bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–03–01
78 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.
  2. The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy.
  3. Role of mitochondrial dysfunction in muscle wasting in cancer cachexia: a narrative review.
  4. Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation.
  5. Regulation of mitophagy by Fis1 and Fascin1-organized actin.
  6. Components of Panax ginseng and Rhodiola rosea regulate mitophagy via the SIRT1/3-PGC-1α-NRF2 pathway to improve myocardial ischemia-reperfusion injury.
  7. Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment.
  8. Mitigation of Ischemia/Reperfusion-Induced Acute Kidney Injury by Canagliflozin Is Associated with Altered Mitochondrial Dynamics and Reduced Proliferation in Swine.
  9. Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury.
  10. Un-PINning Cardiac Regeneration: LPIN1 and the Rewiring of Mitochondrial Dynamics.
  11. Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
  12. Hyperglycemia-induced SIRT3 inhibition contributes to diabetic cardiomyopathy by impairing Cav-3-mediated mitophagy.
  13. Fatty acid oxidase Ehhadh mediates stem cell fate remodeling via mitophagy activation.
  14. Alleviation of cigarette smoke-induced cellular senescence in BALB/c mice by the Lipoxin A4 receptor agonist BML-111 is associated with mitophagy.
  15. C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.
  16. Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
  17. Dual regulation of PINK1/PARKIN-mediated mitochondrial autophagy in ovarian cancer progression and drug resistance: mechanisms and therapeutic potentials.
  18. Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.
  19. Onconase Induces Apoptosis in Dabrafenib-Resistant Melanoma Cell Lines Through Dysregulation of ROS Homeostasis, Antioxidant Protein Expression, and Mitochondrial Dynamics.
  20. Monitoring neuronal mitophagy and locomotion deficits in a C. elegans model of Alzheimer's disease.
  21. AhR activation inhibits DRP1-induced mitochondrial fission in airway smooth muscle during asthma.
  22. Efficacy of nicotiflorin in ameliorating septic acute kidney injury: the role of PINK1/parkin in mitochondrial restoration and oxidative stress reduction.
  23. Melatonin improves spermatogenesis and alleviates oxidative stress in cryopreserved testicular tissue through suppression of the ROS/PINK1-Parkin mitophagy axis.
  24. Vitamin D disrupts NS1-TUFM interaction to suppress pathogenic mitophagy in RSV-induced mitochondrial injury of bronchial epithelial cells.
  25. Punicalagin Promotes Peripheral Nerve Repair by Enhancing Mitophagy via the TLR4/MAPK Signaling Pathway and Facilitating Angiogenesis.
  26. Lysophosphatidylcholine promotes pulmonary fibrosis following lung injury by facilitating alveolar type 2 cell senescence via Mfsd2a-dependent, Drp1-mediated mitochondrial fission.
  27. Selenomethionine Alleviates Zearalenone-Induced Liver Injury in Rabbits Through SIRT1-FOXO1/P53 Signaling Pathway.
  28. Renal-targeted tFNA-TPP nanoagonist treats acute kidney injury by amplifying mitophagy.
  29. Comprehensive analysis of mitochondrial unfolded protein response related genes for prognosis and therapeutic response in pancreatic cancer.
  30. Nanotherapeutic strategy via ADSC-mitoEVs rescues ischaemic angiogenesis through mitophagy and mitochondrial metabolic reprogramming.
  31. Engineering Mitochondrial Biogenesis in iPSC-CMs: CRISPR-Guided Approaches for Advanced Cardiomyocyte Development.
  32. Knockout of the C4BPA Gene Promotes Mitophagy via Activation of the Pink1/Parkin Pathway and Alleviates the Inflammatory Response by Inhibiting the NF-κB Signalling Pathway in Bovine Mammary Epithelial Cells.
  33. Cell-Penetrating Botulinum Neurotoxin Type A Proteins Alleviate Skeletal Muscle Hypertrophy with Associated Alterations of Mitochondrial Homeostasis.
  34. Erlotinib Induces Cell Death by Blocking NIX-mediated Mitophagy Through Lysosomal Swelling in IDH1-mutant Cholangiocarcinoma.
  35. DEHP Exposure Affects Mitochondrial Function During Ovarian Follicle Development.
  36. Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.
  37. Comprehensive analysis of mitophagy-related genes reveals prognostic signatures in breast cancer: based on immune landscapes and treatment target predict.
  38. Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
  39. Correction: Guo et al. Bioinformatic Analysis of the Value of Mitophagy and Immune Responses in Corneal Endothelial Dysfunction. Curr. Issues Mol. Biol. 2025, 47, 670.
  40. Kaempferol Alleviates Glucocorticoid-Induced Osteonecrosis of the Femoral Head by Modulating Macrophage M1/M2 Polarization Through RhoA/ROCK-Mediated Mitophagy Activation.
  41. A novel mechanism of selenium deficiency driving aberrant Th17 cell differentiation via GPX3-targeted PIG3: mitophagy blockade exacerbates mtDNA release.
  42. Metabolic plasticity and virulence of Cryptococcus neoformans are regulated by mitochondrial homeostasis.
  43. NMN prevents obesity-induced osteoporosis by promoting mitophagy to restore type H vessels.
  44. Regulation of Mitochondrial Biogenesis in Diabetic Retinopathy.
  45. Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
  46. ATF5-mediated mitochondrial UPR inhibited RANKL in Porphyromonas gingivalis LPS-treated osteoblasts.
  47. p300-mediated histone H3K18 lactylation promotes mitochondrial ROS accumulation via mitophagy inhibition to potentiate dopamine agonists efficacy in prolactinomas.
  48. P2X7R deficiency alleviates cardiac senescence by enhancing mitophagy via the HuR/TRIM26/NR4A1 axis.
  49. Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
  50. Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe.
  51. Autophagy in Sensorineural Hearing Loss: Jekyll or Hyde?
  52. TSPO-Mediated Mitochondrial Retrograde Signaling Primes the Microglial NLRP3 Inflammasome.
  53. Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
  54. Corylin promotes longevity in Caenorhabditis elegans through DAF-16 and SKN-1 coordinated activation of autophagy-mitochondrial homeostasis axis.
  55. [Effect of warming needle moxibustion on mitochondrial autophagy in rats with chronic fatigue syndrome based on AMPK/ULK1 signaling pathway].
  56. Astaxanthin improves assisted reproductive outcomes in patients with poor ovarian response by alleviating oxidative stress and regulating granulosa cell mitochondrial function.
  57. Inhibiting HSP27 activates the XBP1s/CerS1 interplay, which triggers DRP1-driven mitophagy, thereby protecting against cell death and promoting the KSHV lytic cycle in primary effusion lymphoma cells.
  58. Modulation of mitochondrial biogenesis by flavonoids via SIRT1 signalling in metabolic syndrome: a systematic review.
  59. GDF15-Treated iPSC-MSC-Derived Exosomes Alleviate Fibrosis Post-Myocardial Infarction via Repression of the MFAP4/ERK/Drp1 Axis.
  60. TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia.
  61. Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
  62. Targeting SIRT3 in Diabetic Cardiomyopathy: Mechanism-Based Therapeutic Strategies.
  63. Research progress on mitochondria in bone defect repair: mechanisms and therapeutic implications.
  64. OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.
  65. Mitochondrial acid-sensing ion channel 1a deficiency induces mitochondrial dysfunction in pulmonary arterial smooth muscle cells.
  66. Renoprotection by 5-Methoxytryptophan in Kidney Disease.
  67. Mitochondria in Renal Ischemia-Reperfusion Injury: From Mechanisms to Therapeutics.
  68. IMP2 enhances M2 macrophage polarization via LKB1-AMPK-mediated mitochondrial dynamics and fatty acid β-oxidation to ameliorate diabetic osteoporosis.
  69. Targeting a Shared Mitophagy Regulator: The SIRT1-FOXO3-DEPP1 Axis Underpins the Dual Bone and Brain Benefits of Total Flavonoids from Drynaria fortunei.
  70. The Gut-Extracellular Vesicle-Mitochondria Axis in Reproductive Aging: Antioxidant and Anti-Senescence Mechanisms.
  71. Characterization of Conformational Dynamics and Structural Plasticity of the Catalytic Domain of Human Mitochondrial YME1L Protease.
  72. VPS35 Deficiency Markedly Reduces the Proliferation of HEK293 Cells.
  73. Cooperative Architecture of Mitochondrial Proteome Homeostasis.
  74. Orchestrating diabetic wound repair via mitochondria-targeted delivery of dihydromyricetin with tailored ADSC-derived biohybrid nanovesicles.
  75. Formononetin, an active component of RAS-RH, ameliorates radiation-induced mitochondrial fission dysfunction in endothelial cells via TCs-ECs crosstalk.
  76. Ginsenoside Rg2 ameliorates acute cold exposure/rewarming-induced myocardial injury via modulating HMGB1/TLR4/NF-κB and PGC-1α signaling pathways: Role of SIRT1.
  77. Integrated Bioinformatics Analysis of Screen Mitochondrial Autophagy-Related Core Genes and Construct Diagnostic Model for Alzheimer's Disease.
  78. Rethinking mitochondria as a target for cancer therapy.
  1. Can J Cardiol. 2026 Feb 23. pii: S0828-282X(26)00152-2. [Epub ahead of print]
    Mitochondrial Quality Control in Macrophages during Cardiovascular Disease.
    Ryan C Falconer, Emily A Day.
      Macrophages are key cells of the innate immune system. Within the cardiovascular system, macrophages exhibit marked phenotypic plasticity, enabling them to sense local cues and regulate vascular inflammation, myocardial injury, and tissue remodeling. Mitochondria serve as multifunctional organelles in macrophages, integrating cellular metabolism with the production of immunogenic signals that shape inflammatory responses. In cardiovascular disease (CVD), mitochondrial dysfunction in macrophages drives maladaptive inflammatory responses that when unresolved, lead to chronic inflammation and tissue injury underlying adverse cardiovascular outcomes. To preserve mitochondrial integrity under diverse conditions, cells engage an interconnected network of mitochondrial quality control (MQC) mechanisms, namely mitochondrial biogenesis, maintenance of mitochondrial DNA (mtDNA), remodelling by fission and fusion, mitophagy, and the mitochondrial unfolded protein response. This review examines how these MQC systems govern macrophage polarization, inflammatory signalling, and survival in CVD, focusing on atherosclerosis, myocardial infarction, and heart failure. We discuss evidence demonstrating that the dysregulation of these mechanisms in macrophages, contributes to cardiovascular impairment, with particular emphasis on how dysregulated mitochondrial dynamics, heightened mitochondrial oxidative stress, and mtDNA release converge to amplify inflammation in CVD. We further highlight clinical evidence suggesting that current therapies, such as statins, SGLT2 inhibitors, and GLP-1 receptor agonists enhance macrophage MQC to alleviate stress, improve metabolic function, and dampen inflammation, which may contribute to their cardiovascular benefit. By examining the role of MQC in macrophages within the cardiovascular system, this review establishes the mechanisms governing mitochondrial homeostasis and dysfunction as a critical immunometabolic axis and potential therapeutic avenue underlying cardiovascular disease.
    Keywords:  Immunometabolism; Macrophages; Mitochondria; Mitochondrial Quality Control; cGAS-STING
    DOI:  https://doi.org/10.1016/j.cjca.2026.02.034
  2. J Biol Chem. 2026 Feb 25. pii: S0021-9258(26)00196-1. [Epub ahead of print] 111326
    The AAA-ATPase Yta4 inhibits the interaction between Ppa2 and Atg43 to promote Atg43 phosphorylation and mitophagy.
    Ke Liu, Jiajia He, Yifan Wu, Chenhui Zhao, Shuaijie Yan, Fangyuan Xiong, Xing Liu, Xuebiao Yao, Chuanhai Fu.
      AAA-ATPase Yta4/Msp1/ATAD1 is a well-known quality control factor that clears mistargeted tail-anchored proteins and precursor proteins on mitochondria. However, whether Yta4 preserves mitochondrial homeostasis through alternate pathways remains unclear. Traditionally, mitophagy has been recognized as a crucial pathway for eliminating dysfunctional mitochondria, thereby ensuring the maintenance of mitochondrial homeostasis. In this study, we unveil a novel role for Yta4 in sustaining mitochondrial homeostasis by facilitating mitophagy in fission yeast. The absence of Yta4 delays the phosphorylation of the mitophagy receptor Atg43 and specifically inhibits mitophagy. Additionally, Atg43 phosphorylation sites Ser32, Ser35, and Ser36, which are crucial for mitophagy, were identified. We further found that the phosphatase Ppa2 plays a major role in Atg43 dephosphorylation and inhibits excessive mitophagy. Yta4 physically interacts with both Atg43 and Ppa2, and coordinates with Ppa2 to modulate Atg43 phosphorylation and mitophagy. Moreover, Yta4 and Ppa2 bind to the same cytosolic region of Atg43, and Yta4 inhibits the interaction between Atg43 and Ppa2. Collectively, our findings suggest that Yta4 promotes mitophagy by ensuring the effectiveness of Atg43 phosphorylation. Thus, our findings reveal the novel function of Yta4 in regulating mitophagy and expand the understanding of the molecular mechanisms underlying mitophagy in fission yeast.
    Keywords:  ATAD1; PP2A; fission yeast; mitochondria; phosphatase; phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2026.111326
  3. J Transl Med. 2026 Feb 25.
    Role of mitochondrial dysfunction in muscle wasting in cancer cachexia: a narrative review.
    Xiaoyu Su, Sutong Wang, Yiwei Qu, Yong Wang, Zhihan Tian, Xingliang Chao, Ziyuan Li, Dufang Ma.
      
    Keywords:  Cachexia; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Muscle wasting
    DOI:  https://doi.org/10.1186/s12967-026-07906-8
  4. Free Radic Biol Med. 2026 Feb 19. pii: S0891-5849(26)00146-2. [Epub ahead of print]248 162-176
    Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation.
    Lisha Tang, Nan Wu, Qiaoling Xiao, Jing Yang, Jun Ren, Xinyi Chen, Wen Zhao, Yongcan Liu, Jiayuan Hu, Zailin Yang, Xiaoling Gao, Ling Zhang.
      Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutation is a common genetic subtype with unique pathological features. However, current therapies remain challenged by relapse and drug resistance, underscoring an urgent need for novel therapeutic strategies. In this study, we identified hyperactivated mitophagy as a critical metabolic vulnerability in NPM1-mutated AML through bioinformatics analysis and experimental validation. Mechanistically, augmented mitophagy was driven by high expression of the mitophagy receptor optineurin (OPTN), which was upregulated by cytoplasmic dislocation of CCCTC binding factor (CTCF) in cells harboring the NPM1 mutant. Functionally, OPTN-mediated mitophagy promoted leukemogenesis by maintaining mitochondrial homeostasis, thereby sustaining leukemia cell proliferation and conferring chemoresistance. Correspondingly, genetic inhibition of OPTN suppressed mitophagy, disrupted mitochondrial homeostasis, and sensitized cells to cytarabine (Ara-C), ultimately potentiating its antileukemic efficacy in a cell-derived xenograft (CDX) model. Collectively, these findings indicate that OPTN-mediated mitophagy is an oncogenic driver in NPM1-mutated AML and that, targeted inhibition of this process is a promising strategy for overcoming chemoresistance, particularly in combination with conventional chemotherapy.
    Keywords:  Acute myeloid leukemia; Chemotherapeutic sensitivity; Mitochondrial homeostasis; Mitophagy; Nucleophosmin 1; OPTN
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.049
  5. Curr Biol. 2026 Feb 24. pii: S0960-9822(26)00134-X. [Epub ahead of print]
    Regulation of mitophagy by Fis1 and Fascin1-organized actin.
    Shintaro Nakajima, Ting-Yu Wang, Tsui-Fen Chou, Yogaditya Chakrabarty, David C Chan.
