitro experiments confirmed that this material significantly reduces ROS levels within BMSCs under oxidative stress, maintains mitochondrial membrane potential, and promotes chondrogenic differentiation by upregulating genes such as Sox9, Col II, and ACAN. In vivo studies demonstrated that the CeUA@GelMA group achieved hyaline-like cartilage regeneration 8 weeks post-operation. The surface roughness of the newly formed cartilage was comparable to that of natural cartilage, with collagen and glycosaminoglycan density approaching normal cartilage levels. In summary, this research offers an innovative strategy and hydrogel material for cartilage tissue engineering through the regulation of mitochondrial homeostasis.
    Keywords:  Cartilage repair; CeO2; Mitophagy; ROS; Urolithin A
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102785
  25. FASEB J. 2026 Feb 15. 40(3): e71481
    Deficiency of FNDC5/Irisin Impairs the Protective Effect of Exercise Against Post-Infarction Myocardial Mitochondrial Injury.
    Shuguang Qin, Yixuan Ma, Wujing Ren, Yue Xi, Hangzhuo Li, Wenyan Bo, Zhenjun Tian.
      There is ample evidence that exercise contributes to prevention and treatment of myocardial infarction. Although transmembrane protein fibronectin type III domain protein 5 (FNDC5)/Irisin is known to mediate the protective effects of exercise on ischemic heart, its effects and mechanisms on mitochondria after myocardial infarction are not fully defined. We randomized wild and FNDC5 knockout (KO) mice on which to construct a post-infarction exercise rehabilitation model, and subsequently compared the differences in cardiac and myocardial mitochondrial structure and function between groups; the FNDC5/Irisin-AMPK-Sirt1 mitochondrial pathway was further assessed by applying recombinant human Irisin, FNDC5 and/or Sirt1 knockdown (KD) treatment to neonatal mouse cardiomyocytes. Transmission electron microscopy was used to examine mitochondrial structure, Oxygraph-2k was used to measure mitochondrial function, and immunoblotting was used to assess mitochondrial genesis, mitophagy marker proteins, and pathway-related proteins. FNDC5KO induced abnormalities of myocardial mitochondrial genesis and mitophagy, weakened the improvement effect of exercise toward mitochondrial injury and was associated with deteriorated cardiac function after myocardial infarction. Sirt1KD weakened the FNDC5/Irisin-mediated regulatory effect of exercise on mitochondrial genesis and mitophagy in primary cardiomyocytes. Exercise induced FNDC5/Irisin is an important regulator of the ameliorative effects of Sirt1 on cardiac function and mitochondrial remodeling during infarction rehabilitation.
    Keywords:  cardiac function; cardiomyocytes; mitochondrial genesis; mitophagy; rehabilitation
    DOI:  https://doi.org/10.1096/fj.202500863RRRR
  26. Liver Res. 2025 Dec;9(4): 324-337
    Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis.
    Qian Zeng, Yina Sun, Mengzhen Lei, Zihan Liu, Xijing Yan, Rong Li, Jun Zheng, Jiandong Zha, Lijun Zhang, Xiaoling Guan, Jia Yao.
       Background and aims: Hepatic ischemia-reperfusion injury (HIRI) is a major contributor to liver dysfunction and failure, particularly in the context of liver transplantation. Its pathogenesis is primarily driven by ferroptosis, oxidative stress, and mitochondrial dysfunction. Given the interplay among these mechanisms through redox imbalance and disrupted energy metabolism, nicotinic acid (NA)-recognized for its antioxidative and metabolic regulatory properties-emerges as a promising therapeutic candidate. This study aims to investigate the protective effects of NA on HIRI and elucidate its underlying mechanisms.
    Methods: An HIRI model in mice and a hypoxia/reoxygenation (H/R) model in primary hepatocytes were established to evaluate the effects of NA treatment on oxidative stress. NA was administered prior to model induction. N-acetylcysteine (NAC) was used as a comparator. Comprehensive assessments of ferroptosis, oxidative stress, mitophagy, and mitochondrial biogenesis markers were conducted using Western blotting, immunohistochemistry, immunofluorescence, and biochemical assays.
    Results: NA pretreatment reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) levels, suppressed inflammation by decreasing neutrophil infiltration and macrophage activation, and mitigated oxidative stress by lowering reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It enhanced antioxidant defenses, inhibited ferroptosis, and improved mitochondrial health through increased mitophagy, mitochondrial biogenesis, and mitochondrial permeability transition pore (mPTP) stabilization, leading to enhanced ATP production and mitochondrial function in HIRI.
    Conclusions: NA improves mitochondrial function by promoting mitophagy and mitochondrial biogenesis, which reduces ferroptosis and oxidative stress, thereby alleviating HIRI.
    Keywords:  Ferroptosis; Hepatic ischemia-reperfusion injury (HIRI); Mitochondrial biogenesis; Mitophagy; Nicotinic acid (NA)
    DOI:  https://doi.org/10.1016/j.livres.2025.11.001
  27. Plant Cell Environ. 2026 Jan 29.
    Bamboo Rapid Growth: Energy Homoeostasis, Mitochondrial Dynamics and Membrane Crosstalk.
    Xueqi Zhao, Cunfu Lu.
      
    DOI:  https://doi.org/10.1111/pce.70424
  28. Acupunct Med. 2026 Jan 26. 9645284251414435
    Electroacupuncture pretreatment regulates mitophagy in ULK1 knockout mice subjected to cerebral ischemia-reperfusion injury.
    Cheng Hu, Yudi Zhou, Sha Li, Yaomei Cui, Menglin He, Rong Zou, Chenlu Mao, Weiqian Tian.
       BACKGROUND: Electroacupuncture (EA) pretreatment can alleviate cerebral ischemia/reperfusion (I/R) injury and mitochondrial impairment. However, the potential protective mechanism associated with mitophagy has not been well elucidated. The aim of this study was to investigate the effect of EA on FUN14 domain-containing protein 1 (FUNDC1) and mitophagy in unc-51 like kinase 1 (ULK1) knockout mice after cerebral I/R injury.
    METHODS: EA pretreatment was conducted at GV20 and GV26 before ischemia for 30 min over 5 consecutive days in ULK1 knockout mice that underwent modeling of cerebral I/R injury. Neurological function of the mice was assessed using Longa neurological deficit scoring. The area of cerebral infarction was measured by 2,3,5-triphenyltetrazolium (TTC) staining. Mitochondrial structural alterations were observed under transmission electron microscopy, while the mitochondria were stained using MitoTracker Green and the lysosomes were stained with Lyso Tracker Red. Changes in mitochondrial membrane potential were detected by JC-1 staining, and alterations in autophagy-related protein or gene expression were examined using Western blot analysis, qRT-PCR and immunohistochemistry.
    RESULTS: EA-pretreated mice exhibited significantly decreased neurological deficit scores, cerebral infarct volumes and edema compared with the untreated I/R group of mice. EA pretreatment also reversed I/R-induced mitochondrial structural abnormalities and loss of mitochondrial membrane potential. Furthermore, EA pretreatment upregulated p-mTORC1 compared with no treatment. Protein and mRNA expression of ULK1, FUNDC1 and mTORC1 did not significantly differ between the groups.
    CONCLUSION: EA pretreatment at GV20 and GV26 alleviated cerebral I/R injury and mitochondrial impairment in ULK1 knockout mice. Knockout of ULK1 did not completely eliminate the regulatory effect of EA.
    Keywords:  FUN14 domain-containing protein 1; cerebral ischemia/reperfusion injury; electroacupuncture; electroacupuncture pretreatment; mitophagy; phosphorylated unc-51 like kinase 1
    DOI:  https://doi.org/10.1177/09645284251414435
  29. Ecotoxicol Environ Saf. 2026 Jan 01. pii: S0147-6513(25)01970-0. [Epub ahead of print]309 119625
    Icaritin alleviates UVB-induced skin damage by inhibiting ferroptosis via modulation of mitochondrial dynamics.
    Wenru Zhi, Ying Zheng, Dandan Gou, Lu Guo, Yuheng Li, Hefei Huang, Mingcheng Du, Dianmei Yu, Keming Lu, Jin'e Wang, Zhiyong Zhou.
      Ultraviolet B (UVB) radiation is the main environmental cause of skin damage, and ferroptosis plays a crucial role in its damage process. This study investigated the protective effects and mechanisms of icaritin (ICT) against UVB-induced skin injury. Our results showed that ICT significantly alleviated UVB-induced cutaneous dryness, erythema, and epidermal hyperplasia in mice, while increasing collagen fiber content. In vitro, ICT restored the viability of UVB-exposed L929 fibroblasts. Meanwhile, ICT significantly inhibited ferroptosis in fibroblasts, manifested by downregulation of COX2, upregulation of GPX4 and FTH1, and reduction of lipid ROS and lipid peroxidation levels. Further investigation revealed that, ICT ameliorated mitochondrial dysfunction by restoring membrane potential, enhancing ATP production, decreasing ROS, and normalizing the NAD+ /NADH ratio. Morphological and protein analysis confirmed that ICT improves mitochondrial homeostasis by regulating mitochondrial dynamics, thereby inhibiting ferroptosis. These findings confirmed that ICT as a promising therapeutic agent for UVB-induced skin damage.
    Keywords:  Ferroptosis; Icaritin; Mitochondrial dynamics; Skin damage; Ultraviolet B
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119625
  30. Autophagy. 2026 Jan 29.
    PRKAB2 as a tumor suppressor in renal cell carcinoma: inhibiting mitophagy via the LRPPRC-PRKN/parkin interaction and cardiolipin biosynthesis.
    Kailei Chen, Yuanpeng Zhang, Hailong Ruan, Zhihao Wei, Keshan Wang, Qi Cao, Qi Wang, Zirui Dong, Yilong Wu, Hongmei Yang, Lei Liu, Yuenan Liu, Xiaoping Zhang.
      Renal cell carcinoma (RCC) is characterized by dysregulated lipid metabolism and a high propensity for developing resistance to targeted therapies. Mitophagy is a key process involved in the progression of various cancers, including RCC. Here, using in vivo genome-wide CRISPR screening, we identified PRKAB2 as a crucial tumor suppressor in RCC. Reduced PRKAB2 expression correlated with poor prognosis and aggressive clinical features, whereas overexpression of PRKAB2 markedly inhibited RCC cell proliferation, migration, invasion, tumor growth, and metastasis both in vitro and in vivo. Mechanistically, PRKAB2 overexpression inhibited mitophagy primarily through two distinct mechanisms. First, PRKAB2 enhanced the binding between LRPPRC and PRKN/parkin, competitively reducing PRKN's interaction with PINK1 and thus suppressing ubiquitin-dependent mitophagy. Second, PRKAB2 promoted AMPK phosphorylation, which in turn suppressed SREBF1/SREBP1-mediated transcriptional activation of CRLS1, leading to decreased CRLS1 expression and reduced synthesis of cardiolipin, a lipid essential for mitophagy. Importantly, PRKAB2 overexpression significantly restored sensitivity to tyrosine kinase inhibitors (TKIs) in sunitinib-resistant RCC cells. Conversely, forced PRKN expression promoted resistance to these drugs, further implicating mitophagy as a key mechanism underlying TKI resistance. Depmap analysis confirmed the association between increased mitophagy and TKI resistance. Overall, our findings identify PRKAB2 as a critical tumor suppressor in RCC, regulating both protein-protein interactions and lipid metabolism to suppress mitophagy. Targeting PRKAB2-associated pathways may provide a promising therapeutic strategy to enhance treatment efficacy and overcome drug resistance in RCC.
    Keywords:  Cardiolipin; PRKAB2; TKI resistance; mitophagy; renal cell carcinoma
    DOI:  https://doi.org/10.1080/15548627.2026.2623985
  31. Free Radic Biol Med. 2026 Jan 22. pii: S0891-5849(26)00055-9. [Epub ahead of print]246 316-333
    Chronic stress-induced steroids mediate mitochondrial fission and fibrosis in the trabecular meshwork via the MIEF1-MAOA complex.
    Yilin Sun, Yingjian Sun, Mingxuan Wang, Zhibo Si, Zhaoying Zhang, Yajuan Zheng.
      Glaucoma remains the leading cause of irreversible blindness worldwide. Trabecular meshwork (TM) dysfunction, particularly fibrosis, is a major driver of elevated intraocular pressure (IOP). Although steroid-induced glaucoma is well established, the impact of chronic stress-related endogenous steroids on TM pathology remains unclear. This study established a corticosterone induced chronic stress mouse model and a cortisol treated human TM cells (HTMCs) model that demonstrated that sustained steroid elevation promotes TM fibrosis and mitochondrial dysfunction. RNA sequencing of HTMCs after cortisol treatment revealed monoamine oxidase A (MAOA) upregulation and enrichment of profibrotic pathways. Cortisol increased mitochondrial elongation factor 1 (MIEF1) and dynamin-related protein 1 (DRP1) phosphorylation at Ser616 (p-DRP1Ser616), driving excessive fission. Knockdown of MAOA or MIEF1 reduced oxidative stress, mitochondrial fragmentation, and extracellular matrix remodeling, whereas overexpression of MAOA and MIEF1 produced the opposite effect. Molecular docking, molecular dynamics simulations, and co-immunoprecipitation confirmed that MAOA interacts with MIEF1 and enhances MIEF1-DRP1 coupling. This study identified the MIEF1-MAOA-DRP1 pathway as a mediator of stress-induced TM fibrosis. It provides new insight into the pathogenesis of glaucoma and identifies MAOA as a potential intervention target for treating glaucoma.
    Keywords:  Extracellular matrix; Glaucoma; Mitochondrial dynamics; Mitochondrial elongation factor 1; Monoamine oxidase A; Trabecular meshwork
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.037
  32. Metabolites. 2025 Dec 23. pii: 12. [Epub ahead of print]16(1):
    Rutin Maintains the Thermogenic Phenotype of Beige Adipocytes and Concomitantly Suppresses Mitophagy Against Obesity in HFD Mice.
    Jianmei Li, Kexin Li, Shengnan Li, Jingxun Cui, Shuangying Zhou, Huiwen Wu.
       BACKGROUND: The browning of white adipose tissue for thermogenesis is an effective strategy for combating obesity. The formation of beige adipocytes is reversible, making their maintenance a key therapeutic target. Rutin has been shown to promote the transition from white to beige adipocytes. It remains unclear whether rutin can prevent the reversion of beige adipocytes to white adipocytes and what mechanisms underlie this process.
    OBJECTIVES: This study aims to determine whether rutin can sustain the thermogenic phenotype of beige adipocytes and to elucidate its mechanism.
    METHODS: We established a beige adipocyte model with CL-316, 243(CL) in vitro. A white adipocyte model was created by CL withdrawal after 3 days. Then, we conducted a co-intervention with CL and rutin, as well as sustained rutin intervention on beige adipocytes following CL withdrawal. In vivo, we utilized a C57BL/6 mouse model, including ND, high-fat diet (HFD), and HFD + Rutin groups. The mice were further divided into Cold and -Cold groups, with the former undergoing 7 days of exposure to 4 °C and the latter experiencing 10 days of 22-24 °C. Rutin was administered continuously until the conclusion of the experiment.
    RESULTS: Rutin consistently ameliorates metabolic disorders and prevents the expansion of adipose tissue. It concomitantly suppresses mitochondrial autophagy during beige induction, upregulates thermogenic markers in brown adipocytes, and safeguards the mitochondrial-related functional indicators.
    CONCLUSIONS: In summary, rutin obstructs the transformation of beige adipocytes into white adipocytes and concomitantly suppresses mitochondrial autophagy, thereby continuously improving obesity induced by a high-fat diet.
    Keywords:  beige adipocytes; mitophagy; obesity; rutin
    DOI:  https://doi.org/10.3390/metabo16010012
  33. Int J Biol Macromol. 2026 Jan 22. pii: S0141-8130(26)00398-3. [Epub ahead of print]344(Pt 1): 150472
    Deletion of Glaesserella parasuis nanA promotes apoptosis by inhibiting PINK1/Parkin pathway.
    Yaqin Liu, Yuqing Tan, Shijiao Huan, Ziyue Wu, Zhixin Lei.