      Mitophagy, the autophagic degradation of mitochondria, plays a central role in controlling the quality and quantity of mitochondria, thereby ensuring cellular health. The mitochondrial outer membrane protein Fis1 is important for several types of mitophagy, but its mechanism of action remains unclear. F-actin is recruited to autophagic cargo and is important for autophagic progression, but the mechanism for its recruitment is poorly understood. To address the molecular function of Fis1, we performed affinity purification of Fis1 and mass spectrometry and identified the actin-bundling protein Fascin1 as a physical interactor. We demonstrate that Fis1 is required for recruitment of Fascin1 as well as F-actin to mitochondria under stress conditions, including mitochondrial depolarization and iron chelation. Iron chelation also triggers mitophagy that is independent of the Parkinson's associated gene Parkin, and we show that Fis1 enables recruitment of Fascin1-organized F-actin to facilitate proper morphogenesis of autophagosomes and the ensuing mitochondrial degradation. In contrast, although Parkin-mediated mitophagy also relies on Fis1, it is unaffected by loss of Fascin1 or F-actin recruitment. These findings indicate that Fis1 has distinct modes of action in mitophagy, depending on the triggering cellular stress. They establish Fis1 as a key driver of Fascin1 and F-actin recruitment to mitochondria, events that are critical for autophagosome morphogenesis during iron-chelation-induced mitophagy.
    Keywords:  Fascin1; Fis1; actin; autophagy; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.cub.2026.01.062
  6. Front Pharmacol. 2026 ;17 1716078
    Components of Panax ginseng and Rhodiola rosea regulate mitophagy via the SIRT1/3-PGC-1α-NRF2 pathway to improve myocardial ischemia-reperfusion injury.
    Ming Yao, Xiaoli Wang, Hongyu Wei, Lisha Wang, Dongze Zhang, Zheng Liang, Rong He, Yuan He, Lihong Jiang, Yingzi Cui.
       Introduction: The combination of ginsenoside Rg1 and salidroside (PRC) exhibits cardioprotective potential against myocardial ischemia-reperfusion injury (MIRI), yet its underlying mechanism remains unclear.
    Materials and Methods: An in vivo rat model of MIRI and an in vitro H/R model using H9c2 cardiomyocyte were established. PRC was administered, and its effects on myocardial injury, oxidative stress, mitochondrial function, and endothelial markers were evaluated. Key proteins in the SIRT1/3-PGC-1α-NRF2 pathway and mitophagy (Beclin 1, p62, PINK1, Parkin, TOM20) were analyzed by Western blot. The functional necessity of SIRT1/3 was validated using siRNA knockdown.
    Results: PRC reduced infarct size, ameliorated mitochondrial ultrastructure, and attenuated oxidative stress in vivo. In vitro, PRC enhanced cell viability, restored ATP and mitochondrial membrane potential, and suppressed ROS production ROS. Mechanistically, PRC activated the SIRT1/3-PGC-1α-NRF2 axis, normalized PINK1/Parkin expression, preserved mitochondrial content (indicated by restored TOM20 levels), and inhibited excessive autophagy (evidenced by downregulated Beclin1 and upregulated p62). Notably, silencing SIRT1 or SIRT3 abolished these protective effects, confirming their essential upstream regulatory roles.
    Conclusion: PRC attenuates MIRI by activating the SIRT1/3-PGC-1α-NRF2 pathway to modulate PINK1/Parkin-dependent mitophagy, thereby restoring mitochondrial homeostasis. Our study elucidates a novel mechanism underlying this natural product combination and highlights the SIRT1/3 axis as a promising therapeutic target for cardioprotection.
    Keywords:  ginsenoside Rg1; mitochondrial function; mitophagy; myocardial ischemia-reperfusion injury; salidroside
    DOI:  https://doi.org/10.3389/fphar.2026.1716078
  7. Neoplasia. 2026 Feb 21. pii: S1476-5586(26)00020-5. [Epub ahead of print]74 101291
    Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment.
    Jie Chen, Xinyu Chu, Yue Wu, Li Su, Mingqi Wang, Xuemei Zhao, Xiaohong Wei, Guiyang Xia, Huan Xia, Sheng Lin, Mei Zhang.
      Chemotherapy-related cognitive impairment (CRCI), colloquially termed "chemobrain," remains a debilitating and underaddressed sequela of cancer treatment. Despite its prevalence and profound impact on quality of life, the precise pathophysiological mechanisms remain incompletely understood. This review synthesizes emerging evidence positioning mitochondrial quality control (MQC) dysfunction as a central mechanistic hub in CRCI pathogenesis. We critically evaluate how diverse chemotherapeutic agents, including anthracyclines, alkylating agents, platinum compounds, antimetabolites, and microtubule inhibitors, converge on distinct yet overlapping pathways of MQC impairment. These agent-specific mechanisms collectively compromise the five fundamental pillars of MQC: biogenesis, mitophagy, dynamics, and proteostasis, along with the formation of mitochondria-derived vesicles. MQC failure subsequently drives a feed-forward cycle of neuroinflammation, blood-brain barrier disruption, synaptic loss, and ultimately, cognitive dysfunction. We further examine promising therapeutic strategies targeting MQC, encompassing mitochondria-targeted antioxidants, metabolic regulators, biogenesis activators, mitochondrial dynamics modulators, mitophagy activators, multi-targeted drugs, as well as physical and nutritional interventions that collectively enhance neuronal mitochondrial resilience. By elucidating the mechanistic centrality of MQC in CRCI, this review provides a robust framework for developing targeted interventions that may preserve cognitive function without compromising anticancer efficacy, thereby addressing a critical unmet need in cancer survivorship care and accelerating the transition towards precision neuroprotection in oncology.
    Keywords:  Chemotherapy-related cognitive impairment; Mitochondrial biogenesis; Mitochondrial quality control; Neuroinflammation; Therapeutic interventions
    DOI:  https://doi.org/10.1016/j.neo.2026.101291
  8. Biomolecules. 2026 Feb 10. pii: 279. [Epub ahead of print]16(2):
    Mitigation of Ischemia/Reperfusion-Induced Acute Kidney Injury by Canagliflozin Is Associated with Altered Mitochondrial Dynamics and Reduced Proliferation in Swine.
    Zaria K Killingsworth, Malikeya Chaudhary, John A Mares, Hengying Ellery, Cassie J Rowe, Ian J Stewart, Patrick F Walker, David M Burmeister.
      Increasing evidence implicates mitochondrial/cellular dynamics in ischemia reperfusion (I/R)-induced acute kidney injury (AKI). Sodium-glucose-co-transporter-2 inhibitors (SGLT2is, e.g., canagliflozin, CG) have been shown to mitigate I/R-induced AKI. Here, we hypothesized that CG-improved AKI was associated with altered mitochondrial dynamics and apoptosis in a previously established swine model. CG (300 mg, PO) significantly increased pro-apoptotic genes Bid, Bad, Bax, Bak1 and Casp1 expression (all p < 0.05). Pink1 (p = 0.0019), Optn (p = 0.038), and Map1lc3 (p = 0.0093) expression also increased with CG, implicating mitophagy; PINK1 protein levels were unchanged. The expression of mitochondrial fission regulator Fis1 increased with CG treatment (p = 0.0015) while fusion regulator Opa1 expression decreased (p = 0.038). TUNEL staining showed increased apoptosis primarily in damaged proximal tubular cells of CG animals. Ki67 staining revealed I/R-injury increased cell proliferation throughout the kidney, which was significantly attenuated with CG. Moreover, correlative analysis revealed that AKI severity positively correlated with cell proliferation. In this large animal model, CG reduced AKI via increased mitochondrial fission and pro-apoptotic gene expression, potentiating clearance of damaged mitochondria, and decreased cell proliferation. Future studies should evaluate other SGLT2is as a potential therapeutic for I/R AKI.
    Keywords:  Canagliflozin (CG); REBOA; SGLT2 inhibitor; acute kidney injury (AKI); apoptosis; cell proliferation; hemorrhagic shock; ischemia reperfusion injury (I/R); mitochondrial dynamics; swine
    DOI:  https://doi.org/10.3390/biom16020279
  9. Cell Death Discov. 2026 Feb 21. pii: 104. [Epub ahead of print]12(1):
    Novel mechanism of neuronal hypoxia response: HIF-1α/STOML2 mediated PINK1-dependent mitophagy activation against neuronal injury.
    Yuning Li, Zirui Xu, Zhengming Tian, Mengyuan Guo, Qianqian Shao, Yingxia Liu, Yakun Gu, Feiyang Jin, Xunming Ji, Jia Liu.
      Hypoxic stress contributes to brain disorders by causing neuronal injury, making it crucial to understand neuronal hypoxic response mechanisms for disease resistance. In the early stage of stress, neurons initiate a series of compensatory pathways to resist cell damage, but the underlying mechanisms have not been fully elucidated. In this study, we found that hypoxia transiently activates PTEN-induced kinase 1 (PINK1)-dependent mitophagy in the early stage before cell damage and neurological dysfunction. When PINK1-dependent mitophagy is inhibited, neuronal injury begins to exacerbate. Under hypoxia, overexpression of PINK1 can resist neuronal injury, while knockdown of PINK1 aggravates neuronal injury, revealing that PINK1-dependent mitophagy plays a key role in neuronal compensatory hypoxia response. Mechanistically, in the early stage of hypoxia, the nuclear translocation of HIF-1α increases, mediating the transcription of its downstream target molecule STOML2. STOML2 translocates to the outer mitochondrial membrane and participates in the cleavage of PGAM5. These processes initiate PINK1-dependent mitophagy. Knockdown of HIF-1α, STOML2, or PGAM5 inhibits mitophagy and worsens hypoxia-induced dysfunction, highlighting this pathway's importance. Intermittent hypoxia, a conditioning strategy, stimulates endogenous protection. Notably, it activates the HIF-1α/STOML2 axis, inducing PINK1-dependent mitophagy and protecting neurons. In conclusion, our study reveals a new "self-protection" mechanism of neurons against hypoxic stress and discovers that intermittent hypoxia can effectively activate this pathway to resist neuronal injury, providing new insights into the mechanisms and interventions of hypoxia-related nerve injury.
    DOI:  https://doi.org/10.1038/s41420-026-02960-z
  10. Circ Res. 2026 Feb 27. 138(5): e328021
    Un-PINning Cardiac Regeneration: LPIN1 and the Rewiring of Mitochondrial Dynamics.
    Edoardo Bertero, Monika M Gladka.
      
    Keywords:  Editorials; RNA, long noncoding; mitochondrial dynamics; myocardial infarction; regeneration
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.328021
  11. Autophagy Rep. 2026 ;5(1): 2629624
    Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
    Mariana Joaquim, Maike F Dohrn, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.
    Keywords:  Charcot–Marie–Tooth type 2A (CMT2A); HSPA8/HSC70; MFN2; protein import; proteasome; VCP/p97; PINK1; apoptosis; mitophagy; proteostasis
    DOI:  https://doi.org/10.1080/27694127.2026.2629624
  12. Biochem Pharmacol. 2026 Feb 20. pii: S0006-2952(26)00166-8. [Epub ahead of print]248 117835
    Hyperglycemia-induced SIRT3 inhibition contributes to diabetic cardiomyopathy by impairing Cav-3-mediated mitophagy.
    Zhenshuai Jin, Yanwei Ji, Wating Su, Lu Zhou, Lei Gao, Xinyu Wen, Hepeng Tang, Zhong-Yuan Xia, Shaoqing Lei.
      Diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients, with impaired mitophagy contributing its pathogenesis. Sirtuin 3 (SIRT3) and caveolin-3 (Cav-3) are protective proteins involved in mitophagy, although their precise mechanisms remain unclear. This study investigated the interplay between SIRT3, Cav-3, and mitophagy in DCM. We found that the diabetic C57BL/6 mice exhibited impaired cardiac structure and function, accompanied by reduced mitophagy and decreased expression of SIRT3 and Cav-3. Cav-3 KO mice with diabetes showed further worsened cardiac dysfunction and mitophagy impairment without further affecting SIRT3 expression. In cultured H9C2 cardiomyocytes, both SIRT3 siRNA and Cav-3 siRNA exacerbated high glucose (HG)-induced cardiomyocyte damage and reduced mitophagy occurrence. Interestingly, SIRT3 siRNA significantly decreased Cav-3 expression, but vice not. Additionally, Cav-3 overexpression rescued HG-induced cardiomyocyte injury and mitophagy impairment without affecting SIRT3 expression. Collectively, our findings suggest that hyperglycemia-induced SIRT3 suppression contributes to DCM by impairing Cav-3-mediated mitophagy.
    Keywords:  Cav-3; Diabetes; Diabetic cardiomyopathy; Mitophagy; SIRT3
    DOI:  https://doi.org/10.1016/j.bcp.2026.117835
  13. Free Radic Biol Med. 2026 Feb 20. pii: S0891-5849(26)00144-9. [Epub ahead of print]248 109-126
    Fatty acid oxidase Ehhadh mediates stem cell fate remodeling via mitophagy activation.
    Jingxuan Zhou, Longyun Zhang, Tingjun Liu, Jiatong Sun, Yuxi Sun, Shaorong Gao, Kerong Shi.
      Orchestrated cellular fate remodeling is integral to tissue repair/replenishment. Extrinsic cues can trigger a switch from self-renewal priming to differentiation initiation in stem cells. However, cell fate remodeling-based therapy and/or transplanting stem cells suffer from limitations of retention and/or low efficiency. The study found reprogramming fatty acid metabolic flux facilitated cell fate remodeling. Knockdown of Ehhadh, a bi-functional fatty acid oxidase, promotes somatic cell reprogramming into iPSCs, but inhibits ESCs differentiation. Mechanically, Ehhadh knockdown disrupts the mitochondrial homeostasis, resulting in structural damage and functional impairment, via impacting on the stability of mitochondrial inner membrane transporter TIMM23. Meanwhile, Ehhadh knockdown activates AMPK/ULK1 pathway, resulting in mitophagy. The mitochondrial fission/mitophagy inhibitor, Mdivi-1, significantly attenuated Ehhadh-knockdown-induced pluripotent protein expression, but enhanced the Ehhadh-knockdown-inhibited three germ layer markers expression, providing evidence of the mechanistic causality between Ehhadh modulation and mitophagy or cell fate remodeling. In conclusion, the fatty acid oxidase Ehhadh mediates cell fate remodeling via mitophagy. The Ehhadh→mitophagy→cell fate remodeling axis provides evidence for possible strategies of manipulating stem cell fate (stemness perpetuation or differentiation execution) by modulating of fatty acid oxidation efficiency and/or targeting on mitochondrial rejuvenation and reorganization pathways, shedding light on drug development, organ replenishment, stem cell therapy, breed production.
    Keywords:  Cell fate remodeling; ESCs; Ehhadh; Fatty acid oxidation; Mitophagy (mitochondrial autophagy); Somatic cell reprogramming
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.046
  14. Toxicol Appl Pharmacol. 2026 Feb 20. pii: S0041-008X(26)00068-2. [Epub ahead of print]510 117772
    Alleviation of cigarette smoke-induced cellular senescence in BALB/c mice by the Lipoxin A4 receptor agonist BML-111 is associated with mitophagy.
    Xin Li, Hui Xu, Meng Shi, Kai Liu, Xiaoju Liu.
      Cigarette smoke (CS) significantly accelerates age-associated pulmonary pathologies by promoting cellular senescence. BML-111, a synthetic lipoxin A4 analog, exhibits therapeutic potential in inflammatory diseases owing to its antioxidant and anti-inflammatory properties, yet its impact on CS-induced senescence remains undefined. This study investigated the effect and mechanism of BML-111 on CS-induced cellular senescence using a BALB/c mouse model and the murine alveolar macrophage cell line MH-S. Our findings indicate that BML-111 attenuated CS-induced histopathological damage and senescence markers in murine lungs, while substantially suppressing cigarette smoke extract-triggered senescence in MH-S cells. In addition, BML-111 inhibited mitochondrial damage, and promoted autophagosome formation and mitophagy-related protein expression in both in vivo and in vitro models. Crucially, the mitophagy inhibitor Mdivi-1 abrogated BML-111's effects on cellular senescence, mitochondrial damage restoration, and mitophagy. Taken together, BML-111 may mitigate CS-induced cellular senescence in the lung by promoting processes associated with mitophagy initiation, highlighting its potential as a therapeutic strategy against CS-associated lung pathologies.
    Keywords:  BML-111; Cigarette smoke; Macrophages; Mitophagy; Senescence
    DOI:  https://doi.org/10.1016/j.taap.2026.117772
  15. Front Cell Neurosci. 2026 ;20 1731669
    C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.