      Glaesserella parasuis (G. parasuis) is the primary pathogen responsible for Glasser's disease in large-scale pig farms. It causes annual mortality rates of 10-20% in weaned piglets due to meningitis, serositis, and sudden death syndrome. The rapid spread of multidrug-resistant strains has reduced the cure rate of macrolide antibiotics and other drugs, resulting in significant economic losses in the livestock industry. Based on a previously established Tildipirosin-resistant G. parasuis strain (Wang et al., 2025), this study confirmed that nanA is a virulence gene. To investigate its function, we constructed a ΔnanA deletion mutant. The results demonstrated that nanA deletion markedly reduced G. parasuis adhesion to PK-15 cells, cellular toxicity, and minimum inhibitory concentration (MIC), suggesting that this gene plays a crucial role in bacterial pathogenicity and resistance. Further studies revealed that G. parasuis infection induced mitophagy in PK-15 cells, a process that was significantly inhibited by the ΔnanA mutant. By knocking down the Pink1 gene, we confirmed that the ΔnanA mutant strain attenuated G. parasuis-induced mitophagy via the PINK1/Parkin signaling pathway, a mechanism validated in mouse models. Furthermore, qPCR and flow cytometry results indicated that nanA deletion exacerbated G. parasuis-induced apoptosis. In summary, this study demonstrates that G. parasuis enhances its virulence by inducing mitophagy, whereas nanA deletion promotes apoptosis by inhibiting autophagy. These findings elucidate a key aspect of G. parasuis pathogenesis and highlight the central role of NanA in this process.
    Keywords:  Apoptosis; Glaesserella parasuis; Mitophagy; Virulence; nanA gene
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150472
  34. Pharmacol Rep. 2026 Jan 26.
    Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
    Brígida R Pinho, Vasco Martins, Anitta R Chacko, Célia Nogueira, Michael R Duchen, Jorge M A Oliveira.
      
    Keywords:  ATP synthase; Autophagy; Cybrid; Mitochondrial DNA; Mitochondrion; Ubiquitin
    DOI:  https://doi.org/10.1007/s43440-026-00829-7
  35. Biochem Cell Biol. 2026 Jan 01. 104 1-15
    NCOR1 alleviates myocardial infarction by improving lipid peroxidation through PPARG/PINK1-mediated mitophagy.
    Zhenzhen Liu, Yanru He, Wenjing Zhu.
      Abnormal lipid accumulation following myocardial infarction (MI) serves as a critical pathological factor contributing to cardiomyocyte injury. The nuclear receptor corepressor 1 (NCOR1) is famous as a key regulator in atherosclerosis, fatty liver, and other metabolic diseases, and recent evidence suggested that NCOR1 exerted a protective action in damaged heart cells. In this study, in a murine MI model induced by left anterior descending coronary artery ligation, we observed a significant downregulation of NCOR1 in myocardial tissues. NCOR1 was also downregulated in oxygen-glucose deprivation (OGD)-treated H9C2 cells, in which NCOR1 overexpression improved lipid metabolic dysregulation and peroxidation. Mechanistically, NCOR1 interacted with peroxisome proliferator activated receptor gamma (PPARγ) protein, which transcriptionally activated the expression of the mitophagy marker gene PINK1. Either knockdown of PPARγ or PINK1 was able to reverse the improvement of NCOR1 overexpression on OGD-induced dysregulation of mitophagy, lipid peroxidation, and cardiomyocyte damage. Finally, we demonstrated that NCOR overexpression (mediated by lentiviral vector) reduced infarct size, attenuated myocardial damage, and significantly improved cardiac function in MI mice. These findings not only identify NCOR1 as a novel protector in hypoxic-ischemic myocardium but also delineate the "NCOR1-PPARγ-PINK1" axis as a novel mechanism for improving mitochondrial function and lipid peroxidation, offering a promising therapeutic target for MI treatment.
    Keywords:  NCOR1; PPARγ; lipid peroxidation; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.1139/bcb-2025-0075
  36. Biology (Basel). 2026 Jan 13. pii: 139. [Epub ahead of print]15(2):
    Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
    Jessica Ábalos-Martínez, Francisco Visiedo, María Victoria Cascajo-Almenara, Celeste Santos-Rosendo, Victoria Melero-Jiménez, Carlos Santos-Ocaña, Luis Vázquez-Fonseca, Fernando Bugatto.
      Preeclampsia is a serious pregnancy disorder of unknown etiology. One of its cellular hallmarks is increased mitochondrial dysfunction in placental tissue. Further investigation into this aspect may help elucidate the molecular basis of preeclampsia. A total of 24 pregnant women who delivered by cesarean section participated in the study: n = 13 controls and n = 11 diagnosed with preeclampsia. Maternal blood samples were collected to assess the biochemical profile, and demographic and clinical data were recorded. Placental trophoblast samples were processed to isolate mitochondria and perform molecular biology assays. Women with preeclampsia exhibited the characteristic clinical features of the disease, along with biochemical alterations consistent with an inflammatory process. A significant decrease (73%) in mitochondrial DNA (mtDNA) copy number in trophoblastic tissue and a reduction in citrate synthase (CS) activity (-51%) in cytotrophoblast mitochondria-enriched fractions were observed in preeclampsia, indicating mitochondrial dysfunction accompanied by a loss of functional mitochondrial mass. In addition, we detected a marked decrease in MnSOD levels (-32%), together with an increase in the LC3II/LC3I ratio (47%) in cytotrophoblast mitochondria-enriched fractions, supporting the presence of mitochondrial alterations and suggesting the possible activation of mitophagy specifically in this cell type. Moreover, coenzyme Q10 (CoQ10) levels were elevated by 31% in trophoblastic villi. A pronounced 2.5-fold increase in CoQ10 normalized to CS activity (CoQ10/CS) was detected specifically in cytotrophoblasts from preeclamptic placentas. Importantly, we did not observe these alterations in the syncytiotrophoblast. In conclusion, preeclampsia is associated with mitochondrial dysfunction and increased CoQ10 levels normalized to CS activity, specifically in cytotrophoblast mitochondria, with findings being consistent with a possible involvement of mitophagy in this cell type. These findings suggest that cytotrophoblast mitochondrial metabolism may be more affected in preeclampsia compared with syncytiotrophoblasts, and that CoQ10 accumulation together with the possible activation of mitophagy may represent cellular defense mechanisms. Due to the limitations of the study, it should be considered exploratory and hypothesis-generating, and its results should be regarded as preliminary.
    Keywords:  coenzyme Q10; cytotrophoblast; mitochondria; mitophagy; preeclampsia
    DOI:  https://doi.org/10.3390/biology15020139
  37. Food Sci Nutr. 2026 Feb;14(2): e71500
    Pinellia pedatisecta Schott-Derived Exosome-Like Nanovesicles Promote Apoptosis in Colorectal Cancer by Regulating the Lysosome-Mediated Mitophagy Pathway.
    Pingsheng Zhou, Qingling Zhang, Xiaotao Zhou, Ge Zhang, Shiping Cheng.
      Plant-derived exosome-like nanovesicles (ELNs) have shown potential in the treatment of various diseases. This research sought to investigate the effects of Pinellia pedatisecta Schott-derived ELNs (PPS-ELNs) on colorectal cancer (CRC). PPS-ELNs extracted from Pinellia pedatisecta Schott were characterized. CRC cell lines HCT116 and HT-29 were exposed to 10 μg/mL of PPS-ELNs. Normal colon epithelial cells FHC were treated with different concentrations of PPS-ELNs. CRC mice were treated with 12.5 or 25 mg/kg of PPS-ELNs. Subsequent experiments, including cellular uptake assay, CCK-8 assay, colony formation assay, flow cytometry, Western blot, transmission electron microscopy, LysoTracker Red staining, immunofluorescence, ELISA, in vivo imaging, TUNEL staining, immunohistochemistry, HE staining, and biochemical analysis, were conducted to explore the anti-CRC effects and potential mechanisms of PPS-ELNs. Lysosome inhibitor chloroquine was employed to elucidate the underlying mechanism in vitro. The isolated PPS-ELNs were successfully characterized. Cellular uptake of PPS-ELNs was observed in CRC cell lines. Notably, PPS-ELNs did not affect FHC cell viability, while significantly inhibiting proliferation and inducing apoptosis and mitophagy in CRC cell lines. Furthermore, PPS-ELNs induced oxidative stress and reduced lysosomal damage in HCT116 cells. The effects of PPS-ELNs on HCT116 cells were reversed by chloroquine. In CRC mice, PPS-ELNs were primarily accumulated in tumors. PPS-ELNs markedly reduced tumor growth, induced apoptosis, and decreased Ki67 expression. Additionally, PPS-ELNs decreased Gal3 expression, increased autophagosomes, and altered mitophagy-related protein levels in tumor tissues. Importantly, PPS-ELNs displayed an excellent safety profile in vivo. PPS-ELNs inhibit CRC progression through the lysosome-mediated mitophagy pathway.