    James A K Lee, Chloe Moutin, Sarah Granger, Katie Roome, Allan Shaw, Scott P Allen, Laura Ferraiuolo, Pamela J Shaw, Heather Mortiboys.
       Introduction: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited.
    Results: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed.
    Conclusion: Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.
    Keywords:  ALS (Amyotrophic lateral sclerosis); ULK1; autophagy; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fncel.2026.1731669
  16. Nat Struct Mol Biol. 2026 Feb 27.
    Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
    Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.
      Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.
    DOI:  https://doi.org/10.1038/s41594-026-01756-0
  17. J Ovarian Res. 2026 Feb 27.
    Dual regulation of PINK1/PARKIN-mediated mitochondrial autophagy in ovarian cancer progression and drug resistance: mechanisms and therapeutic potentials.
    Jing Xu, Fangyuan Liu, Qiaochu Chen, Yue Li, Jaifei Liu, Fengjuan Han.
      
    Keywords:  Chemotherapy resistance; Mechanisms; Mitophagy; Ovarian cancer; PINK1/PARKIN
    DOI:  https://doi.org/10.1186/s13048-026-02013-0
  18. Res Sq. 2026 Feb 17. pii: rs.3.rs-8815446. [Epub ahead of print]
    Recessive PPTC7 deficiency triggers excessive mitophagy to cause a severe inborn error of metabolism with hypomyelinating leukodystrophy.
    Keri-Lyn Kozul, Ali AlAsmari, Essa Alharby, Reem Zakzouk, Youmian Yan, Aziza Mushiba, Anwar Alhamad, Emily Harrelson, Maya Ayach, Kevin Cho, Heba Zahid, Francisca De Luna Vitorino, Richard Searfoss, Xingyu Liu, Mohammed A Saleh, Muhammad Latif, Lianjie Wei, Ali Aldawood, Laila Alsuhaibani, Mohammed Abdulhafith Bafail, Thiago Menezes, Manar Samman, Hannah Pletcher, Ibrahim Sandokji, Walaa Borhan, Tessa Lochetto, Abrar Alamri, Wedad Mudayfin, Mazin Syed, Leah Shriver, Benjamin Garcia, Eissa Faqeih, Gary Patti, Natalie Niemi, Naif Almontashiri.
      The mitochondrial phosphatase PPTC7 has emerged as a potent regulator of metabolism and mitophagy as its global knockout leads to perinatal lethality in mice. However, no known Mendelian diseases have been linked to PPTC7 deficiency, rendering its role in human pathophysiology unclear. Here, we identify two independent homozygous variants in PPTC7 : a missense variant, p.D158N, and a duplication variant (c.*57dup) within the 3` untranslated region (UTR). These variants were detected in three patients from two unrelated families presenting with a primary mitochondrial disease characterized by hypomyelinating leukodystrophy, recurrent metabolic and lactic acidosis, and anemia with immune dysregulation. Patient samples, including plasma and primary fibroblasts, showed robust metabolic and mitochondrial dysfunction, with substantial phenotypic overlap with Pptc7 knockout murine fibroblast models. PPTC7 patient fibroblasts carrying the p.D158N variant and CRISPR-knocked in cells to model the 3`UTR variant showed hallmarks of excessive BNIP3- and NIX-mediated mitophagy, including aberrant mitochondrial morphology, diminished mitochondrial protein expression, and increased mt-Keima flux. Critically, increased mitophagy in these cellular models was rescued by exogenous PPTC7 expression, confirming dysfunction derives from loss of this mitochondrial phosphatase. Mechanistically, we found that the p.D158N variant, affecting a highly conserved residue, disrupts metal binding to compromise both the enzymatic phosphatase function of PPTC7 as well as its negative regulation of BNIP3 and NIX. Collectively, these data provide the first known cases with a recessive inborn error of mitophagy due to PPTC7 deficiency and underscore the importance of this mitochondrial phosphatase in maintaining metabolic health and balanced mitophagy.
    DOI:  https://doi.org/10.21203/rs.3.rs-8815446/v1
  19. Int J Mol Sci. 2026 Feb 07. pii: 1638. [Epub ahead of print]27(4):
    Onconase Induces Apoptosis in Dabrafenib-Resistant Melanoma Cell Lines Through Dysregulation of ROS Homeostasis, Antioxidant Protein Expression, and Mitochondrial Dynamics.
    Carlotta Passarini, Alessia Cardile, Filippo Zuanetti, Valentina Zanrè, Raffaella Pacchiana, Adriana Celesia, Federica Danzi, Alessandra Fiore, Giovanni Gotte, Marta Menegazzi.
      Advanced melanoma remains difficult to treat due to its intrinsic resistance to conventional therapies and the frequent development of acquired resistance to targeted agents, such as BRAF inhibitors. Onconase (ONC), an amphibian ribonuclease with established antitumor activity, had been previously shown to have selective cytotoxicity toward melanoma cells. In this study, we investigated the molecular mechanisms underlying ONC-induced cytotoxicity in BRAF-mutated melanoma cell lines that are either sensitive or resistant to the BRAF inhibitor dabrafenib. We focused on oxidative stress regulation, mitochondrial dynamics, and cell death-related signaling pathways. ONC treatment resulted in a marked increase in reactive oxygen species (ROS) levels, concomitant with a pronounced downregulation of NRF2 and multiple NRF2-dependent antioxidant proteins. These effects were particularly evident in dabrafenib-resistant melanoma cells. In parallel, ONC impaired mitochondrial plasticity by inhibiting mitochondrial biogenesis and fission, as evidenced by reduced PGC1α, DRP1, and FIS1 expression. Confocal analysis confirmed the presence of more enlarged mitochondria in ONC-treated cells. Mitophagy and autophagy are hindered by ONC due to the downregulation of PINK1, beclin1, ATG3 expression, as well as the lack of LC3B activation. These mitochondrial defects were associated with mitochondrial-dependent apoptosis, characterized by caspase-9 activation and strong downregulation of the antiapoptotic protein survivin. Lipid peroxidation was also induced by ONC, especially in the A375 cell line. Additionally, ONC inhibited key proliferation-related signaling pathways, including STAT3 and NF-κB, and reduced cyclin-dependent kinase 1, 2, and 4 activities. Collectively, these findings demonstrate that ONC disrupts redox homeostasis, mitochondrial function, and survival signaling in melanoma cells, exerting particularly potent effects in BRAF inhibitor-resistant populations. This study provides mechanistic insight into the anti-melanoma activity of ONC and supports its potential therapeutic application in drug-resistant melanoma.
    Keywords:  DRP1; FSP1; GCLM; HO-1; OPA1; PINK1; SLC7A11; SOD2; c-Myc; survivin
    DOI:  https://doi.org/10.3390/ijms27041638
  20. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00243-2. [Epub ahead of print]203 89-110
    Monitoring neuronal mitophagy and locomotion deficits in a C. elegans model of Alzheimer's disease.
    Giorgos Garcia Niforos, Eleni Tsakiri, Konstantinos Palikaras.
      Neurodegenerative diseases, such as Alzheimer's disease (AD), pose significant socioeconomic and personal burdens due to progressive cognitive and motor decline. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and tau tangles, alongside with emerging evidence linking metabolic dysfunction to its early disease pathogenesis. Impaired mitochondrial selective autophagy (known as mitophagy) and excessive mitochondrial dysfunction have been implicated as key contributors to disease progression. To uncover the mechanistic underpinnings of AD, Caenorhabditis elegans offers a powerful model system providing a fully mapped nervous system, transparency for live imaging, and evolutionary conserved pathways mirroring human pathophysiology. Here, we employ a pan-neuronal Aβ1-42 -expressing C. elegans strain to phenocopy early metabolic disturbances characteristic of AD. Our methodology integrates automated motility tracking with confocal microscopy, utilizing the mitochondria-targeted Rosella biosensor to assess mitophagy dynamics in vivo. This platform enables quantitative assessment of locomotion deficits and spatiotemporal monitoring of mitophagy alterations driven by Aβ1-42-induced toxicity. Our method provides a robust tool for screening genetic and pharmacological interventions aimed at mitigating AD-associated mitochondrial dysfunction and neurodegeneration.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; Mitochondria; Mitophagy; Motility; Neurodegeneration; Neurons
    DOI:  https://doi.org/10.1016/bs.mcb.2025.12.001
  21. Am J Respir Cell Mol Biol. 2026 Feb 21. pii: aanag019. [Epub ahead of print]
    AhR activation inhibits DRP1-induced mitochondrial fission in airway smooth muscle during asthma.
    Mohammad Irshad Reza, Cheyenne Tandberg, Ashish Kumar, Premanand Balraj, Michael A Thompson, Y S Prakash, Christina M Pabelick, Rodney D Britt, Venkatachalem Sathish.
      In asthma, pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) drive excessive mitochondrial fission in ASM cells through activating dynamin-related protein 1 (DRP1). Recently, we demonstrated that aryl hydrocarbon receptor (AhR) is expressed in human ASM and is upregulated during inflammation and asthma. This study explores the role of AhR in regulating mitochondrial fission in human ASM cells under pro-inflammatory and asthmatic conditions. Primary human nonasthmatic and asthmatic ASM cells were treated with 6-formylindolo[3,2-b]carbazole (FICZ: AhR agonist), with or without TNFα. Mitochondrial morphology was assessed using MitoTracker staining. DRP1 expression was evaluated in whole-cell and mitochondrial fractions. Loss- and gain-of-function studies (AhR inhibition, knockdown, and overexpression) were performed. AhR binding on the DRP1 promoter and promoter activity were assessed by ChIP-qPCR and luciferase reporter. The effects of AhR activation on oxygen consumption rate (OCR) was analyzed using seahorse XF-Pro. AhR activation significantly inhibited TNFα- and asthma-induced mitochondrial fission in ASM cells via inhibiting DRP1 in both inactive and active forms. In contrast, AhR inhibition or knockdown aggravated mitochondrial fission, while AhR overexpression failed to prevent TNFα-induced fission without ligand activation. Mechanistically, AhR bound the DRP1 promoter and suppressed its promoter activity, consistent with a genomic mode of action, while failing to alter ERK1/2 phosphorylation. Additionally, AhR activation also reduced TNFα- and asthma-induced increase in OCR. Collectively, this study shows that AhR activation prevents mitochondrial fission by inhibiting DRP1 in ASM during inflammation and highlights AhR as a promising therapeutic target for asthma and other airway diseases associated with mitochondrial dysfunction.
    Keywords:  Airway smooth muscle cells; Aryl hydrocarbon receptor; Asthma; Inflammation; Mitochondrial dynamics
    DOI:  https://doi.org/10.1093/ajrcmb/aanag019
  22. Ren Fail. 2026 Dec;48(1): 2624206
    Efficacy of nicotiflorin in ameliorating septic acute kidney injury: the role of PINK1/parkin in mitochondrial restoration and oxidative stress reduction.
    Zhuangzhi Yang, Xiaowei Zhou, Chenhao Wu, Xia Lin.
      Objectives: Nicotiflorin has demonstrated efficacy in mitigating acute liver injury, and therefore, its potential in treating septic acute kidney injury (AKI) merits further investigation. This study evaluated whether nicotiflorin restores mitochondrial function and reduces oxidative stress in septic AKI via mediating the PTEN-induced putative protein kinase 1 (PINK1)/Parkin signaling pathway.
    Methods: Lipopolysaccharide (LPS) was applied to replicate septic AKI in C57BL/6 mice and NRK-52E cells, which were later treated with nicotiflorin. Renal function was assessed through biochemical markers, histopathology, and immunofluorescence. The impact of nicotiflorin on cell viability, apoptosis, and mitochondrial function was analyzed using cell counting kit 8 assay and flow cytometry. Mtphagy and Lyso staining was utilized to evaluate the effect of nicotiflorin on mitophagy in LPS-induced cells. Molecularly, Western blot was employed to quantify protein expressions of genes related to apoptosis, mitophagy and oxidative stress in vivo and in vitro.
    Results: Nicotiflorin treatment significantly improved renal dysfunction, kidney damage, reduced levels of apoptosis-related proteins, increased expressions of PINK1, Parkin, and LC3II/LC3I, and decreased expression of p62 in LPS-induced mice. In NRK-52E cells, nicotiflorin abrogated LPS-triggered reduction in cell viability, increase in apoptosis, elevation in ROS and mitochondrial mass, reduction in mitochondrial membrane potential, upregulation of apoptotic proteins, downregulated NF-E2-related factor-2 (Nrf2), PINK1, Parkin and LC3II/LC3I, and increased expressions of kelch-like ECH-associated protein 1 (KEAP1) and p62.
    Conclusions: Nicotiflorin attenuates mitochondrial dysfunction and oxidative stress in septic AKI via PINK1/Parkin signaling pathway, suggesting its potential as a therapeutic agent for septic AKI.
    Keywords:  Nicotiflorin; PTEN-induced putative protein kinase 1/parkin signaling pathway; acute kidney injury; sepsis
    DOI:  https://doi.org/10.1080/0886022X.2026.2624206
  23. Free Radic Biol Med. 2026 Feb 23. pii: S0891-5849(26)00157-7. [Epub ahead of print]248 238-254
    Melatonin improves spermatogenesis and alleviates oxidative stress in cryopreserved testicular tissue through suppression of the ROS/PINK1-Parkin mitophagy axis.
    Menghui Ma, Yanqing Li, Jintao Guo, Linyan Lv, Zhenhan Xu, Peigen Chen, Haicheng Chen, Junxian He, Wenlong Su, Haitao Zeng, Cong Fang, Xiaoyan Liang, Guihua Liu.
      Testicular tissue cryopreservation is essential for fertility preservation in prepubertal boys who cannot produce semen, but the process triggers oxidative stress, mitochondrial dysfunction, and excessive mitophagy that deplete spermatogonial stem cells (SSCs) and compromise later spermatogenesis. We evaluated whether melatonin (MLT), a mitochondria-targeted antioxidant, mitigates cryoinjury in a prepubertal C57BL/6 mouse model using a controlled slow-freezing protocol supplemented with graded MLT doses. Across histology, immunofluorescence, Western blotting, transmission electron microscopy, flow cytometry, ELISAs, and integrated transcriptomic-metabolomic profiling, cryopreservation alone induced reactive oxygen species (ROS) overproduction, disrupted mitochondrial integrity, activated PINK1/Parkin-mediated mitophagy, and increased apoptosis with loss of undifferentiated spermatogonial marker (PLZF) and SSC marker (UCHL1). MLT at an optimal concentration of 10-7 M preserved testicular architecture, maintained undifferentiated spermatogonia and SSC marker expression, suppressed ROS accumulation, restored redox balance, and alleviated mitochondrial damage while tempering excessive PINK1/Parkin-dependent mitophagy. Omics analyses showed that MLT reprogrammed cryo-induced disturbances in oxidative stress and metabolic pathways and was associated with suppression of MAPK-mediated apoptotic signaling. In an ectopic transplantation (xenograft) model, grafts pretreated with MLT exhibited improved spermatogenic recovery and reduced fibrotic remodeling compared with untreated controls. Pharmacologic activation of mitophagy with CCCP supported the role of mitophagy modulation in MLT's protective effects. Collectively, these data indicate that 10-7 M MLT effectively safeguards cryopreserved testicular tissue by maintaining SSC viability and mitochondrial/redox homeostasis while limiting maladaptive mitophagy and apoptosis, supporting its use as a practical adjunct to male fertility preservation protocols for prepubertal patients undergoing gonadotoxic therapy.
    Keywords:  Melatonin; Mitophagy; PINK1-Parkin pathway; Spermatogonial stem cells; Testis cryopreservation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.060
  24. J Microbiol. 2026 Jan;64(1): e2508009
    Vitamin D disrupts NS1-TUFM interaction to suppress pathogenic mitophagy in RSV-induced mitochondrial injury of bronchial epithelial cells.
    Li Peng, Yao Liu, Xiaofang Ding, Tuhong Yang, Lili Zhong, Fangcai Li.