    Keywords:  Pinellia pedatisecta Schott; apoptosis; colorectal cancer; exosome‐like nanovesicles; lysosome; mitophagy
    DOI:  https://doi.org/10.1002/fsn3.71500
  38. J Transl Med. 2026 Jan 27.
    Zalcitabine induces ferroptosis in multiple myeloma through the TFAM-cGAS-STING-SLC7A11 axis.
    Juan Hui, Jiao Jia, Juan Feng, Hailong Tang, Li Xu, Wenrui Sun, Hongjuan Dong, Shan Gao, Chunyan Zhang, Biao Tian, Guangxun Gao.
      
    Keywords:  Ferroptosis; Mitophagy; Multiple myeloma; TFAM; Zalcitabine; cGAS-STING pathway
    DOI:  https://doi.org/10.1186/s12967-026-07749-3
  39. Commun Biol. 2026 Jan 24.
    Development of capsaicin-derived prohibitin ligands to modulate the Aurora kinase A/PHB2 interaction and mitophagy in cancer cells.
    Amel Djehal, Claire Caron, Deborah Giordano, Valentina Pizza, Kimberley Farin, Angelo Facchiano, Laurent Désaubry, Giulia Bertolin.
      Aurora kinase A/AURKA is a serine/threonine kinase frequently overexpressed in cancer. Recent discoveries pointed to subcellular pools of AURKA, including at mitochondria. There, AURKA induces organelle clearance by mitophagy together with the autophagy mediator LC3, and its receptor PHB2.Here, we show that the natural product capsaicin modifies the AURKA/PHB2 interaction. We synthesize 16 capsaicin analogs, and Förster's Resonance Energy Transfer/Fluorescence Lifetime Imaging Microscopy (FRET/FLIM) in breast cancer cells reveals that compounds 12 and 13 increase the AURKA/PHB2 interaction. Molecular docking shows that they bind to the inhibitory pocket of PHB2 and to the AURKA active site. We demonstrate that compound 13 specifically inhibits mitophagy while leaving AURKA activation unaltered at centrosomes. Our results demonstrate that compound 13 is a PHB ligand acting on the AURKA/PHB2 interaction. Thanks to its specificity, it may lead to the development of anticancer drugs targeting the mitochondrial functions of AURKA.
    DOI:  https://doi.org/10.1038/s42003-026-09573-3
  40. Medicina (Kaunas). 2026 Jan 14. pii: 166. [Epub ahead of print]62(1):
    Association of HIF1α, BNIP3, and BNIP3L with Hypoxia-Related Metabolic Stress in Metabolic Syndrome.
    Tuğba Raika Kıran, Lezan Keskin, Mehmet Erdem, Zeynep Güçtekin, Feyza İnceoğlu.
      Background and Objectives: Metabolic syndrome (MetS) is a complex condition marked by insulin resistance, central obesity, dyslipidemia, and chronic inflammation. Emerging evidence highlights the roles of hypoxia and mitochondrial stress in its pathophysiology. Hypoxia-inducible factor-1 alpha (HIF1α) and the mitophagy-associated proteins BNIP3 and BNIP3L are key components of hypoxia-responsive mitochondrial stress signaling. This study aimed to evaluate the circulating levels of HIF1α, BNIP3, and BNIP3L in MetS and to explore their associations with metabolic and inflammatory parameters. Materials and Methods: Serum concentrations of HIF1α, BNIP3, and BNIP3L were measured by ELISA in 40 patients with MetS and 40 age and sex-matched controls. Biochemical, hematological, and anthropometric parameters were assessed, and receiver operating characteristic (ROC) analyses were performed to evaluate diagnostic performance. Results: Serum levels of HIF1α, BNIP3, and BNIP3L levels were significantly higher in MetS patients compared with controls (p = 0.001). ROC analysis demonstrated strong diagnostic potential, particularly for BNIP3 (AUC = 0.928), followed by HIF1α (AUC = 0.885) and BNIP3L (AUC = 0.770). These markers showed significant associations with metabolic indicators such as BMI, fasting glucose, triglycerides, and inflammatory markers. Conclusions: The coordinated upregulation of circulating HIF1α, BNIP3, and BNIP3L in MetS is associated with metabolic dysregulation and systemic inflammation, reflecting alterations in hypoxia-responsive mitophagy-associated signaling rather than direct functional impairment of mitophagy. These findings support the potential relevance of these markers as indicators of metabolic stress in MetS. Further tissue-based and mechanistic studies are warranted to clarify their role in disease pathophysiology.
    Keywords:  BNIP3; BNIP3L; HIF1α; hypoxia; metabolic stress; metabolic syndrome; mitophagy; mitophagy-related signaling
    DOI:  https://doi.org/10.3390/medicina62010166
  41. Chin Med. 2026 Jan 26. 21(1): 55
    Molecular mechanism of berberine in ameliorating leptin resistance and mitochondrial dysfunction through the TRIB1-C/EBPα axis in obesity.
    Xuelian Zhang, Chenyang Zhang, Xiangrui Meng, Jianyuan Tang.
      Hyperleptinemia and mitochondrial dysfunction in obesity form a vicious cycle, underscoring the need for targeted interventions. This study suggests that berberine reduces leptin synthesis and improves leptin resistance by upregulating adipose tissue pseudokinase TRIB1 expression, promoting COP1-mediated C/EBPα ubiquitination and degradation, enhancing STAT3 phosphorylation, and suppressing SOCS3 expression. Meanwhile, TRIB1 appears to mediate the remodeling of mitochondrial dynamics by increasing the expression of fusion proteins MFN1 and L-OPA1, inhibiting the activity of the fission protein DRP1, reversing mitochondrial fragmentation, improving respiratory metabolic capacity, and thereby enhancing brown adipose tissue (BAT) thermogenesis. In TRIB1 knockout mice, the dual effects of berberine-central reduction of high-fat diet intake and peripheral promotion of lipolysis and thermogenesis-were largely abolished. Collectively, these findings support a model in which TRIB1 serves as a critical mediator through which berberine coordinates leptin signaling and mitochondrial function, providing mechanistic insight that may inform future strategies for obesity intervention.
    Keywords:  Berberine; Energy expenditure; Leptin signaling; Metabolic remodeling; Mitochondrial fission/fusion; TRIB1
    DOI:  https://doi.org/10.1186/s13020-025-01296-7
  42. Int J Mol Sci. 2026 Jan 09. pii: 661. [Epub ahead of print]27(2):
    Investigating the Potential Role of Capsaicin in Facilitating the Spread of Coxsackievirus B3 via Extracellular Vesicles.
    Shruti Chatterjee, Ramina Kordbacheh, Haylee Tilley, Devin Briordy, Richard T Waldron, William D Cutts, Jayden Aleman, Alexis Cook, Raeesa Dhanji, Lok-Yin Roy Wong, Stephen J Pandol, Brandon J Kim, DeLisa Fairweather, Jon Sin.
      Coxsackievirus B3 (CVB3) is a picornavirus that causes systemic inflammatory diseases including myocarditis, pericarditis, pancreatitis, and meningoencephalitis. We have previously reported that CVB3 induces mitochondrial fission and mitophagy while inhibiting lysosomal degradation by blocking autophagosome-lysosome fusion. This promotes the release of virus-laden mitophagosomes from host cells as infectious extracellular vesicles (EVs), enabling non-lytic viral egress. Transient receptor potential vanilloid 1 (TRPV1), a heat and capsaicin-sensitive cation channel, regulates mitochondrial dynamics by inducing mitochondrial membrane depolarization and fission. In this study, we found that TRPV1 activation by capsaicin dramatically enhances CVB3 egress from host cells via EVs. Released EVs revealed increased levels of viral capsid protein VP1, mitochondrial protein TOM70, and fission protein phospho-DRP1. Moreover, these EVs were enriched in heat shock protein HSP70, suggesting its role in facilitating infectious EV release from cells. Furthermore, TRPV1 inhibition with capsazepine and SB-366791 significantly reduced viral infection in vitro. Our in vivo studies also found that SB-366791 significantly mitigates pancreatic damage and reduces viral titers in a mouse model of CVB3 pancreatitis. Given the lack of understanding regarding factors that contribute to diverse clinical manifestations of CVB3, our study highlights capsaicin and TRPV1 as potential exacerbating factors that facilitate CVB3 dissemination via mitophagy-derived EVs.
    Keywords:  HSP70; TRPV1; capsaicin; capsazepine; coxsackievirus B3; extracellular vesicles; mitophagy; pancreatitis
    DOI:  https://doi.org/10.3390/ijms27020661
  43. Pharmaceuticals (Basel). 2025 Dec 22. pii: 23. [Epub ahead of print]19(1):
    A Combined SIRT5 Activation and SIRT3 Inhibition Prevents Breast Cancer Spheroids Growth by Reducing HIF-1α and Mitophagy.
    Federica Barreca, Michele Aventaggiato, Mario Cristina, Luigi Sansone, Manuel Belli, Maria Beatrice Lista, Gaia Francisci, Sergio Valente, Dante Rotili, Antonello Mai, Matteo Antonio Russo, Marco Tafani.
      Background/Objectives: Metabolic reprogramming is an essential feature of tumors. Mitochondrial sirtuins SIRT3 and SIRT5 differently regulate glutamine metabolism with SIRT5 inhibiting glutaminase (GLS) and SIRT3 increasing glutamate dehydrogenase (GDH). Considering the important and interconnected role of glutamine, SIRT3 and SIRT5 for cancer growth and progression, our hypothesis is that a simultaneous modulation of SIRT3 and SIRT5 could represent a valid anti-tumoral strategy. Methods: wt and GLS1-silenced triple negative breast cancer spheroids were treated with 3-TYP, a selective SIRT3 inhibitor, and with MC3138, a new selective SIRT5 activator, both alone and in combination. The effects of such treatments on hypoxia, autophagy and mitophagy markers were determined by immunofluorescence and Western blot. Mitochondria morphology was studied by transmission electron microscopy (TEM) and mitochondrial ROS production by confocal analysis. Results: We observed that 3-TYP+MC3138 treatment decreased the size of spheroids by affecting HIF-1α, c-Myc, glutamine transporter SLC1A5 and autophagy (LC3II) and mitophagy (BNIP3) markers. Moreover, such treatments altered the morphology and conformation of the mitochondria. Finally, we also documented an increase in mitochondria reactive oxygen species (mtROS). Conclusions: The combined inhibition of SIRT3 and activation of SIRT5 greatly reduces the size of spheroids through the inhibition of hypoxic response, which is then followed by the alteration of the autophagic and mitophagic process and the toxic accumulation of mitochondrial ROS, representing a new anti-tumoral strategy.
    Keywords:  autophagy; glutamine metabolism; mitophagy; sirtuins; triple negative breast cancer
    DOI:  https://doi.org/10.3390/ph19010023
  44. Mol Neurobiol. 2026 Jan 28. 63(1): 400
    Gastrodin Ameliorates Pain-Depression Comorbidity through SIRT3-Dependent Alleviation of Oxidative Stress and Promotion of Mitochondrial Biogenesis.
    Feiran Zhou, Yijian Luo, Yan Liu, Lin Luo, Ping Jiang, Qing Liu, Ying Zhang.
      Neuropathic pain (NP) and depression frequently co-occur, creating a complex clinical challenge with limited therapeutic options due to poorly understood shared mechanisms. Our preliminary screening identified the mitochondrial deacetylase SIRT3 as a potential key regulator of this comorbidity. Building on this finding, we hypothesized that Gastrodin, a natural compound with documented neuroprotective properties, exerts its therapeutic effects by targeting SIRT3. This study was therefore designed to investigate whether Gastrodin alleviates NP-depression comorbidity through a SIRT3-dependent mechanism. A rat model of NP-depression comorbidity was established by combining spared sciatic nerve injury (SNI) with chronic unpredictable mild stress (CUMS). Behavioral tests were conducted to assess mechanical allodynia, thermal hyperalgesia, and depression-like behaviors. Molecular mechanisms were evaluated using Western blot, ELISA, qPCR, and transmission electron microscopy. The specific role of SIRT3 was confirmed using the inhibitor 3-TYP in vivo and siRNA in vitro. Gastrodin administration (200/300 mg/kg) significantly ameliorated both pain hypersensitivity and depression-like behaviors in the comorbidity model. Mechanistically, Gastrodin upregulated SIRT3 expression and enhanced its deacetylase activity in the hippocampus, as evidenced by reduced acetylation of SOD2. This led to attenuated neuroinflammation (TNF-α, IL-1β, IL-6) and oxidative stress (MDA, ROS). Furthermore, Gastrodin improved mitochondrial ultrastructure and promoted mitochondrial biogenesis via the PGC-1α/TFAM pathway in astrocytes. Critically, all therapeutic benefits of Gastrodin were abolished upon SIRT3 inhibition. Gastrodin exerts dual therapeutic effects on NP-depression comorbidity by activating the SIRT3 pathway, thereby rescuing mitochondrial function in hippocampal astrocytes. These findings identify Gastrodin as a promising candidate for treating pain-depression comorbidity and underscore SIRT3 as a critical therapeutic target.
    Keywords:  Depression; Gastrodin; Mitochondria biogenesis; Neuropathic pain; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-026-05677-3
  45. Int J Med Sci. 2026 ;23(2): 620-635
    Molecular Subtyping and Prognostic Prediction in Pancreatic Cancer Based on Mitophagy-Related Genes.
    Yunlong Cai, Taohua Yue, Yongchen Ma, Guanyi Liu, Jixin Zhang, Long Rong.
      Background: Pancreatic cancer (PaC) is characterized by poor prognosis. This study aimed to identify mitophagy-related clusters and develop a prognostic model for PaC. Methods: Differentially expressed genes (DEGs) between PaC and normal tissues were identified from the TCGA and GTEx cohorts. Mitophagy-related genes (MRGs) were sourced from Reactome, GO, and KEGG databases. The intersection of DEGs and MRGs identified differentially expressed MRGs (DeMRGs). Consensus clustering identified PaC subtypes based on DeMRG expression. Univariate Cox analysis was used to find prognosis-related genes, and LASSO regression analysis was employed to develop the prognostic model. A nomogram was constructed to predict survival probabilities. Results: A total of 7,240 DEGs were identified between PaC tissues and normal controls. From these, 12 DeMRGs were identified, and consensus clustering revealed three distinct molecular clusters. A prognostic model based on six significant genes (PAPPA, NBPF12, CXCL11, CKLF-CMTM1, CCDC6, AHNAK) was developed using LASSO regression analysis. This model demonstrated good predictive performance for overall survival in the TCGA cohort, with AUC values of 0.78, 0.74, and 0.82 for 1-, 2-, and 3-year survival in the training set, and 0.73, 0.82, and 0.73 in the validation set. External validation in independent GEO cohorts demonstrated moderate predictive performance. The nomogram demonstrated good calibration and accuracy in predicting survival. Significant correlations were found between the risk model and immune cell infiltration. High-risk patients showed higher sensitivity to dasatinib and staurosporine. Conclusions: The study identified mitophagy-related molecular clusters and developed a prognostic model for PaC. This model may help predict overall survival and guide personalized treatment strategies for PaC patients.
    Keywords:  gene expression analysis; mitophagy; pancreatic cancer; prognosis
    DOI:  https://doi.org/10.7150/ijms.121350
  46. J Transl Med. 2026 Jan 24.
    Targeting the mitochondrial metabolite-dynamics-MDVs-MitoEVs axis: a new frontier in osteoarthritis management.
    Taotao Zhang, Hongmei Zhang, Xinzhao Chen, Yingxiang Liu, Xiaoxiao Han, Weiwei Zhu, Yubo Liu, Guang Zeng, Kai Jiao.