      This study aims to examine the mechanism by which vitamin D mitigates bronchiolitis caused by respiratory syncytial virus (RSV) through the regulation of RSV nonstructural protein 1 (NS1)-TUFM-mediated mitophagy in bronchial epithelial cells. Clinical serum and PBMC samples from RSV-infected children and healthy controls were analyzed for vitamin D, mitochondrial DNA, mitophagy markers (LC3, ATG5, VDAC1, TOMM20, and COXIV), TUFM, and inflammatory cytokines (IL-6, IL-8, and TNF-α). In vitro, human bronchial epithelial cells Beas-2B were transfected with RSV-NS1 plasmid and TUFM silencing or overexpression constructs. Vitamin D (0.1-10 μM) was administered to evaluate mitophagy inhibition using Western blot, immunofluorescence, and JC-1 staining. NS1-TUFM interaction was confirmed by co-immunoprecipitation. RSV-positive patients exhibited reduced serum vitamin D, elevated TUFM and mitophagy markers, impaired mitochondrial mass, and increased inflammation. Vitamin D inversely correlated with LC3 and TUFM. RSV-NS1 overexpression induced mitochondrial translocation of NS1, TUFM-dependent mitophagy activation, and mitochondrial dysfunction (JC-1 depolarization). Vitamin D (10 μM) suppressed mitophagy by redistributing NS1 to the cytosol and reducing mitochondrial TUFM. TUFM overexpression abolished the protective effects of vitamin D on mitophagy and inflammation. In conclusion, vitamin D inhibits mitophagy in bronchial epithelial cells infected with RSV by disrupting NS1-TUFM interaction, suggesting that the vitamin D-TUFM axis may serve as a potential therapeutic target.
    Keywords:  RSV NS1; RSV bronchiolitis; TUFM; Vitamin D; mitophagy
    DOI:  https://doi.org/10.71150/jm.2508009
  25. Phytother Res. 2026 Feb 23.
    Punicalagin Promotes Peripheral Nerve Repair by Enhancing Mitophagy via the TLR4/MAPK Signaling Pathway and Facilitating Angiogenesis.
    Anhao Guo, Ke Wang, Jinghao Liang, Chuanpeng Xia, Kongmei Luo, Salah Alqadhi, Hanwen Zhang, Shanying Xiao, Tao Lin, Zhe Zhang, Long Wu, Hede Yan.
      Peripheral nerve injury (PNI) often leads to functional impairment, and current therapeutic options are limited. Punicalagin (PUN), a polyphenolic compound derived from Punica granatum, exhibits antioxidant and anti-inflammatory properties. This study investigated the therapeutic potential of PUN for PNI and its underlying mechanisms, focusing on mitochondrial autophagy (mitophagy), TLR4/MAPK signaling, and angiogenesis. In vitro, Schwann cells were treated with PUN under oxidative stress induced by tert-butyl hydroperoxide to evaluate cell viability, mitochondrial function, mitophagy, reactive oxygen species (ROS) levels, and apoptosis. PUN at non-toxic concentrations (≤ 20 μM) promoted mitophagy, attenuated ROS accumulation, and inhibited apoptosis. These effects were partially reversed by the mitophagy inhibitor Bafilomycin A1. Network pharmacology and molecular docking identified TLR4 as a primary target, and Western blot analyses demonstrated that PUN modulated downstream MAPK signaling. In vivo, intraperitoneal PUN administration in rats after sciatic nerve crush injury improved gastrocnemius muscle preservation, promoted axonal regeneration and remyelination, enhanced neovascularization, and significantly improved functional recovery, as measured by the sciatic functional index. Collectively, these findings indicate that PUN facilitates peripheral nerve repair through coordinated regulation of mitophagy, TLR4/MAPK signaling, and angiogenesis, highlighting its potential as a non-surgical therapeutic agent to promote nerve regeneration and functional recovery after PNI.
    Keywords:  TLR4/MAPK pathway; angiogenesis; axon regeneration; mitochondrial autophagy; peripheral nerve injury; punicalagin
    DOI:  https://doi.org/10.1002/ptr.70281
  26. Free Radic Biol Med. 2026 Feb 23. pii: S0891-5849(26)00155-3. [Epub ahead of print]248 255-271
    Lysophosphatidylcholine promotes pulmonary fibrosis following lung injury by facilitating alveolar type 2 cell senescence via Mfsd2a-dependent, Drp1-mediated mitochondrial fission.
    Tianxiang Li, Qingqing Zhao, Ying Gao, Yi Zhang, Zhongquan Song, Wucui Huang, Xiaoli Zhu.
      Idiopathic pulmonary fibrosis (IPF) is widely recognized as a disease originating from alveolar epithelial injury, with senescent alveolar type 2 (AT2) cells playing a key role in the pathogenesis. Previous studies have reported that lysophosphatidylcholine (LPC) levels are abnormally elevated in IPF patients and in mouse models of bleomycin-induced pulmonary fibrosis. However, the role and involved mechanism of LPC in the pathogenesis of pulmonary fibrosis remains unclear. Here, we found that bleomycin-injury increased levels of total LPC, particularly LPC16:0, in both mouse bronchoalveolar lavage fluids (BALF) and AT2 cells during the early stages of the disease. These increased LPC were showed to be closely associated with Mfsd2a upregulation and worsened cellular senescence in AT2 cells. In vitro and in vivo, LPC significantly upregulated expression of Mfsd2a, a known LPC transporter, which enhanced LPC uptake by AT2 cells, leading to intracellular LPC overload. The overloaded LPC enhanced dynamin-related protein 1 (Drp1) phosphorylation at Ser616, inducing excessive mitochondrial fission and mitochondrial ROS (mitoROS) overproduction, which ultimately promoted AT2 cell senescence and pulmonary fibrosis. Importantly, LPC induced mitochondrial fission and cellular senescence in AT2 cells in a Mfsd2a-dependent manner. Furthermore, treatment with Mdivi-1 (an inhibitor of Drp1 phosphorylation) or Mito-TEMPO (a mitochondria-targeted antioxidant) effectively alleviated LPC- or bleomycin-induced AT2 cell senescence. Our results reveal a novel mechanism by which LPC promotes pulmonary fibrosis by facilitating AT2 cell senescence via Mfsd2a-dependent, Drp1-mediated mitochondrial fission. These findings provide new mechanistic insights into lung injury-induced pulmonary fibrosis, suggesting LPC and its regulatory pathways as attractive targets for this disease intervention.
    Keywords:  Alveolar type 2 cell senescence; Lung injury; Lysophosphatidylcholine; Mfsd2a; Mitochondrial fission; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.058
  27. Antioxidants (Basel). 2026 Jan 30. pii: 176. [Epub ahead of print]15(2):
    Selenomethionine Alleviates Zearalenone-Induced Liver Injury in Rabbits Through SIRT1-FOXO1/P53 Signaling Pathway.
    Xiaoguang Chen, Wenjuan Wei, Haonan Li, Wenjing Xu, Qiongxia Lv, Yumei Liu, Ziqiang Zhang.
      Zearalenone (ZEA) is a common estrogenic mycotoxin in rabbit breeding that causes various toxic effects. Selenomethionine (SeMet) is a feed additive with potent anti-inflammatory and antioxidant properties. To evaluate the protective role and action mechanism of SeMet against ZEA-induced liver injury, 90-day-old rabbits were randomized into five groups: control, ZEA-alone, and SeMet pretreatment at 0.2, 0.35, and 0.5 mg/kg. SeMet was administered for 21 days, followed by continuous intragastric ZEA (1.2 mg/kg B.W.) for 7 days starting on day 15. As a result, ZEA exposure significantly elevated liver function parameters, disrupted lobular architecture, and impaired glycogen synthesis. It also induced liver oxidative stress, thus upregulating expressions of Bax, Cyt C, Caspase-3, and Caspase-9, triggering hepatocyte apoptosis, mitochondrial damage, and mitophagy. SeMet pretreatment activated SIRT1, reduced the acetylated FOXO1/P53 levels, and enhanced CAT and SOD2 expression, mitigating ZEA-induced oxidative stress, apoptosis, and mitophagy. Based on the above findings, SeMet's alleviating effect might be mediated via the SIRT1-FOXO1/P53 pathway, with 0.35 mg/kg of SeMet exerting the optimal efficacy, highlighting its therapeutic potential for mitigating ZEA-induced hepatotoxicity in rabbits.
    Keywords:  apoptosis; liver injury; mitophagy; oxidative stress; selenomethionine; zearalenone
    DOI:  https://doi.org/10.3390/antiox15020176
  28. Mater Today Bio. 2026 Apr;37 102926
    Renal-targeted tFNA-TPP nanoagonist treats acute kidney injury by amplifying mitophagy.
    Jinguo Xu, Yujun Li, Jiafeng Xu, Ruobing He, Fengchi Jiang, Jiaxue Lu, Tao Xu, Jie Wang, Chengxin Zhang.
      Acute kidney injury (AKI) is a critical clinical syndrome closely associated with mitochondrial dysfunction. Its etiology encompasses both intrinsic renal factors and extrarenal factors, such as cardiac complications following heart surgery. AKI remains a formidable therapeutic challenge due to the absence of strategies capable of precisely targeting and reversing mitochondrial dysfunction, a key pathological driver. To address this, we developed a renal-targeted mitochondrial autophagy inducer, tFNA-TPP, by covalently linking tetrahedral framework nucleic acid (tFNA) with triphenylphosphine (TPP) using click chemistry. This nanocomposite demonstrates a 91.6% efficiency in targeting the kidneys and functions as an integrated system for ROS scavenging and mitophagy activation. The tFNA component promotes renal accumulation and neutralizes reactive oxygen species, while the TPP moiety ensures precise delivery to damaged mitochondria, enhancing organelle-specific autophagy. In AKI models induced by both cisplatin and ischemia-reperfusion, tFNA-TPP effectively enhanced mitophagic flux, as evidenced by a 4.2-fold increase in the LC3-II/LC3-I ratio and a reduction in p62 expression, facilitating the clearance of impaired mitochondria and the restoration of renal function. By concurrently addressing oxidative stress and mitochondrial integrity, our study establishes a versatile platform for organelle-level therapy, offering a transformative approach for treating AKI and other conditions driven by mitochondrial dysregulation.
    Keywords:  AKI; Mitochondria targeting; Mitophagy; Reactive oxygen species; tFNA-TPP
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102926
  29. Front Immunol. 2026 ;17 1717925
    Comprehensive analysis of mitochondrial unfolded protein response related genes for prognosis and therapeutic response in pancreatic cancer.
    Chengqing Li, Cuiling Lu, Zheng Ma, Ting Zhao, Mingming Xiao, Zhonglei Xu, Zhenxing Sun, Qihao Wu, Lei Wang, Liang Zhao.
       Background: Pancreatic cancer (PC) is a highly aggressive malignancy of the digestive system, with an extremely poor prognosis. The mitochondrial unfolded protein response (UPRmt) can maintain mitochondrial homeostasis and promote tumor progression and chemotherapy resistance. Nevertheless, the functions of UPRmt-related genes (MRGs) in PC remain undefined.
    Methods: Gene expression data were obtained from TCGA, GEO, and CPTAC databases. Consensus clustering was performed based on MRGs, with subsequent evaluation of immune infiltration patterns across clusters. Prognostic MRGs were identified using three machine learning algorithms: LASSO regression, Random Survival Forest (RSF), and Extreme Gradient Boosting (XGBoost), combined with Cox regression analysis to establish a MRGs risk score (MRS). Quantitative real-time PCR (qRT-PCR) and western blotting were employed to validate potential mechanisms. Drug sensitivity profiling distinguished therapeutic responses between risk groups. Finally, we developed an MRS-based prognostic nomogram and validated it in multiple cohorts.
    Results: PC patients were stratified into two distinct UPRmt clusters with notable differences in overall survival (OS) and immune cell infiltration. Through screening, we established a novel MRS based on three prognostic core genes (CAT, CEBPB, and PRKN). High MRS patients showed significantly poorer OS compared to low MRS patients. We observed marked differences in drug sensitivity between subgroups and further predicted potential therapeutic agents targeting MRS. The prognostic nomogram based on MRS demonstrated strong predictive accuracy for 1-, 2-, and 3-year OS across both training and validation PC cohorts. Furthermore, western blot analysis preliminarily validated the potential association between UPRmt and both P53 signaling and glycolysis pathways.
    Conclusion: Our study systematically characterizes the prognostic and therapeutic implications of MRGs in PC, establishing a 3-gene MRS capable of reliably predicting OS in PC patients and exploring UPRmt potential oncogenic mechanisms. These findings provide a valuable reference for individualized therapeutic strategies in PC management.
    Keywords:  drug sensitivity; machine learning; mitochondrial unfolded protein response; nomogram; pancreatic cancer; prognosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1717925
  30. J Nanobiotechnology. 2026 Feb 25.
    Nanotherapeutic strategy via ADSC-mitoEVs rescues ischaemic angiogenesis through mitophagy and mitochondrial metabolic reprogramming.
    Yuan-Zheng Zhu, Min-Chen Zhang, Xue-Er Li, Xing-Hong Zeng, Xue-Ting Gong, Yu-Zi Wu, Ze-Jun Dong, Shu Wu, Xue-Fei Liu, Abdul Haseeb Khan, Yang-Yan Yi.
      Ischaemic vascular diseases are critically linked to mitochondrial dysfunction in endothelial cells, which impairs angiogenesis and tissue repair. Although mitochondrial transplantation has emerged as a promising regenerative strategy, its clinical translation remains limited by inefficient delivery and poor retention in target tissues. Here, we demonstrate that mitochondrial-enriched extracellular vesicles derived from adipose-derived stem cells (ADSC-mitoEVs) function as an efficient cell-free nanotherapeutic that restores angiogenic function both in vitro and in a murine model of diabetic hindlimb ischaemia. Mechanistically, ADSC-mitoEV uptake triggers PINK1/Parkin-mediated mitophagy in recipient endothelial cells, a process essential for initiating angiogenesis. Moreover, ADSC-mitoEVs also directly deliver functional mitochondrial proteins, including superoxide dismutase 2 (SOD2), into the endogenous mitochondrial network, which enhances antioxidant activity and improves bioenergetic capacity independently of mitophagy, as demonstrated by reduced reactive oxygen species and elevated ATP production even in PINK1-silenced cells. Our findings establish ADSC-mitoEVs as a versatile cell-free nanotherapeutic that promotes mitochondrial quality control and metabolic reprogramming, offering a potent therapeutic avenue for ischaemic vascular diseases.
    Keywords:  Adipose-derived stem cells; Extracellular vesicles; Ischaemic vascular diseases; Mitochondrial transfer; Mitophagy
    DOI:  https://doi.org/10.1186/s12951-026-04183-x
  31. J Cardiovasc Dev Dis. 2026 Feb 03. pii: 77. [Epub ahead of print]13(2):
    Engineering Mitochondrial Biogenesis in iPSC-CMs: CRISPR-Guided Approaches for Advanced Cardiomyocyte Development.
    Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.
      Human iPSC-derived cardiomyocytes (iPSC-CMs) exhibit fetal-like mitochondrial networks and limited oxidative metabolism, constraining their translational utility. The key bottleneck is mitochondrial immaturity, resulting from blunted PGC-1α-NRF1/2-TFAM axis activation and insufficient nuclear-mitochondrial coordination, rather than sarcomeric or electrophysiological immaturity alone. This review synthesizes genome-guided interventions (CRISPRa and mtDNA editing) and complementary environmental strategies-including metabolic substrate switching, electromechanical stimulation, and extracellular vesicle (EV)-mediated mitochondrial transfer-to drive mitochondrial biogenesis and maturation in iPSC-CMs. We systematically reviewed studies (2005-2025) targeting (1) key regulators of mitochondrial biogenesis (PGC-1α, NRF1/2, TFAM), (2) CRISPR-based transcriptional activators/repressors and mtDNA editors (DdCBE, mitoTALENs), and (3) maturation approaches such as metabolic conditioning, electromechanical stimulation, 3D tissue culture, and EV-mediated mitochondrial transfer. CRISPRa-mediated activation of PGC-1α, NRF1, and GATA4, combined with mtDNA base editors, enhances mitochondrial mass and OXPHOS function, while integration with environmental maturation strategies further promotes adult-like phenotypes. Integrative approaches that combine genome-guided interventions (CRISPRa, mtDNA editing) with environmental maturation cues yield the most adult-like iPSC-CM phenotypes reported to date. CRISPR-guided mitochondrial biogenesis thus represents a frontier for producing metabolically competent, structurally mature iPSC-CMs for disease modeling and therapy. Remaining translational challenges include efficient mitochondrial delivery, metabolic homeostasis, and multi-omics validation. We propose standardized workflows to couple nuclear and mitochondrial editing with maturation strategies.