      
    Keywords:  MDVs; MitoEVs; Mitochondrial dynamics; Mitochondrial metabolism; Osteoarthritis
    DOI:  https://doi.org/10.1186/s12967-025-07615-8
  47. Hereditas. 2026 Jan 26.
    Ferroptosis-dependent small extracellular vesicles ULK1 enhances mitophagy and suppresses breast cancer migration.
    Anan Wang, Min Chen, Yonghui Luo, Li Li, Jiahao Rong, Lei Liu, Chenghao Yi.
      
    Keywords:  Breast cancer; Ferroptosis; Mitophagy; SEVs; ULK1
    DOI:  https://doi.org/10.1186/s41065-025-00621-2
  48. Antioxidants (Basel). 2026 Jan 22. pii: 144. [Epub ahead of print]15(1):
    OPA1 as a Cancer Target: Molecular Mechanisms, Structural Insights, and Strategies for Drug Development.
    Antonio Curcio, Ludovica Ganino, Ilenia Valentino, Massimo Gentile, Stefano Alcaro, Roberta Rocca, Anna Artese, Nicola Amodio.
      Mitochondria are highly dynamic organelles that integrate metabolic regulation, signal transduction, and programmed cell death with their canonical role in adenosine triphosphate (ATP) production. Their ability to undergo continuous remodeling through the opposing processes of fusion and fission is essential for maintaining cellular homeostasis, preserving organelle quality control, and enabling adaptive responses to metabolic and oxidative stress. Among the core regulators of mitochondrial dynamics, the dynamin-related guanosine triphosphatase (GTPase) OPA1 plays a central role in inner membrane fusion, cristae architecture maintenance, bioenergetic efficiency, and the modulation of redox balance and apoptotic signaling. Accumulating evidence indicates that dysregulation of OPA1 expression or activity contributes to the initiation and progression of multiple malignancies, underscoring its importance in tumor cell survival, proliferation, metabolic adaptation, and resistance to stress. Here, we summarize current knowledge on OPA1 dysregulation in cancer and, based on preliminary, unpublished in silico analyses, we highlight the growing relevance of OPA1 as a therapeutic target, particularly through its GTPase domain and the still understudied Interface 7. Overall, these findings outline how integrated computational approaches could potentially guide the identification of novel OPA1 modulators, offering a conceptual framework that highlights OPA1 as a promising, yet still largely underexplored, target in oncology.
    Keywords:  OPA1; SBVS; docking; mitochondria; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/antiox15010144
  49. Cell Death Dis. 2026 Jan 28. 17(1): 144
    Correction: Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.
    Su Hyeon Wang, Duk-Shin Lee, Tae-Hyun Kim, Ji-Eun Kim, Tae-Cheon Kang.
      
    DOI:  https://doi.org/10.1038/s41419-025-08409-y
  50. Diabetes Obes Metab. 2026 Jan 28.
    Dapansutrile preserves pancreatic beta-cell function by regulating insulin vesicle membrane fusion and mitochondrial homeostasis.
    Ying Wu, Hongxing Fu, Min Zhu, Yuanfa Yao, Luhong Jin, Xihua Lin, Jiaqiang Zhou.
       AIMS/HYPOTHESIS: Pancreatic beta-cell dysfunction is pivotal in diabetes pathogenesis, with the NOD-like receptor protein 3 (NLRP3) inflammasome playing a crucial role. Dapansutrile (DAPA), a novel NLRP3 inhibitor, demonstrates promise in diabetes management.
    METHODS: The diabetic model of high-fat diet (HFD) + streptozotocin (STZ) mice was utilized to assess glucose metabolism indicators following DAPA intervention. Experiments involving pancreatic islets from normal mice or humans, as well as INS-1 cell lines, were conducted to evaluate CCK8, glucose-stimulated insulin secretion (GSIS), calcium ion imaging, vesicle fusion and mitochondrial function after exposure to palmitic acid (PA) and DAPA intervention. Additionally, the study explored the efficacy of islet transplantation in type 1 diabetes mice using islets treated with DAPA in vitro.
    RESULTS: This study showed that DAPA improved fasting blood glucose level, glucose tolerance and glucose metabolism in diabetes mice. The experimental work on pancreatic islets and INS-1 cells exposed to PA confirmed that DAPA enhanced GSIS, restored pancreatic function, improved calcium ion flux, mitochondrial dynamics and vesicle fusion. Notably, through the application of pancreatic islet transplantation technology, we illustrated that DAPA effectively addresses systemic glucose metabolism issues at the beta-cell level.
    CONCLUSIONS/INTERPRETATION: DAPA targets the NLRP3 inflammasome in pancreatic beta cells of diabetic mice to preserve function, maintain mitochondrial homeostasis and offer potential avenues for diabetes management strategies.
    Keywords:  Dapansutrile; NLRP3; inflammasome inhibitor; insulin vesicles; mitochondria; pancreatic beta‐cells
    DOI:  https://doi.org/10.1111/dom.70492
  51. J Adv Res. 2026 Jan 26. pii: S2090-1232(26)00088-3. [Epub ahead of print]
    High-protein diet promotes aging by activating the CG6415/AMT gene and disrupting mitochondrial homeostasis.
    Xiaoqing Xu, Yang Wang, Qianmin Liu, Yue Li, Shuo Yang, Runyi Zhou, Yina Wang, Xiang Qi, Can Zhang, Fengmin Zhang, Yue Wu, Yuhao Li, Ying Li.
       INTRODUCTION: Dietary protein has multiple physiological functions. However, high-protein diets have been proven to elevate the risk of all-cause mortality. Aging is a dynamic and complex process, but the impact of dietary protein on aging remains unclear.
    OBJECTIVES: To explore the effects of high-protein diets on aging at multiple life stages and the underlying mechanisms.
    METHODS: Drosophila were used to assess the effects of diets with 5%, 10%, 15%, 20%, 25%, and 30% protein energy supply on lifespan. Transcriptomic and proteomic analyses at multiple life-stage points screened pathways and key genes consistently affected by high-protein diets. Knockout and overexpression of the key gene CG6415 in Drosophila verified its mediating role in high-protein diets' impact on aging. Based on the insights from the omics data of gene-knockout Drosophila, the mechanism by which the human homologous AMT gene of CG6415 affects aging was verified in the mammalian genetic background using the human embryonic kidney 293 T cell. According to the effects of high-protein diets on Drosophila's amino acid profiles, lifespan observations with individual supplementation of 20 amino acids, and verification using CG6415 gene-knockout Drosophila, the amino acids that play key roles in the impact of high-protein diets on aging were identified.
    RESULTS: There is an inverted U-shaped relationship between lifespan and dietary protein energy ranging from 5% to 30%. Glycine, serine, and threonine metabolism pathway and the CG6415 gene can be activated by high-protein diets of various proportions at multiple life-stage points. The CG6415/AMT gene inhibits oxidative phosphorylation, disrupts mitochondrial homeostasis, and subsequently activates the p53-p21 pathway, promoting aging and stress-induced damage. Supplementing isoleucine can partially simulate the role of high-protein diets in regulating CG6415-mediated aging.
    CONCLUSIONS: High-protein diet promotes aging, partly via activation of the CG6415/AMT gene and subsequent disruption of mitochondrial homeostasis. Isoleucine plays a relatively key role in this process.
    Keywords:  Aging; Amino acid; High-protein diet; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.jare.2026.01.063
  52. Front Endocrinol (Lausanne). 2025 ;16 1733368
    Transcriptome analysis and RT-qPCR validation of mitophagy-related key genes in the progression of diabetic retinopathy.
    Yifan Zhang, Liangjie Niu, Huika Xia, Jianmin Wang.
       Background: Diabetic retinopathy (DR), a prevalent microvascular complication of diabetes mellitus (DM), likely involves mitophagy in its progression. However, the exact mechanisms remain poorly understood.
    Methods: This study analyzed DR datasets GSE189005 and GSE221521 from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs 1) between patients with DR and controls were identified from GSE189005. Simultaneously, mitophagy-related genes (MRGs) were analyzed to determine DEGs 2. The datasets were integrated to obtain differentially expressed MRGs. A machine learning-based approach was used to identify key candidate genes, followed by expression validation. Additionally, a nomogram was constructed for DR risk prediction; correlation analysis was performed between key genes and immune cells; RT-qPCR analysis was conducted to verify gene expression.