    Keywords:  CRISPR activation (CRISPRa); PGC-1α signaling; cardiomyocyte maturation; extracellular vesicle therapy; iPSC-cardiomyocytes; metabolic conditioning in iPSC-CMs; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial genome editing; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.3390/jcdd13020077
  32. Vet Sci. 2026 Feb 04. pii: 151. [Epub ahead of print]13(2):
    Knockout of the C4BPA Gene Promotes Mitophagy via Activation of the Pink1/Parkin Pathway and Alleviates the Inflammatory Response by Inhibiting the NF-κB Signalling Pathway in Bovine Mammary Epithelial Cells.
    Yanlong Zhou, Zhihui Zhao, Xuanxu Chen, Weihua Shao, Qiwen Lu, Qiuyan Tao, Qianchao Xu, Ruiwen Chen, Ping Jiang, Ziwei Lin, Haibin Yu.
      Mastitis is a prevalent disease in the dairy cattle industry and has adverse effects on dairy cows' health and milk quality. Importantly, mastitis is associated with the inflammatory response and mitophagy. As a complement-regulatory factor, C4b-binding protein alpha (C4BPA) has been shown to modulate inflammatory factors. This study further investigates its role and mechanisms in regulating mitophagy and inflammatory responses. Following C4BPA knockout, bovine mammary epithelial cells (BMECs) exhibited reduced expression of TLR4 and key pro-inflammatory cytokines, namely the tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Electron microscopy revealed a marked increase in mitochondrial membrane rupture, as well as cristae disorder and damage and increased reactive oxygen species (ROS) levels. Moreover, Pink1 and Parkin protein levels were increased, as was LC3B lipidation (LC3B-II), whereas p62 protein expression was significantly downregulated. Immunofluorescence indicated substantially increased LC3 colocalization with mitochondria, suggesting that C4BPA gene knockout activated Pink1/Parkin-mediated mitophagy. The fact that C4BPA knockout decreased the levels of p-IκB and p-p65 while increasing those of IκBα and p65 therefore indicates its regulatory role in the NF-κB-mediated inflammatory response. Together, these findings reveal that C4BPA deficiency in BMECs not only activates Pink1/Parkin-mediated mitophagy but also suppresses the NF-κB-mediated inflammatory response. This study provides novel potential molecular targets for predicting mastitis in dairy cattle.
    Keywords:  C4BPA; NF-κB; inflammatory response; mitophagy
    DOI:  https://doi.org/10.3390/vetsci13020151
  33. Toxins (Basel). 2026 Feb 19. pii: 103. [Epub ahead of print]18(2):
    Cell-Penetrating Botulinum Neurotoxin Type A Proteins Alleviate Skeletal Muscle Hypertrophy with Associated Alterations of Mitochondrial Homeostasis.
    Lu Li, Xuan Wei, Liling Jiang, Zhen Gao, Jia Liu.
      Skeletal muscle is the largest metabolic demanding organ in human body. Alterations of skeletal muscle in shape and size significantly affect its biological functions. Botulinum neurotoxin type A1 (BoNT/A1) has been successfully used in clinics to treat masseter, trapezius and gastrocnemius hypertrophy. Here, we used a healthy rat-based skeletal muscle hypertrophy model to evaluate the muscle-reducing activity of recombinant BoNT/A1 (rBoNT/A1) with genetically fused cell-penetrating peptides (CPPs), which was previously reported to increase the cellular uptake of BoNT/A1. Analyses of treated muscle sections using hematoxylin-eosin and immunofluorescence staining showed that both wild-type rBoNT/A1 without modification (WT-rBoNT/A1) and rBoNT/A1 with CPP fusion (CPP-rBoNT/A1) could induce myocomma atrophy and altered gastrocnemius muscle fiber proportions as a result of denervation and reinnervation. Importantly, rBoNT/A1 with the fusion of a specific CPP, zinc finger protein (ZFP), resulted in the highest degree of muscle atrophy and greatest increase in the ratio of type I muscle fibers over type II fibers. An examination of gastrocnemius muscle cells at the subcellular levels using TEM staining revealed swelled mitochondria and diminished mitochondrial crista upon rBoNT/A1 administration. Transcriptomic RNA sequencing (RNA-Seq) analysis followed by RT-qPCR validation showed that rBoNT/A1 treatment also caused changes in mitochondrial biogenesis and mitophagy. Collectively, our results demonstrated that rBoNT/A1 proteins could alleviate skeletal muscle hypertrophy, with associated alterations of mitochondrial homeostasis.
    Keywords:  botulinum neurotoxin type A; cell-penetrating peptides; hypertrophy; mitochondrial homeostasis; skeletal muscle
    DOI:  https://doi.org/10.3390/toxins18020103
  34. Anticancer Res. 2026 Mar;46(3): 1349-1364
    Erlotinib Induces Cell Death by Blocking NIX-mediated Mitophagy Through Lysosomal Swelling in IDH1-mutant Cholangiocarcinoma.
    Yonghyun Kang, Chorong Kim, Chan Yeop Jeong, DA Sol Lee, Changhoon Yoo, Inkeun Park, Seonmin Lee, Kyu-Pyo Kim.
       BACKGROUND/AIM: Metabolic alterations resulting from mutation in tricarboxylic acid cycle enzymes such as isocitrate dehydrogenase 1 (IDH1) have been observed in various cancers. These alterations can be exploited as therapeutic targets to induce metabolic synthetic lethality. This study aimed to characterize the metabolic signature of cholangiocarcinoma (CCA) carrying an IDH mutation and investigate a novel anti-cancer mechanism of erlotinib in inducing cancer cell death through the regulation of altered metabolism.
    MATERIALS AND METHODS: Two CCA cell lines were used: SNU-1079, carrying an IDH1 mutation, and SNU-1196, IDH1 wild-type. Metabolic alterations were validated using liquid chromatography-tandem mass spectrometry. The anti-tumor effects of erlotinib on CCA cell lines were evaluated using cell viability, colony formation, and Annexin V/PI staining assays. Mitochondrial physiology was assessed via microscopy and cytofluorometry following MitoTracker loading. Lysosome swelling was confirmed by detecting cytosolic cathepsin B via western blot and immunocytochemistry using LysoTracker.
    RESULTS: SNU-1079 cells exhibited a mitochondria-independent metabolic feature, suggesting functional mitochondrial alteration. The mitochondrial membrane potential was disrupted, and mitochondrial length was reduced in SNU-1079 cells. This cell line utilized NIX-mediated mitophagy through hyperactivated epidermal growth factor receptor (EGFR) signaling. Erlotinib inhibited EGFR signaling and induced SNU-1079 cell death by interrupting the mitophagic flux. The blockage of mitophagy by erlotinib was associated with lysosomal swelling, indicated by the presence of cytosolic cathepsin B.
    CONCLUSION: The CCA cell line carrying an IDH mutation utilized mitophagy as a novel metabolic compensatory mechanism activated through EGFR-specific signaling. Mitophagy acted as a metabolic synthetic lethality partner to the EGFR inhibitor erlotinib. These findings strongly suggest the potential of erlotinib as a therapeutic strategy for patients with IDH1-mutant CCA.
    Keywords:  EGFR; IDH1; NIX; cholangiocarcinoma; erlotinib; lysosome swelling; mitophagy
    DOI:  https://doi.org/10.21873/anticanres.18034
  35. Environ Toxicol. 2026 Feb 27.
    DEHP Exposure Affects Mitochondrial Function During Ovarian Follicle Development.
    Shu-Jie Yang, Xiao-Kang Lu, Li-Shu Li, Tong Tong, Jun-Yu Qian, Xing Duan.
      The extensive utilization of plastics has resulted in the emergence of di(2-ethylhexyl) phthalate (DEHP) as a major contaminant in the environment, posing serious implications for human and animal health. Multiple investigations suggest that exposure to DEHP impairs female reproductive capacity, causing depletion of primordial follicles and disruption of hormone production. However, the specific mechanisms by which DEHP influences ovarian development and function in females remain unclear. In our work, we conducted an in vivo study using a mouse model exposed to 200 mg/kg DEHP for 28 days. We found that exposure to DEHP inhibited ovarian development and follicle maturation, leading to decreased numbers of primary and antral follicles. Furthermore, we observed that exposure to DEHP destroyed mitochondrial dynamics in the ovary, leading to mitophagy and autophagy. Additionally, DEHP exposure induced oxidative stress and abnormal mitochondrial energy metabolism by inhibiting Sirt3/Sod2-regulated signaling pathway in the ovary. Furthermore, our findings showed that DEHP exposure caused ovarian DNA damage and apoptosis by inhibiting Akt/mTOR signaling cascade. In conclusion, our study shows that DEHP exposure profoundly impairs ovarian function through inhibiting Sirt3/Sod2 and Akt/mTOR signaling pathways. These results provide valuable insights into the detrimental effects of DEHP on the female reproductive system.
    Keywords:  DEHP; mitochondria; mitophagy; ovary; oxidative stress
    DOI:  https://doi.org/10.1002/tox.70060
  36. Int Immunopharmacol. 2026 Feb 20. pii: S1567-5769(26)00249-3. [Epub ahead of print]175 116405
    Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.
    Qing-Hui Li, Min Ji, Shi-Qi Weng, Xia Li, Qin Xiao, Yan Zhou, Tao Luo, Zhao-Xia Liu.
      Imatinib (IMA), a first-line tyrosine kinase inhibitor for hematologic neoplasms, has been demonstrated to potentially contribute to ovarian dysfunction and potential fertility impairment in premenopausal women following extended therapeutic regimens. As a bioactive flavonoid, quercetin (QUE) possesses diverse therapeutic effects, such as reducing oxidative stress, suppressing inflammation, and delaying aging. In our previous study, we demonstrated that QUE may mitigate IMA-induced ovarian damage, although the specific mechanism remained unclear. In this study, we employed an integrated approach combining network pharmacology with in vivo and in vitro experiments to demonstrate whether IMA induces excessive oxidative stress and mitophagy in ovarian granulosa cells, and further determine whether QUE exerts its protective effects through this pathway. We observed that IMA elevated levels of intracellular reactive oxygen species and mitochondrial superoxide, reduced mitochondrial membrane potential, and enhanced apoptosis in KGN cells. In addition, IMA induced the expression of mitophagy (Pink1 and Parkin) and autophagy (ATG5, P62, and LC3B) flow-related proteins in mice ovaries and KGN cells. Finally, we discovered that IMA activated the expression of p-JNK and c-JUN in both mice ovaries and KGN cells, while inhibited the phosphorylation of mTOR. QUE, reactive oxygen species inhibitor (N-Acetylcysteine) and JNK inhibitor (SP600125) played a restorative role to some extent. Our study establishes a theoretical foundation for the application of natural products in fertility preservation therapy for cancer patients.
    Keywords:  Imatinib; Mitophagy; Oxidative stress; Premature ovarian insufficiency; Quercetin; ROS/JNK/c-JUN signaling pathway
    DOI:  https://doi.org/10.1016/j.intimp.2026.116405
  37. Front Immunol. 2026 ;17 1740830
    Comprehensive analysis of mitophagy-related genes reveals prognostic signatures in breast cancer: based on immune landscapes and treatment target predict.
    Hejia Zhao, Wanying Zhang, Yiheng Du, Zheng Kuang, Yilan Tan, Yanjun Chen, Yujie Ma, Fei Zou.
       Background: Breast cancer (BC) is a common malignant tumor with high incidence and mortality rates. Mitophagy refers to a selective form of autophagy that is believed to be closely related to the occurrence and progression of BC. Identifying the mitophagy-related sites associated with BC can help us gain a deeper understanding of the underlying mechanisms of BC, laying the foundation for early diagnosis and effective treatment of BC.
    Method: RNA-seq expression data of BC were obtained from the GEO and TCGA databases. Differentially expressed genes were intersected with mitophagy-related genes from GeneCards to identify BC-associated mitophagy genes. Prognostic biomarkers were screened using Kaplan-Meier (K-M) survival and ROC analyses. Based on mitophagy-related gene expression and survival data, BC patients were classified into high- and low-risk subgroups for immune infiltration and GSEA analyses. Finally, IHC data from the HPA database and in vitro experiments, including siRNA-mediated knockdown, Western blot, CCK-8 proliferation assay, confocal microscopy and drug prediction were performed to validate the expression and biological functions of candidate biomarkers PBK and NEK2.
    Result: Through dual validation of K-M survival analysis and ROC diagnosis-treatment efficacy analysis, we ultimately identified 9 mitophagy-related prognostic biomarkers for BC, and found their expression was significantly upregulated in BC tissues. In addition, the results showed that the degree of immune infiltration in the low-risk subgroup was considered higher than that in the high-risk subgroup. Inhibition of PBK and NEK2 will have an inhibitory effect on the proliferation of BC cell. Furthermore, clinicopathological analyses confirmed a genuinely higher risk in the high-risk subgroup, with PBK and NEK2 independently associated with risk stratification.
    Conclusion: This study elucidated the prognostic value, immune microenvironment characteristics, and molecular mechanisms of mitophagy in BC, and identified nine mitophagy-related biomarkers. Among them, PBK and NEK2 were experimentally confirmed to promote tumor cell proliferation, providing novel insights for early diagnosis and therapeutic strategies in breast cancer.
    Keywords:  breast cancer; early diagnosis; immune cell infiltration; mitophagy; prognostic biomarkers
    DOI:  https://doi.org/10.3389/fimmu.2026.1740830
  38. Nat Commun. 2026 Feb 24.
    Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
    Eleanor Meader, Morgan T Walcheck, Mindy R Leder, Patrice Delaney, Marcelo Falchetti, Ran Jing, Christopher Li, Netra K Kambli, Paul J Wrighton, Wade W Sugden, Mohamad A Najia, Isaac M Oderberg, Vivian M Taylor, Zachary C LeBlanc, Eleanor D Quenzer, Sung-Eun Lim, Thorsten Schlaeger, George Q Daley, Wolfram Goessling, Trista E North.
      Embryonic hematopoietic stem and progenitor cells (HSPCs) have the clinically valuable ability to undergo substantial proliferative expansion while maintaining multipotency, which remains difficult to replicate in culture. Here, we show that newly specified HSPCs achieve this unique state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of mitophagy-reporter zebrafish indicate that mitophagy initiates during endothelial-to-hematopoietic transition and colonization of secondary niches. Knockdown of bnip3lb reduces mitophagy and HSPC numbers in the caudal hematopoietic tissue by promoting myeloid-biased differentiation and apoptosis, which can be rescued by antioxidant exposure. Conversely, chemical or genetic induction of mitophagy enhances embryonic HSPC and lymphoid progenitor numbers. Significantly, compound-mediated mitophagy activation improves ex vivo function of HSPCs derived from human-induced pluripotent stem cells, enhancing serial-replating hematopoietic colony forming potential.
    DOI:  https://doi.org/10.1038/s41467-026-69593-9
  39. Curr Issues Mol Biol. 2026 Feb 05. pii: 181. [Epub ahead of print]48(2):
    Correction: Guo et al. Bioinformatic Analysis of the Value of Mitophagy and Immune Responses in Corneal Endothelial Dysfunction. Curr. Issues Mol. Biol. 2025, 47, 670.
    Ruilin Guo, Chenjia Xu, Yi Yu, Minglu Ma, Xiaojuan Dong, Jing Wu, Chen Ouyang, Jie Ling, Ting Huang.
      There was an error in the original publication [...].
    DOI:  https://doi.org/10.3390/cimb48020181
  40. Biomedicines. 2026 Feb 09. pii: 400. [Epub ahead of print]14(2):
    Kaempferol Alleviates Glucocorticoid-Induced Osteonecrosis of the Femoral Head by Modulating Macrophage M1/M2 Polarization Through RhoA/ROCK-Mediated Mitophagy Activation.
    Yuankai Zhang, Yan Zhao, Shangqing Zhang, Tian Lei, Bocheng Xiang, Xin Zhang, Kai Nan, Lihong Fan.
      Background/Objectives: Dysregulated macrophage M1/M2 polarization is implicated in glucocorticoid-induced osteonecrosis of the femoral head (GONFH). Reprogramming M1 to M2 macrophages represents a potential therapeutic strategy. Kaempferol (KPF), a natural flavonoid with anti-inflammatory properties, may offer benefits, but its mechanism in GONFH is unknown. Purpose: This study aims to explore the therapeutic impact of KPF on GONFH and the mechanisms involved. Methods: In vitro, macrophage viability (CCK-8 assay) and polarization (RT-qPCR, flow cytometry) were assessed. Conditioned medium from KPF-treated macrophages was co-cultured with BMSCs and HUVECs to evaluate osteogenic and angiogenic effects. Mechanisms were analyzed using Western blot, immunofluorescence, and flow cytometry. A rat GONFH model validated in vivo effects. Results: In vitro experiments revealed that KPF significantly augmented the ratio of M2 macrophages while concurrently diminishing the proportion of M1 macrophages. The conditioned medium derived from macrophages treated with KPF markedly improved the osteogenic and angiogenic capabilities of BMSCs and HUVECs. Immunofluorescence staining and Western blot revealed that KPF regulated macrophage polarization by enhancing mitophagy, which was reversed by the addition of a mitophagy inhibitor. Further experiments confirmed that KPF activated mitophagy by inhibiting the RhoA/ROCK signaling pathway. In vivo, KPF increased the proportion of M2 macrophages and promoted the expression of osteogenic and angiogenic markers. Conclusions: In conclusion, our study demonstrates that KPF alleviates GONFH by modulating macrophage M1/M2 polarization through RhoA/ROCK-mediated mitophagy activation. These findings provide novel insights into the treatment of GONFH.
    Keywords:  GONFH; ROCK; RhoA; kaempferol; macrophage polarization; mitophagy
    DOI:  https://doi.org/10.3390/biomedicines14020400
  41. J Adv Res. 2026 Feb 21. pii: S2090-1232(26)00175-X. [Epub ahead of print]
    A novel mechanism of selenium deficiency driving aberrant Th17 cell differentiation via GPX3-targeted PIG3: mitophagy blockade exacerbates mtDNA release.
    Tingting Yu, Xu Shi, Yanju Bi, Tianyou Wang, Shiwen Xu.
       INTRODUCTION: The biological functions of selenium (Se) are mainly realized through selenoproteins. As the only secreted antioxidant enzyme in the glutathione peroxidase family, the deficiency of glutathione peroxidase 3 (GPX3) can affect lymphocyte function. Th17 cells play an important role in immune regulation, but whether they are regulated by GPX3 remains unclear.
    OBJECTIVES: We sought to decipher the regulatory role of GPX3 in the differentiation of Th17 cells in porcine spleen.
    METHODS: While replicating the dietary Se deficiency porcine spleen model in vivo, we established in vitro models using cultured porcine splenic lymphocytes under conditions of Se deficiency, GPX3 knockdown, and p53-inducible gene 3 (PIG3) overexpression. Comprehensive analyses were performed utilizing a suite of techniques, including molecular docking, Co-Immunoprecipitation (Co-IP), Western blot (WB) and mitochondrial DNA (mtDNA) quantification, etc. RESULTS: Our study revealed an interactive relationship between GPX3 and PIG3. Se deficiency downregulated GPX3, thereby suppressing PIG3 expression, which led to intracellular redox imbalance and mitochondrial dysfunction. Concurrently, mitochondrial fusion-fission dynamics became imbalanced, mitophagic flux was obstructed, and mtDNA leaked into the cytoplasm. These alterations ultimately promoted the aberrant differentiation of Th17 cells in porcine splenic lymphocytes by modulating the expression of key factors. Overexpression of PIG3 significantly alleviated oxidative stress induced by low GPX3 expression, restored mitochondrial homeostasis, reduced mtDNA leakage, and suppressed abnormal Th17 differentiation. However, when the autophagic flux inhibitor Baf-A1 was applied under conditions of combined GPX3 knockdown and PIG3 overexpression, the protective effects of PIG3 were reversed, indicating that unimpeded mitophagic flux is essential for the GPX3-PIG3 axis to suppress Th17 differentiation.
    CONCLUSION: Se deficiency impedes mitophagy via the GPX3/PIG3 axis, exacerbates mtDNA leakage, and thereby drives Th17 cell differentiation. Our findings indicate that the GPX3/PIG3 signaling axis may represent a potential therapeutic target for autoimmune diseases.
    Keywords:  GPX3; Mitophagy; PIG3; Selenium deficiency; Th17 cell differentiation; mtDNA
    DOI:  https://doi.org/10.1016/j.jare.2026.02.043
  42. bioRxiv. 2026 Feb 10. pii: 2026.02.06.704083. [Epub ahead of print]
    Metabolic plasticity and virulence of Cryptococcus neoformans are regulated by mitochondrial homeostasis.
    J Alberto Patiño-Medina, Emma Camacho, Arturo Casadevall.
      The mitochondrion is a versatile organelle involved in diverse processes, such as cell death, metal homeostasis, plasma membrane and cell wall integrity, stress response, oxygen concentration, temperature, and metabolic adaptation, in addition to its role in generating energy. Consequently, mitochondrial fitness is essential for the pathogenicity of various organisms, including fungi. Cryptococcus neoformans is a fungal pathogen responsible for over 180,000 HIV-related deaths each year. In this study, we analyzed C. neoformans metabolic plasticity when grown with non-fermentable carbon sources and their impact on virulence and mitochondrial homeostasis. Growth on non-fermentable carbon sources increased thermotolerance, glucuronoxylomannan (GMX) content in the capsule, melanization rate, urease activity, biofilm formation, and virulence. Moreover, cells grown on non-fermentable carbon sources manifested increased mitochondrial number and activity. Conversely, mutants of the master regulator of mitochondrial biogenesis, the Hap complex, the catalytic subunit 1 of protein kinase A, or media supplementation with antioxidants, decreased the use of alternative carbon sources, capsule formation, melanin synthesis, urease activity, mitochondrial number, and resistance to both fluconazole and macrophage killing. Our results implicate mitochondrial homeostasis in virulence regulation via the PKA pathway, suggesting that targeting fungal mitochondrial homeostasis could be a therapeutic approach for cryptococcosis.
    DOI:  https://doi.org/10.64898/2026.02.06.704083
  43. Biochem Pharmacol. 2026 Feb 20. pii: S0006-2952(26)00170-X. [Epub ahead of print] 117839
    NMN prevents obesity-induced osteoporosis by promoting mitophagy to restore type H vessels.
    Meng Shen, Xinru Yu, Jun Wang, Kainong Sun, Wei Xiong, Ye Li, Qian Zhang.
      Obesity-induced osteoporosis is a growing global health challenge, necessitating more therapeutic strategies. Emerging evidence links the reduction of bone-specific type H vessels to osteoporosis due to their crucial role in angiogenesis-osteogenesis coupling. Nicotinamide Mononucleotide (NMN) is known to improve metabolic diseases, but its role in regulating type H vessels in obesity-induced osteoporosis remains unclear. An obesity-induced osteoporosis mouse model was established using a high-fat diet (HFD). In vitro, primary bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) were stimulated with palmitic acid (PA) to mimic a high-fat environment. Bones were evaluated using Micro-CT. The angiogenic capacity of HUVECs was examined by scratch assay. Potential targets of NMN in restoring type H vessels were explored via network pharmacology. Signaling pathways were investigated using immunofluorescence, western blot, and real-time PCR. NMN significantly inhibited HFD-induced osteoporosis by restoring impaired type H vessels in obese mice, thereby enhancing angiogenesis-osteogenesis coupling. In vitro, NMN rescued the PA-induced dysfunction in BMSCs and HUVECs, promoting osteogenic differentiation and migratory capacity, respectively. Mechanistically, NMN rescued HFD-impaired mitophagy in type H vessels via inhibiting Src activation, and inhibited obesity-induced polyamine accumulation. This effect was supported by restored mitochondrial membrane potential, enhanced LC3/TOMM20 co-localization, and upregulation of mitophagy-related genes. These findings demonstrate that NMN protects against obesity-induced osteoporosis by restoring type H vessels and enhancing angiogenesis-osteogenesis coupling, a process mediated by the Src/LC3 signaling pathway and subsequent mitophagy promotion. Our study elucidates a novel mechanism and highlights NMN as a promising therapeutic agent for treating obesity-related osteoporosis.
    Keywords:  Mitophagy; NMN; Osteoporosis; Src-family kinases; Type H vessel
    DOI:  https://doi.org/10.1016/j.bcp.2026.117839
  44. Cells. 2026 Feb 17. pii: 357. [Epub ahead of print]15(4):
    Regulation of Mitochondrial Biogenesis in Diabetic Retinopathy.
    Jay Kumar, Renu A Kowluru.
      Mitochondrial dysfunction plays a major role in diabetic retinopathy development and in its resistance to halt after the reversal of hyperglycemia (metabolic memory). Diabetes also upregulates many long noncoding RNAs, RNAs with >200 nucleotides with no reading frame, and several of them resist reversal after hyperglycemia cessation. Our aim was to investigate the role of LncRNA HOTAIR, a master regulator of chromatin dynamics, in mitochondrial biogenesis in diabetic retinopathy and in metabolic memory. Using retinal endothelial cells and Müller cells, incubated in high glucose (20 mM D-glucose), the effect of HOTAIR-siRNA on mitochondrial biogenesis was investigated by quantifying mitochondrial mass, copy numbers, and mtDNA replication, structure, and function. HOTAIR's role in metabolic memory was investigated by analyzing mitochondrial biogenesis in HOTAIR-siRNA transfected cells incubated in high glucose for four days, followed by normal glucose (5 mM D-glucose) for four days. HOTAIR was upregulated in both retinal vascular and nonvascular cells, and HOTAIR-siRNA ameliorated decreases in mtDNA biogenesis and protected their mitochondria from structural/functional damage. Reversal of high glucose insult failed to ameliorate HOTAIR upregulation and impaired mtDNA biogenesis in both endothelial and Müller cells, but regulation of HOTAIR during high glucose incubation, which followed normal glucose, prevented a decrease in mitochondrial mass and mtDNA copies. Thus, HOTAIR has a major role in mitochondrial biogenesis and in the continued impaired biogenesis in both vascular and nonvascular cells. Regulating HOTAIR may provide a therapeutic option to inhibit the development/progression of diabetic retinopathy.
    Keywords:  Müller cells; diabetic retinopathy; long noncoding RNAs; mitochondria; mitochondrial DNA; retina
    DOI:  https://doi.org/10.3390/cells15040357
  45. Cells. 2026 Feb 20. pii: 372. [Epub ahead of print]15(4):
    Mitochondria at the Crossroads of Cardiovascular Disease: Mechanistic Drivers and Emerging Therapeutic Strategies.
    Sonila Alia, Gaia Pedriali, Paolo Compagnucci, Yari Valeri, Valentina Membrino, Tiziana Di Crescenzo, Elena Tremoli, Laura Mazzanti, Arianna Vignini, Paolo Pinton, Michela Casella.
      Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control-encompassing fusion-fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis-compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS-STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease.
    Keywords:  cardiovascular disease; inflammation; mitochondrial dysfunction; mitochondrial quality control; mitochondrial signaling; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/cells15040372
  46. Arch Oral Biol. 2026 Feb 20. pii: S0003-9969(26)00062-2. [Epub ahead of print]185 106556
    ATF5-mediated mitochondrial UPR inhibited RANKL in Porphyromonas gingivalis LPS-treated osteoblasts.
    Tianrui Yang, Weiman Sun, Lang Lei.
       OBJECTIVE: The purpose of this study was to investigate whether mitochondrial unfolded protein response (UPRmt) was induced in Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS)-treated osteoblasts and to study the relationship among UPRmt, mitochondrial function and bone resorption in periodontitis.
    DESIGN: Osteoblasts were treated with P.gingivalis-LPS. Nicotinamide riboside (NR) and doxycycline (DOX) were used to enhance UPRmt, while small interference RNA was transfected to knock down activating transcription factor 5 (ATF5). Protein and mRNA levels of genes involved in UPRmt and bone metabolism were measured. Intracellular reactive oxygen species (ROS), mitochondrial ROS and mitochondrial membrane potential were detected by flow cytometry and confocal imaging.
    RESULTS: UPRmt and receptor activator of NF-κB ligand (RANKL) expression were induced in P. gingivalis-LPS-treated osteoblasts. Enhancement of UPRmt by NR or DOX decreased RANKL and RANKL/osteoprotegerin (OPG) ratio in osteoblasts. UPRmt inhibition by ATF5 knockdown aggravated mitochondrial dysfunction and promoted RANKL expression in P.gingivalis-LPS-treated osteoblasts.
    CONCLUSIONS: ATF5-mediated UPRmt regulates RANKL expression through mtROS and mitochondrial membrane potential. UPRmt could be a potential target involved in the regulation of bone resorption in periodontitis.
    Keywords:  Activating transcription factor 5; Mitochondrial unfolded protein response; Porphyromonas gingivalis; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.archoralbio.2026.106556
  47. Redox Biol. 2026 Feb 11. pii: S2213-2317(26)00075-3. [Epub ahead of print]91 104077
    p300-mediated histone H3K18 lactylation promotes mitochondrial ROS accumulation via mitophagy inhibition to potentiate dopamine agonists efficacy in prolactinomas.
    Sihan Li, Qian Jiang, Quanji Wang, Xingbo Li, Zihan Wang, Linpeng Xu, Shuyan Luo, Yaorui Wang, Huaqiu Zhang, Kai Shu, Ting Lei, Yimin Huang, Zhuowei Lei.
      Prolactinomas are the most common functional pituitary adenomas, and dopamine agonists (DAs) are the first-line therapy; however, approximately 10-30% of patients develop resistance, highlighting the need for effective sensitization strategies. In clinical specimens, we observed reduced p300 expression in tumors with poor DA responsiveness, and p300 levels were inversely associated with DA dosage. In cellular and xenograft models, DAs decreased p300 by suppressing the cAMP/PKA/CREB pathway. We therefore tested whether upregulating or activating p300 could enhance DA efficacy and investigated the underlying mechanism using immunohistochemistry, immunofluorescence, Western blot, genetic manipulations, RNA sequencing, CUT&Tag, ChIP-qPCR, Seahorse metabolic assays, flow cytometry, co-immunoprecipitation, and GST pull-down assays. Augmenting p300 markedly potentiated DA-induced antitumor effects in vitro and in vivo, a process accompanied by the elevated histone H3K18 lactylation (H3K18la). Mechanistically, p300-dependent H3K18la promoted transcriptional upregulation of Ndufs7 and Washc1. NDUFS7 induction was associated with increased mitochondrial ROS, whereas WASH1 bound the ubiquitin-associated domain of p62, impairing recognition and clearance of damaged mitochondria, suppressing mitophagy, and thereby sustaining mitochondrial ROS accumulation and apoptosis. Moreover, YF-2, a p300 HAT-domain activator, synergized with DAs to inhibit tumor growth in MMQ and AtT-20 cells. Together, these data identify a p300-H3K18la-NDUFS7/WASH1 axis that links mitophagy inhibition to mitochondrial ROS accumulation and provide a mechanistic rationale for targeting p300 as an adjuvant approach to improve DAs efficacy in prolactinomas.
    Keywords:  H3K18la; Mitophagy; Prolactinoma; ROS; p300
    DOI:  https://doi.org/10.1016/j.redox.2026.104077
  48. Clin Transl Med. 2026 Mar;16(3): e70621
    P2X7R deficiency alleviates cardiac senescence by enhancing mitophagy via the HuR/TRIM26/NR4A1 axis.
    Yixin Zhou, Xin Zhong, Zhijie Mao, Yunxuan Chen, Jincheng Xing, Jiaxu Shen, Wenli Zhang, Ji Zhang, Jiaxuan Mei, Zhentong Yang, Zhuoqun Wang, Bozhi Ye, Jiahui Lin, Yonghua Wang, Zhouqing Huang.
       BACKGROUND: Ageing is a significant risk factor for pathophysiological alterations in the heart, but the intrinsic mechanisms by which these occur have yet to be fully elucidated. Purinergic 2×7 receptor (P2X7R) is important for the pathogenesis of numerous cardiovascular diseases; nevertheless, its function in the process of cardiac ageing remains uncertain.