    Results: Integration of datasets revealed 13 differentially expressed MRGs. Five key candidate genes were identified via machine learning, and expression validation confirmed the differential expression of SLC1A5 and RPS21 in DR. The nomogram incorporating these two genes showed high predictive accuracy for DR risk. SLC1A5 was strongly positively correlated with CD56 bright NK cells (r = 0.82) and negatively correlated with CD56 dim NK cells (r = -0.80). RPS21 exhibited the strongest positive correlation with CD56 dim NK cells (r = 0.77) and the strongest negative correlation with CD56 bright NK cells (r = -0.75). RT-qPCR analysis indicated significant upregulation of SLC1A5 and downregulation of RPS21 in DR samples.
    Conclusions: This study suggests that SLC1A5 and RPS21 are involved in DR progression, offering potential therapeutic targets. However, further experimental validation is necessary to confirm their functional roles and clinical relevance.
    Keywords:  RPS21; SLC1A5; bioinformatics analysis; diabetic retinopathy; mitophagy-related genes
    DOI:  https://doi.org/10.3389/fendo.2025.1733368
  53. Free Radic Biol Med. 2026 Jan 23. pii: S0891-5849(26)00056-0. [Epub ahead of print]
    Insulin-like Growth Factor 2 mRNA-binding Protein 2 Regulates PINK1 Expression through m6A Pathway to Promote Mitophagy in BMSCs Alleviating Postmenopausal Osteoporosis.
    Yu Ji, Yajun Cui, Lingshuang Li, Tianyu Cao, Hongrui Liu, Minqi Li.
      The senescence and altered differentiation potential of bone marrow mesenchymal stem cells (BMSCs) contribute to the pathogenesis of postmenopausal osteoporosis (PMOP). Insulin-like growth factor 2 mRNA-binding protein (IMP2) has been demonstrated to regulate BMSCs. However, its specific mechanistic actions remain unclear, particularly due to the lack of concrete evidence within the ovariectomy (OVX) in vivo microenvironment. In this study, we utilized Cre-LoxP technology to achieve BMSC-specific IMP2 knockout. This approach conclusively demonstrated in vivo that IMP2 deficiency induces BMSC senescence, suppresses osteogenic differentiation capacity, and leads to significant bone mass reduction in mice. Under OVX conditions, IMP2 knockout also aggravates bone loss. Mechanistically, we argued that IMP2 stabilizes PINK1 mRNA via the N6-methyladenosine (m6A) pathway; upon IMP2 silencing, reduced PINK1 protein expression attenuates mitophagy in BMSCs, ultimately culminating in accelerated cellular senescence and diminished osteogenic potential, with the postmenopausal environment further aggravating this cascade.
    Keywords:  BMSCs; IMP2; PINK1; PMOP; m(6)A; senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.038
  54. Gene. 2026 Jan 24. pii: S0378-1119(26)00032-6. [Epub ahead of print] 150023
    NIPSNAP3B elevates mitochondrial biogenesis to attenuate lipid accumulation in childhood obesity via AMPK pathway.
    Kaifeng Li, Mengran Wang, Yanhong Liu, Ruining Lu, Heng Zhang, Xiaohui Sui, Guiju Zhang, Xuan Li.
       OBJECTIVE: Childhood obesity (CO) has become a global epidemic, leading to rising burden of many diseases and premature death. Thus, this study was conducted to screen the mitochondria-associated biomarkers for patients with CO, as well as the involved molecular mechanism.
    METHODS: After downloading GSE29718 and GSE104815 datasets from GEO database, differential expression analysis was conducted to screen the DEGs. Then the obtained DEGs were intersected with the mitochondrial-associated genes, and mitochondrial-related genes in CO were acquired, followed by key mitochondrial-related genes screening utilizing three machine learning algorithms. The qRT-PCR and western blot were employed to determine the expression of key genes. Gain-of-function experiment was applied to investigate the function of NIPSNAP3B in CO in vitro.
    RESULTS: Total 364 DEGs were screened, then 18 mitochondrial-related genes in CO were obtained. These 18 mitochondrial-associated genes in CO enriched in pyruvate metabolism, arginine biosynthesis, and AMPK signaling pathway, etc. ACACB and NIPSNAP3B were considered as the key mitochondrial-related genes. Of note, NIPSNAP3B overexpression markedly reduced the TG level and the protein expression levels of PPARγ and C/EBPα in MDI-induced 3 T3-L1 cells. Also, ATP content, mitochondrial mass, MMP, and protein expression levels of PGC-1α, NRF1, and TFAM were changed after NIPSNAP3B upregulation in MDI-induced 3 T3-L1 cells. However, opposite results were observed after NIPSNAP3B downregulation. Compound C (AMPK inhibitor) or AMPK knockdown administration could reverse the effect of NIPSNAP3B on adipocyte lipid deposition and mitochondrial biogenesis.
    CONCLUSION: NIPSNAP3B enhances mitochondrial biogenesis to attenuate lipid accumulation via AMPK pathway in CO.
    Keywords:  AMPK pathway; Childhood obesity; Lipid accumulation; Mitochondrial biogenesis; NIPSNAP3B
    DOI:  https://doi.org/10.1016/j.gene.2026.150023
  55. J Integr Neurosci. 2026 Jan 23. 25(1): 45758
    Lutein Attenuates Parkinson's Disease Progression by Regulating Mitochondrial Function via the TRIM31/Drp1 Signaling Pathway.
    Jiabin Duan, Wenbin Duan, Xiaomin Pu, Changdi Ma, Huai Huang, Zhenghu Xu.
       BACKGROUND: Mitochondrial dysfunction is closely associated with the pathogenesis of Parkinson's disease (PD). Lutein has been shown to exert protective effects in neurological disorders. This study aimed to investigate the ameliorative effects of lutein on mitochondrial function in PD and its underlying molecular mechanisms.
    METHODS: Animal and cellular PD models were established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and treatment of SH-SY5Y cells with 1-methyl-4-phenylpyridinium ion (MPP+), respectively. Motor function was assessed using the rotarod, adhesive removal, and pole tests. Mitochondrial function was evaluated using MitoSOX Red staining, JC-1 staining, and adenosine triphosphate (ATP) content measurement. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to measure the levels of relevant proteins and mRNA.
    RESULTS: Lutein significantly ameliorated MPTP-induced motor dysfunction in PD mice, increased the number of tyrosine hydroxylase (TH)-positive neurons, and alleviated damage to striatal brain tissue. At the cellular level, lutein significantly suppressed MPP+-induced apoptosis of SH-SY5Y cells, upregulated the expression of B-cell lymphoma-2 (Bcl-2), and downregulated the expression of Bcl-2-associated X protein (Bax) and cleaved caspase-3. Additionally, lutein significantly reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential, increased ATP levels, and increased the activity of mitochondrial respiratory chain complex I. At the molecular level, lutein promoted the ubiquitination of dynamin-related protein 1 (Drp1), whose degradation was impaired in the PD model. This effect was mediated by the E3 ubiquitin ligase Tripartite Motif-containing protein 31 (TRIM31), whose expression was downregulated in the disease state. Functional experiments confirmed that overexpression of TRIM31 enhanced Drp1 ubiquitination and improved mitochondrial function, whereas TRIM31 knockdown partially attenuated the therapeutic effects of lutein.
    CONCLUSION: In summary, this study revealed, for the first time, that lutein alleviates PD progression by increasing Drp1 ubiquitination and degradation via TRIM31 transcription and translation, ultimately improving neuronal mitochondrial function. These findings not only elucidate a novel mechanism underlying lutein's neuroprotective effect but also identify a potential therapeutic target and offer a new strategy for PD treatment.
    Keywords:  Drp1; Parkinson’s disease; TRIM31; lutein; mitochondrial function; neurons
    DOI:  https://doi.org/10.31083/JIN45758
  56. Int J Mol Sci. 2026 Jan 08. pii: 630. [Epub ahead of print]27(2):
    Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
    Francesco Bellomo, Domenico De Rasmo.
      Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.
    Keywords:  bioenergetics; cAMP; cysteamine; cystinosis; flavonoids; ketogenic diet; lysosomal storage diseases; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/ijms27020630
  57. Adv Sci (Weinh). 2026 Jan 28. e23583
    Lactylation Reprogramming in the Bone Infection Microenvironment Identifies PGK1 K361 as a Potential Therapeutic Target for Osteogenic Dysfunction.
    Han-Jun Qin, Si-Ying He, Ting-Hui Xiao, Da-Mao Dai, Xin-Jia Hu, Nan Jiang.
      Bone infections pose a significant global challenge in orthopedics, often leading to poor bone healing, limb dysfunction, and the need for additional surgeries. Lysine lactylation (Kla) has emerged as a novel post-translational modification, garnering considerable research attention. However, its role in bone infection remains unclear. In this study, results show that Kla levels are significantly higher in the bone tissues of infected patients than in the uninfected controls. Global Kla quantitative proteomics identified 491 Kla sites on 201 proteins, each with distinct expression patterns in bone tissue. Phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme, undergoes lactylation at residue K361. By designing adenoviral vectors that mimic either the lactylated or delactylated forms of this site and employing adeno-associated viruses to specifically target osteoblasts, in vitro and in vivo studies suggest that modifying PGK1 at K361 through Kla may offer a promising strategy for treating infection-induced osteogenic dysfunction. Integrating patient proteomic data further reveals and validates a novel mechanism: PGK1 K361 lactylation activates VDAC3, triggering FtMt/PINK1/Parkin-mediated mitophagy and inducing ferroptosis in osteoblasts. Collectively, these findings provide new mechanistic insights into osteogenic impairment during bone infection and suggest that PGK1 K361 lactylation is a promising intervention target.
    Keywords:  bone infection; ferroptosis; lysine lactylation; mitophagy; phosphoglycerate kinase 1 (PGK1)
    DOI:  https://doi.org/10.1002/advs.202523583
  58. Mol Cancer. 2026 Jan 27.
    Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
    Hongling Zhong, Renjie Pan, Yuzhen Ouyang, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Hucheng Li, Tianfang Peng, Pan Chen.
      Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.
    Keywords:  Cancer Metabolism Reprograming; Mitochondrial DNA (mtDNA) Damage; Mitochondrial Homeostasis; Mitochondrial-Targeted Therapies; Tumor Microenvironment
    DOI:  https://doi.org/10.1186/s12943-026-02571-3
  59. Curr Issues Mol Biol. 2025 Dec 26. pii: 31. [Epub ahead of print]48(1):
    Autophagy Dysregulation in Crohn's Disease and Colorectal Cancer-An Analysis of BECN1, PINK1, and LAMP2 Gene Expression.
    Magda Bichalska-Lach, Dariusz Waniczek, Paweł Kowalczyk, Mirosław Śnietura, Mariusz Kryj, Martyna Bednarczyk, Małgorzata Muc-Wierzgoń.
      Crohn's disease (CD) and colorectal cancer (CRC) are clinically distinct but pathogenetically related conditions in which significant abnormalities in autophagy are observed. The aim of the study was to evaluate the expression of three key autophagy-related genes, i.e., BECN1 (macroautophagy), PINK1 (mitophagy), and LAMP2 (chaperone-mediated autophagy) in tissue samples from patients with CD and CRC. The study material included samples from 48 patients with CD (n = 96 biopsy samples) and 87 patients with CRC (n = 87 tumors; n = 87 normal paired controls). Transcriptomic analyses were performed using Affymetrix HG-U133A microarrays. They were confirmed by RT-qPCR. The Kruskal-Wallis test with Dunn's post hoc analysis (α = 0.05) and Spearman's correlation coefficients were used for statistical evaluation. Expression of BECN1 and LAMP2 was significantly decreased in both CD and CRC compared to the controls (p = 0.009; p = 0.023, respectively). However, PINK1 showed significantly higher expression levels in CD compared to CRC and the controls (p < 0.001). The clinical stages of CRC (I-IV) did not significantly affect the expression of the analyzed genes. The study findings confirm the presence of common abnormalities in autophagy in CD and CRC, with decreased macroautophagy and chaperone-mediated autophagy, with the compensatory activation of mitophagy. BECN1, PINK1, and LAMP2 expressions may have a diagnostic and therapeutic value in the context of chronic inflammation and colorectal carcinogenesis.
    Keywords:  BECN1; Crohn’s disease; LAMP2; PINK1; autophagy; colorectal cancer
    DOI:  https://doi.org/10.3390/cimb48010031
  60. Mediators Inflamm. 2026 ;2026 3168669
    Bidirectional Regulation of NLRP3 Inflammasome and Mitochondrial Quality Control in Sepsis: Mechanisms and Therapeutic Implications.
    Xiangxin Liao, Yixun Wang, Zhaohui Zhang, Xingguang Qu, Gaosheng Zhou.
      Characterized by its capacity to induce organ failure, sepsis constitutes a life-threatening pathological state with high incidence and mortality rates. Current treatments primarily focus on antimicrobial therapy and organ support, lacking direct interventions targeting the restoration of cellular or organelle function. Among these mechanisms, mitochondrial dysfunction and overactivation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome stand out as key pathological hallmarks. As a classic inflammasome, the NLRP3 inflammasome, upon activation, drives cellular pyroptosis and massive release of inflammatory mediators. Beyond their role as cellular energy generators, mitochondria participate in the modulation of inflammatory responses and oxidative stress control. Mitochondrial quality control (MQC) serves as a prerequisite for the orderly performance of mitochondrial physiological functions. Disruption of MQC invariably results in mitochondrial dysfunction, triggering liberation of mitochondrial reactive oxygen species (mtROS) along with mitochondrial damage-associated molecular patterns (mtDAMPs), which serve as direct triggers for NLRP3 inflammasome formation and stimulation. This process disrupts MQC, exacerbates mitochondrial dysfunction, and forms a mutually reinforcing "MQC imbalance-NLRP3 overactivation" vicious cycle that drives disease progression. This review aims to: (1) systematically elucidate the complex bidirectional regulatory mechanisms between the NLRP3 inflammasome and MQC in the context of sepsis, (2) summarize the latest research progress on targeted intervention strategies based on this vicious cycle, and (3) discuss the challenges in clinical translation and future directions of these strategies.
    Keywords:  NLRP3 inflammasome; mitochondrial dysfunction; mitochondrial quality control; sepsis; targets; treatment
    DOI:  https://doi.org/10.1155/mi/3168669
  61. Redox Biol. 2026 Jan 16. pii: S2213-2317(26)00036-4. [Epub ahead of print]90 104038
    Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.
    Shadi Al-Mesitef, Daisuke Ando, Tomoya Saigasaki, Yuki Sakaguchi, Shunya Akagi, Abdulrahman Mousa, Sherif Rashad, Kuniyasu Niizuma.
      Transfer RNA-derived small RNAs (tDRs) are emerging regulators of cellular stress response, yet their biogenesis and activities during mitochondrial dysfunction remain poorly understood. Here we profiled tDRs generated in HEK293T cells exposed to inhibitors of respiratory complexes I-V (rotenone, TTFA, antimycin A, KCN, oligomycin) or to arsenite and assessed the impact of CRISPR-mediated angiogenin (ANG) knockout, ANG over-expression and recombinant ANG supplementation on the stress response and tDRs production. tDR-seq revealed stress-specific, highly ordered tDR repertoires: rotenone and antimycin predominantly induced internal (i-tRF) and 3' tRNA (tRF3) fragments, whereas arsenite induced anticodon-cleaved tRNA halves (tiRNAs). mito-tDRs were mostly internal fragments and antimycin induced the strongest mitochondrial tDRs expression. ANG deletion markedly impaired stress-induced tDR biogenesis and sensitized cells to antimycin and oligomycin stress, whereas its overexpression selectively enhanced tDR biogenesis and conferred protection against these mitochondrial stressor. Synthetic tDR mimics failed to rescue viability, implying that native modification patterns or cooperative tDR pools are required. tDR motif enrichment analysis identified YBX1-binding sites among antimycin-induced tDRs, and genetic perturbation of YBX1 phenocopied aspects of enhanced mitochondrial bioenergetics and stress resistance. Together, these findings demonstrate that context-specific, ANG-directed tDR biogenesis forms a crucial arm of the mitochondrial stress response.
    Keywords:  Angiogenin; Mitochondrial stress; RNA binding proteins; YBX1; tRNA; tRNA derived fragments
    DOI:  https://doi.org/10.1016/j.redox.2026.104038
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