    METHODS: This study utilised P2X7R knockout (P2X7R-/-) mice. An ageing model was established by either maintaining mice until they reached 20 months of age or performing chronic subcutaneous injection of D-galactose (D-gal). Recombinant adeno-associated virus serotype 9 (AAV9) was employed to achieve cardiac-specific overexpression of P2X7R and nuclear receptor subfamily 4 group A member 1 (NR4A1). Cardiac function and histopathological changes in cardiac tissues were evaluated. Transcriptome sequencing was further applied to elucidate the potential mechanisms of P2X7R in cardiac senescence.
    RESULT: Our result show that serum levels of P2X7R increase with advancing age in humans and that P2X7R expression is upregulated during cardiac senescence in mice. P2X7R deficiency alleviates ageing-related cardiac dysfunction, senescence phenotypes and impaired mitophagy. Cardiomyocyte-specific overexpression of P2X7R with AAV9 exacerbates the myocardial dysfunction, senescence phenotype and mitophagy disruption induced by D-gal. Mechanistically, P2X7R promotes human antigen R (HuR) nucleocytoplasmic shuttling in ageing hearts, thereby increasing the mRNA stability of tripartite motif containing 26 (TRIM26) and the expression of the E3 ubiquitin ligase TRIM26. TRIM26 subsequently mediates NR4A1 ubiquitination, leading to its proteasomal degradation, which subsequently suppresses mitophagy in cardiomyocytes and ultimately accelerates cardiac ageing.
    CONCLUSIONS: Our findings provide valuable insights into the role of P2X7R in cardiac ageing and identify the HuR/TRIM26/NR4A1 axis as a key signalling pathway through which P2X7R regulates cardiac ageing.
    Keywords:  NR4A1; P2X7R; TRIM26; ageing; cardiac remodelling; human antigen R; mitophagy
    DOI:  https://doi.org/10.1002/ctm2.70621
  49. Ageing Res Rev. 2026 Feb 21. pii: S1568-1637(26)00054-1. [Epub ahead of print]117 103062
    Linking mitochondrial DNA release to neurodegeneration and cognitive decline.
    Zongwei Fang, Catarina Barbosa, Daniela Marinho, Rita Peixoto, Ildete Luísa Ferreira, João Laranjinha, A Cristina Rego.
      Mitochondrial DNA (mtDNA) has been recognized as a key link between mitochondrial dysfunction and neuroinflammation in neurodegenerative diseases. Beyond being a vulnerable target of oxidative damage, mtDNA can act as a damage-associated molecular pattern when released from mitochondria, triggering innate immune signaling pathways in the nervous system. This review synthesizes current evidence on the mechanisms regulating mtDNA escape from mitochondria into the cytosol and its subsequent intracellular and extracellular effects, reframing mtDNA as an active driver of inflammatory processes rather than a passive by-product of mitochondrial injury. We discuss how defects in mitochondrial quality control, particularly impaired mitophagy and macroautophagy, promote the accumulation of damaged mtDNA, including its release via mitochondria-derived vesicles, exosomes or as cell-free mtDNA. By integrating mitochondrial dysfunction, immune activation, and clearance pathways, this review highlights the mitochondria-immune axis as a central contributor to neurodegeneration and cognitive decline, identifying upstream molecular targets with potential for therapeutic intervention.
    Keywords:  Damage-associated molecular patterns (DAMPs); Inflammation; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Neurodegenerative diseases; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.arr.2026.103062
  50. Biology (Basel). 2026 Feb 09. pii: 302. [Epub ahead of print]15(4):
    Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe.
    Fanghui Ge, Jingxuan Shu, Ziqian Liu, Hong Zhang, Jiandong Wang.
      Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L generation and degradation, the role of NIX/BNIP3L in mediating apoptosis and mitophagy and to advance the understanding of the roles of NIX/BNIP3L in glioblastoma, lung cancer, hepatocellular carcinoma, breast cancer, pancreatic cancer, colorectal cancer and hematologic neoplasms, aiming to enhance treatment precision and improve patient outcomes.
    Keywords:  NIX/BNIP3L; cell death; mitophagy; oxidative stress; tumors
    DOI:  https://doi.org/10.3390/biology15040302
  51. Int J Mol Sci. 2026 Feb 22. pii: 2053. [Epub ahead of print]27(4):
    Autophagy in Sensorineural Hearing Loss: Jekyll or Hyde?
    María Beatriz Durán Alonso.
      Autophagy plays a key role in the development and homeostasis of the cochlear organ. Alterations in the autophagic pathways have been associated with damage to auditory cell types and hearing impairment caused by an array of factors like age, ototoxicity, exposure to high levels of noise, or genetic mutations. Cochlear damage frequently entails mitochondrial dysfunction, impaired mitophagy and the accumulation of high concentrations of free radicals. This review summarizes the observations made to date on the autophagic function in response to cochlear damage and the results of either activating or inhibiting these processes. The data demonstrate that autophagic activity is cell context-dependent and varies according to the cochlear cell type, the toxic agent, its levels and the length and timing of its administration; other factors that influence the autophagic response may be external to the auditory system or related to epigenetic changes or the expression of genetic variants. Modulation of the autophagic status has an effect on auditory cell loss and the progression to hearing impairment and this approach has thus become a promising avenue towards the protection of the hearing function. Nonetheless, this is no easy task and it will require the identification of reliable biomarkers to evaluate the dynamics of autophagic activity as well as the development of specific autophagy modulators that do not exert toxicity.
    Keywords:  aging; autophagy; hearing loss; mitophagy; ototoxicity
    DOI:  https://doi.org/10.3390/ijms27042053
  52. Pharmacol Res. 2026 Feb 19. pii: S1043-6618(26)00060-5. [Epub ahead of print] 108145
    TSPO-Mediated Mitochondrial Retrograde Signaling Primes the Microglial NLRP3 Inflammasome.
    Aarti Singh, Manuel Rigon, Tong Guo, Danilo Faccenda, Gopinath Lakshmanan, Dong Xia, Marta Gramaça Caldeira, Jordi Lopez-Tremoleda, Zahra Falah Hassan Al-Khateeb, Rosella Abeti, Paola Giunti, Michelangelo Campanella.
      Uncontrolled microglial activation is a central driver of neuroinflammatory brain diseases. The mitochondrial translocator protein (TSPO) is a well-established molecular signature of brain inflammation and serves as a diagnostic marker. However, despite this strong association, it remains unclear whether TSPO acts as a positive or negative regulator of microglial function and how it influences the inflammatory and healing responses that follow brain injury. Moreover, recent evidence of species-specific differences in TSPO expression underscores the need to better define its biology in brain-resident macrophages. Here, using a murine microglial model, we demonstrate that TSPO is required for the mitochondrial priming of inflammation and acts as a conduit for its amplification. This function relies on the engagement of multiple intracellular pathways and can be effectively counteracted by the tricyclic indole compound GE-180. Specifically, in response to inflammatory stimuli, TSPO (i) stabilizes on the mitochondrial membrane where it binds and sequesters NOD-like receptor (NLR) proteins, (ii) represses PARK2-mediated mitophagy, and (iii) promotes nuclear retrograde signaling through NF-κB accumulation, thereby enhancing the expression of pro-inflammatory genes. Sustained TSPO-dependent inflammation further drives cellular demise and excitotoxicity. Collectively, these findings advance our understanding of TSPO's molecular physiology in microglia, highlight its pivotal role in mitochondrial control of inflammation, and identify TSPO as a promising target for the pharmacological modulation of neuroinflammatory responses.
    Keywords:  Mitochondria; Mitophagy; NLRP3 and TSPO; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.phrs.2026.108145
  53. Biomolecules. 2026 Feb 14. pii: 302. [Epub ahead of print]16(2):
    Mitochondrial Dysfunctions in Human Primary Coenzyme Q10 Deficiencies.
    Fanny Fontaine, Romain Pénicaud, Stéphane Allouche.
      Coenzyme Q10 (CoQ10) is an essential lipid-soluble molecule that plays a central role in mitochondrial energy production as a mobile electron carrier. In addition to its bioenergetic function, CoQ10 participates in antioxidant defense, redox homeostasis, lipid and nucleotide metabolism, and mitochondrial quality control. Primary CoQ10 deficiencies are rare inherited mitochondrial disorders caused by pathogenic variants in nuclear genes involved in CoQ10 biosynthesis. These defects lead to reduced CoQ10 levels and impaired mitochondrial functions. Clinically, primary CoQ10 deficiencies display remarkable phenotypic heterogeneity, ranging from isolated organ involvement, notably renal or cerebellar disease, to severe multisystemic disorders affecting the nervous system, skeletal muscle, heart, and other organs. Disease onset spans from the antenatal period to adulthood, and clinical severity varies widely, even among patients carrying variants in the same gene. This diversity cannot be fully explained by defective ATP production alone. Growing evidence indicates that disruption of non-bioenergetic functions of CoQ10, including oxidative stress regulation and CoQ-dependent metabolic pathways, contributes significantly to disease pathophysiology and tissue vulnerability. In this review, we summarize current knowledge on CoQ10 biology, biosynthesis, and the clinical spectrum of primary CoQ10 deficiencies, and we discuss emerging mechanisms linking CoQ10 depletion to mitochondrial dysfunctions and human diseases.
    Keywords:  coenzyme Q10; metabolism; mitochondrial disorders; mitophagy; oxidative phosphorylation; oxidative stress; primary coenzyme Q10 deficiency
    DOI:  https://doi.org/10.3390/biom16020302
  54. J Ethnopharmacol. 2026 Feb 21. pii: S0378-8741(26)00267-9. [Epub ahead of print]363 121416
    Corylin promotes longevity in Caenorhabditis elegans through DAF-16 and SKN-1 coordinated activation of autophagy-mitochondrial homeostasis axis.
    Fu-Yi Shi, Chun Li, Xi-Yang Zhang, Li-Lan Ou, Gui-Sheng Wu, Huai-Rong Luo.
       ETHNOPHARMACOLOGICAL RELEVANCE: Corylin is a natural flavonoid isolated from the seeds of Psoralea corylifolia L., a traditional medicinal herb historically used to treat bone-related disorders such as osteoporosis. However, its role in organismal aging and the underlying molecular mechanisms remain largely unexplored.
    AIM OF THE STUDY: This study aimed to evaluate the anti-aging efficacy of corylin and elucidate the molecular basis of its action.
    MATERIALS AND METHODS: Using Caenorhabditis elegans (C. elegans) as a model organism, we systematically assessed the impact of corylin on lifespan and multiple aging-associated phenotypes, including locomotor capacity, muscle integrity, lipofuscin accumulation, and resistance to thermal, pathogenic, and oxidative stress. Neuroprotective potential was evaluated using transgenic models of Parkinson's and Huntington's diseases. To uncover the mechanisms involved, we analyzed the DAF-16/SKN-1 signaling axis and autophagy-related processes using transgenic reporter strains, RNA interference, and RT-qPCR.
    RESULTS: Corylin treatment significantly extended lifespan, improved locomotor performance, and reduced lipofuscin accumulation. Furthermore, it enhanced resistance to environmental stresses and conferred neuroprotection in models of neurodegeneration. Mechanistically, corylin promoted nuclear translocation of DAF-16 and upregulated the expression of DAF-16/SKN-1 target genes. This transcriptional activation was associated with enhanced autophagic flux and improved mitochondrial quality. Crucially, the beneficial effects of corylin were abolished in daf-16 and skn-1 mutants, as well as under autophagy-deficient conditions.
    CONCLUSION: Corylin exerts multifaceted anti-aging effects in C. elegans by coordinately activating the DAF-16/SKN-1 signaling axis, thereby enhancing autophagic flux and maintaining mitochondrial homeostasis. These findings identify corylin as a promising natural candidate for aging intervention.
    Keywords:  Aging; Autophagy; Caenorhabditis elegans; Corylin; Mitophagy
    DOI:  https://doi.org/10.1016/j.jep.2026.121416
  55. Zhen Ci Yan Jiu. 2026 Feb 25. pii: 1000-0607(2026)02-0189-10. [Epub ahead of print]51(2): 189-198
    [Effect of warming needle moxibustion on mitochondrial autophagy in rats with chronic fatigue syndrome based on AMPK/ULK1 signaling pathway].
    Yi-Na Yuan, Di Liu, Jun-Wei Liu, Hua-Yuan Li, Long Li, Yong-Li Wu.
       OBJECTIVES: To observe the effect of warming needle moxibustion (WNM) on the expression of AMP-activated protein kinase (AMPK)/Unc-51 like autophagy activating kinase 1 (ULK1) signaling pathway in chronic fatigue syndrome (CFS) rats, so as to explore its mechanism underlying improvement of CFS.
    METHODS: Male SD rats were randomly divided into control, model, WNM and coenzyme groups, with 10 rats in each group. The CFS model was established by multi-factor compound stress stimulation method (exhaustive swimming + chronic restraint + alternate-day fasting). The rats of the WNM group received warming needle moxibustion stimulation at bilateral "Zusanli" (ST36), "Guanyuan" (CV4) and "Zhongwan" (CV12)for 15 min, once daily for 14 days. The rats of the coenzyme group were administered coenzyme Q10 (1 mg/kg) by gavage once daily for 14 days. Body weight and swimming time of the rats were recorded before and after modeling and after intervention. Behavioral changes were assessed using the open-field test. Histological changes in skeletal muscle were observed via HE staining. The structure of mitochondria and autophagosomes in skeletal muscle were observed using transmission electron microscopy. The protein expression levels of AMPK, phosphorylated (p)-AMPK, ULK1, p-ULK1, microtubule-associated protein 1 light chain 3 (LC3)-Ⅰ and LC3-Ⅱ in skeletal muscle were detected by Western blot, and the ratios of p-AMPK/AMPK, p-ULK1/ULK1 and LC3-Ⅱ/LC3-Ⅰ were calculated. The mRNA expression levels of AMPK, ULK1 and LC3 in skeletal muscle were detected by real-time PCR.
    RESULTS: Compared with the control group, the body weight, swimming time, and the duration of standing and the number of grid crossing were significantly reduced (P<0.05), while the mRNA expression levels of ULK1 and LC3, and the ratio of p-ULK1/ULK1 were significantly increased in the model group (P<0.05). Compared with the model group, the body weight, swimming time, and the duration of standing and the number of grid crossing were significantly increased (P<0.05), and the mRNA expression levels of AMPK, ULK1 and LC3, as well as the ratios of p-ULK1/ULK1 and LC3-Ⅱ/LC3-Ⅰ, were significantly up-regulated in both the WNM and coenzyme groups (P<0.05).
    CONCLUSIONS: Warming needle moxibustion can alleviate chronic fatigue syndrome by activating the AMPK/ULK1 pathway, upregulating the expression of AMPK/ULK1/LC3, and promoting mitochondrial autophagy, thereby enhancing mitochondrial morphology.
    Keywords:  AMPK/ULK1 signaling pathway; Chronic fatigue syndrome; Mitochondrial autophagy; Skeletal muscle; Warming needle moxibustion
    DOI:  https://doi.org/10.13702/j.1000-0607.20250074
  56. J Reprod Immunol. 2026 Feb 17. pii: S0165-0378(26)00033-1. [Epub ahead of print]174 104864
    Astaxanthin improves assisted reproductive outcomes in patients with poor ovarian response by alleviating oxidative stress and regulating granulosa cell mitochondrial function.
    Dongmei Tian, Haonan Ju, Xinghan Cheng, Xin Liang, Shaomi Zhu.
      Poor ovarian response (POR) is a barrier to assisted reproductive technology (ART) success because oxidative stress damages granulosa cells. Follicular fluid samples were prospectively collected from 156 poor ovarian response (POR) patients. A retrospective 1:1 matched analysis was subsequently performed on 60 selected patients (30 with astaxanthin use and 30 without), with the aim of evaluating astaxanthin's impact on reproductive outcomes and exploring its regulatory effects on oxidative stress and cell survival pathway. Patients who received 37.5 mg astaxanthin (Haematococcus pluvialis oil) twice daily for 60-90 days before ovarian stimulation were compared with those who did not. Baseline characteristics and stimulation indices were similar. The astaxanthin group achieved a higher cumulative clinical pregnancy rate (72.0 % vs. 41.7 %, P = 0.032), while oocyte yield, fertilization and embryo quality were comparable. In follicular fluid, astaxanthin supplementation reduced superoxide dismutase and malondialdehyde, increased catalase and showed a trend towards higher glutathione. Granulosa cells from supplemented patients displayed lower reactive oxygen species and apoptosis. Pro‑apoptotic proteins (Bax, caspase‑3, caspase‑9 and cytochrome c) were down‑regulated and anti‑apoptotic Bcl‑2 and mitophagy markers (LC3B, PINK1 and Parkin) were up‑regulated. Astaxanthin supplementation was associated with improved cumulative pregnancy rates in POR patients undergoing ART. The benefit may involve reduced oxidative stress, upregulation of mitophagy-related markers, and inhibition of granulosa-cell apoptosis, supporting its potential as an adjunct therapy for poor ovarian responders.
    Keywords:  Astaxanthin; Granulosa Cells; Mitophagy; Oxidative Stress; Poor Ovarian Response
    DOI:  https://doi.org/10.1016/j.jri.2026.104864
  57. Cell Death Discov. 2026 Feb 26.
    Inhibiting HSP27 activates the XBP1s/CerS1 interplay, which triggers DRP1-driven mitophagy, thereby protecting against cell death and promoting the KSHV lytic cycle in primary effusion lymphoma cells.
    Roberta Gonnella, Vincenzo Corrado, Giulio Francesco Scaffidi, Rossella Benedetti, Michele Di Crosta, Roberta Zarrella, Maria Saveria Gilardini Montani, Roberta Santarelli, Mara Cirone.
      PEL is an aggressive B-cell lymphoma that in the majority of cells harbors latent KSHV, although appropriate stimuli can induce viral replication. These include HDAC inhibitors such as butyrate, activation of endoplasmic reticulum (ER)/UPR stress, and exogenous administration of ceramide 18. These treatments reduce cell survival, but also activate adaptive branches of the UPR such as the Ire1α-XBP1s axis and/or trigger macroautophagy to counteract cell death, processes whose output may be manipulated by KSHV. HSPs are also upregulated by several cytotoxic treatments and support both cell survival and KSHV replication, suggesting a complex relationship between cell and viral fate. In this study, we demonstrate that HSP27 inhibition reduces PEL cell survival, activates ER stress including XBP1s, and upregulates CerS1, the enzyme that synthesizes ceramide 18. We further discovered a crosstalk between XBP1s and CerS1 that enhances protection against ER stress during HSP27 inhibition also promoting DRP1-dependent pro-survival mitophagy and triggers KSHV reactivation from latency. In conclusion this study suggests that HSP27 plays a previously unrecognized central role in controlling the UPR, CerS1 and mitochondrial autophagy, influencing both cell survival and KSHV lytic cycle in PEL cells.
    DOI:  https://doi.org/10.1038/s41420-026-02979-2
  58. Mol Biol Rep. 2026 Feb 24. pii: 422. [Epub ahead of print]53(1):
    Modulation of mitochondrial biogenesis by flavonoids via SIRT1 signalling in metabolic syndrome: a systematic review.
    Prastuti Sahariah, Lunasmrita Saikia, Albert Bharali, Douglas Law, Saikat Sen, Partha Pratim Dutta.
      
    Keywords:  Dyslipidaemia; Flavanols; Insulin Resistance; Mitochondrial Dysfunction; SIRT1
    DOI:  https://doi.org/10.1007/s11033-026-11599-z
  59. FASEB J. 2026 Mar 15. 40(5): e71621
    GDF15-Treated iPSC-MSC-Derived Exosomes Alleviate Fibrosis Post-Myocardial Infarction via Repression of the MFAP4/ERK/Drp1 Axis.
    Jie Qiu, Qian Han, Ying Shen, Qi Yang, Ziqi Li, Yimei Hong, Junxiu Zhao, Fang Lin, Kexin Ma, Bei Hu, Xiaoting Liang, Yuelin Zhang.
      Cardiac fibrosis post-myocardial infarction (MI) induces adverse cardiac remodeling, ultimately resulting in heart failure. Exosomes (EXOs) derived from mesenchymal stem cells (MSCs) have emerged as potent modulators of post-infarction remodeling, capable of limiting fibrotic responses. Our previous study showed that growth differentiation factor 15 as pretreatment promoted the protective effects of MSCs against myocardial fibrosis post-MI via paracrine actions. We investigated whether exosomes derived from GDF15-treated iPSC-MSCs (GDF15-iPSC-MSC-EXOs) could alleviate post-MI fibrosis and further explored the mechanistic pathways underlying their effects. In a mouse model of MI, EXOs released from iPSC-MSCs and GDF15-treated iPSC-MSCs were collected from culture supernatants and subsequently administered intramuscularly around the infarct area. Cardiac fibrosis was assessed by Masson's trichrome staining. A collagen synthesis model in mouse cardiac fibroblasts (mCFs) was established by transforming growth factor-β1 (TGF-β1) treatment in vitro. The mitochondrial morphology of mCFs under TGF-β1 stimulation was evaluated by Mitotracker staining. Delivery of EXOs from GDF15-treated iPSC-MSCs resulted in less fibrotic remodeling and better ventricular function after MI than exosomes from untreated cells. In TGF-β1-stimulated fibroblasts, both exosome types reduced fibrosis markers by preventing mitochondrial fission, with GDF15-iPSC-MSC-EXOs affording stronger protection. These effects were partly attenuated in the presence of the mitochondrial fission activator FCCP. Mechanistically, GDF15, which is rich in GDF15-iPSC-MSC-EXOs, inhibited TGF-β1-induced mCF activation via repression of the MFAP4/ERK/Drp1 pathway through a direct physical interaction with MFAP4. GDF15 conditioning strengthened the capacity of iPSC-MSC-derived exosomes to mitigate cardiac fibrosis following MI via inhibition of mitochondrial fragmentation in CFs by repressing the MFAP4/ERK/Drp1 pathway. GDF15 pretreatment is a novel strategy to enhance the cardioprotection of iPSC-MSC-EXOs against cardiac fibrosis post-MI.
    Keywords:  cardiac fibrosis; exosomes; growth differentiation factor 15; iPSC‐MSCs; mitochondrial fission
    DOI:  https://doi.org/10.1096/fj.202504078R
  60. Cells. 2026 Feb 13. pii: 341. [Epub ahead of print]15(4):
    TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia.
    Elena-Andreea Burlacu, Robin Schellingen, Amanda Moya-Gómez, Sanne G S Verberk, Nathan Stas, Sofie Kessels, Yeranddy A Alpizar, Jean-Michel Rigo, Annelies Bronckaers, Jerome J A Hendriks, Christel Faes, Bert Brône.
      Microglia perform surveillance and phagocytosis to maintain the homeostasis of the central nervous system (CNS). These processes are energetically demanding, and given the critical roles of mitochondria in providing ATP, the characteristics of the mitochondrial network can modulate microglial behavior. Although the Ca2+-permeable Transient Receptor Potential Vanilloid 4 (TRPV4) is known for regulating microglial morphology and migration, and it is implicated in mitochondrial calcium uptake, it is unknown whether TRPV4 affects the mitochondrial network in microglia. Our study provides evidence that TRPV4 plays a role in the integrity and complexity of the mitochondrial network in microglia. Quantification of the Mitochondrial Fragmentation and Complexity Index (MFCI) and increased pDrp1 (Ser616) showed a shift towards mitochondrial network fragmentation, and lowered complexity in Trpv4 knockout versus wild-type primary murine microglia in vitro. The distribution of mitochondria within microglia showed significant differences in density at 10-32 µm away from the nucleus. Furthermore, acute pharmacological TRPV4 inhibition with GSK2193874 did not induce significant mitochondria network fragmentation. Our findings establish TRPV4 as a regulator of mitochondrial dynamics and adaptive responses, highlighting its importance for maintaining homeostasis in microglia and the entire CNS.
    Keywords:  TRPV4; microglia; mitochondria
    DOI:  https://doi.org/10.3390/cells15040341
  61. bioRxiv. 2026 Feb 17. pii: 2026.02.15.706043. [Epub ahead of print]
    Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
    Shikha Yadav, Sheela Nagarkoti, Varadarajan Sudhahar, Kamarajan Rajagopal, Archita Das, Stephanie Kelley Spears, Tohru Fukai, Masuko Ushio-Fukai.
      Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein DRP1 promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated "redox-dead" DRP1-C631A knock-in mutant ( Drp1 C/A ) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1 macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2 macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia-serum starvation (HSS) rapidly induced cytosolic ROS production and DRP1-CysOH formation in wild type macrophages. In contrast, Drp1 C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD.
    DOI:  https://doi.org/10.64898/2026.02.15.706043
  62. Cardiovasc Drugs Ther. 2026 Feb 24.
    Targeting SIRT3 in Diabetic Cardiomyopathy: Mechanism-Based Therapeutic Strategies.
    Xiaofang Zhang, Hui Lin, Xinrou Yu, Tiantian Lu, Jun Wang, Hui Ji, Dihua Huang, Dajun Lou.
      
    Keywords:  Diabetic cardiomyopathy; Mitochondrial homeostasis; Molecular mechanisms; Oxidative stress; Sirtuin 3
    DOI:  https://doi.org/10.1007/s10557-026-07843-0
  63. Front Bioeng Biotechnol. 2026 ;14 1763027
    Research progress on mitochondria in bone defect repair: mechanisms and therapeutic implications.
    Zhicheng Hu, Gang Chen, Zhisheng Long.
      Bone defect repair faces clinical challenges due to complex conditions caused by various factors such as trauma and aging. Traditional treatments have certain limitations, which seriously affect patients' prognosis. As the core organelle of cells, mitochondria regulate the activity of key cells including osteoblasts, osteoclasts, and bone marrow mesenchymal stem cells through functions such as oxidative phosphorylation (OXPHOS), production and scavenging of reactive oxygen species (ROS), regulation of Ca2+ concentration, modulation of cell death, and immune response, as well as dynamic processes including fusion, fission, mitophagy, and transport. Moreover, mitochondria interact synergistically with the neuro-vascular-muscle axis, participating deeply in bone defect repair. This article systematically reviews the mechanisms and research progress of mitochondria in bone defect repair, providing a theoretical basis for the development of novel mitochondria-targeted repair strategies and facilitating the research and development of efficient clinical treatment regimens. This will help to develop new treatment strategies for bone defects. These strategies will be more effective, safe and targeted for individual patients.
    Keywords:  bone defect repair; mitochondria; mitochondrial dynamics; mitochondrial function; osteogenesis
    DOI:  https://doi.org/10.3389/fbioe.2026.1763027
  64. JACC Basic Transl Sci. 2026 Feb;pii: S2452-302X(25)00413-9. [Epub ahead of print]11(2): 101460
    OPA1 Deficiency Impairs NGF Signaling and Drives Sympathetic Neurodegeneration.
    Marco Ronfini, Valentina Prando, Vittoria Di Mauro, Lolita Dokshokova, Erika Lazzeri, Irene Costantini, Lukas Alàn, Erwan Andre Riviere, Alex Incensi, Camilla Olianti, Chiara La Morgia, Rocco Liguori, Leonardo Sacconi, Vincenzo Donadio, Luca Scorrano, Valerio Carelli, Marco Mongillo, Tania Zaglia.
      Peripheral sympathetic neurodegeneration drives cardiac dysfunction in dominant optic atrophy, revealing a critical neuro-cardiac link. Optic atrophy factor-1 haploinsufficiency disrupts mitochondrial dynamics and neurotrophic signaling, causing targeted sympathetic denervation and arrhythmias. Restoring nerve growth factor transport and mitochondrial health in sympathetic neurons represents a promising therapeutic avenue for cardiac autonomic disorders. Future research must unravel mechanisms of neurocardiac crosstalk to develop precise interventions against neurogenic cardiac disease progression.
    Keywords:  dominant optic atrophy; mitochondria; nerve growth factor; optic atrophy factor-1; sympathetic neurons
    DOI:  https://doi.org/10.1016/j.jacbts.2025.101460
  65. Am J Physiol Lung Cell Mol Physiol. 2026 Feb 25.
    Mitochondrial acid-sensing ion channel 1a deficiency induces mitochondrial dysfunction in pulmonary arterial smooth muscle cells.
    Megan N Tuineau, Lindsay M Herbert, Heaven E Medina, Jay S Naik, Thomas C Resta, Nikki L Jernigan.
      Pulmonary hypertension (PH) is a progressive vascular disease driven by pulmonary arterial remodeling, characterized by cellular hyperproliferation, resistance to apoptosis, and phenotypic plasticity. Our laboratory has shown that the proton-gated cation channel, acid-sensing ion channel 1a (ASIC1a), is essential for the development of chronic hypoxia (CH)-induced PH in rodents. Importantly, ASIC1a activation occurs without changes in total ASIC1a levels but reflects a hypoxia-dependent redistribution to the plasma membrane in pulmonary arterial smooth muscle cells (PASMCs). In neurons, mitochondrial-localized ASIC1a (mtASIC1a) contributes to oxidative stress-induced mitochondrial membrane potential (ΔΨm) depolarization and apoptosis. Although mtASIC1a has not been described in vascular cells, its role in PASMCs may be relevant to mitochondrial dysfunction and apoptosis resistance in PH. We hypothesize that mtASIC1a is a crucial regulator of PASMC mitochondrial homeostasis, and its loss following CH promotes mitochondrial dysfunction and apoptosis resistance. Consistent with this, mtASIC1a localization was decreased in PASMCs and intrapulmonary arteries from CH rats compared to controls. Functionally, PASMCs from CH rats or Asic1a knockout mice exhibited ΔΨm hyperpolarization, elevated mitochondrial Ca2+ and superoxide, impaired mitophagy, and reduced cleaved caspase-3. Transmission electron microscopy revealed mitochondrial morphological changes, including increased size and circularity, decreased aspect ratio, and reduced mitochondrial number per cell, while fusion/fission proteins remained largely unchanged. Lentiviral restoration of mtASIC1a prevented ΔΨm hyperpolarization and restored caspase-3 cleavage. These findings identify mtASIC1a as a novel regulator of mitochondrial function in PASMCs, where its loss following CH promotes ΔΨm hyperpolarization, impaired mitophagy, and resistance to apoptosis.
    Keywords:  apoptosis; mitochondria; mitochondrial membrane potential; mitophagy; pulmonary hypertension
    DOI:  https://doi.org/10.1152/ajplung.00324.2025
  66. Biomolecules. 2026 Feb 02. pii: 223. [Epub ahead of print]16(2):
    Renoprotection by 5-Methoxytryptophan in Kidney Disease.
    Jonah P Gutierrez, Tram N Diep, Shaona Niu, Liang-Jun Yan.
      Kidney disease, be it acute or chronic, has a complex pathology and is a significant human health problem. Increasing interest has been focused on exploring therapeutic targets that can be used to safeguard kidney function under a variety of detrimental conditions. In this article, we review the protective effects of 5-methoxytryptophan (5-MTP), a tryptophan metabolite, on kidney injury. Published studies indicate that serum 5-MTP level is decreased in patients with chronic kidney disease (CKD), suggesting that 5-MTP is a biomarker for CKD and has therapeutic values. Indeed, rodent models of kidney injury induced by folic acid, lipopolysaccharide (LPS), unilateral ureteral obstruction (UUO), and ischemia/reperfusion all demonstrate that exogenous 5-MTP exhibits nephroprotective effects. The underlying mechanisms involve antioxidative damage via activating antioxidant systems such as heme oxygenase-1, anti-inflammation, anti-fibrosis, and enhanced mitophagy. To further explore the underlying mechanisms and the potential of 5-MTP as a kidney therapeutic compound, future studies need to include more rodent models of kidney injury induced by a variety of insults. Moreover, how to boost endogenous 5-MTP content and its potential synergistic effects with other therapeutic approaches aiming to combat kidney diseases also remain to be explored.
    Keywords:  5-methoxytryptophan (5-MTP); fibrosis; inflammation; kidney; mitophagy; oxidative damage
    DOI:  https://doi.org/10.3390/biom16020223
  67. Biomedicines. 2026 Jan 29. pii: 310. [Epub ahead of print]14(2):
    Mitochondria in Renal Ischemia-Reperfusion Injury: From Mechanisms to Therapeutics.
    Yijun Pan, Jiefu Zhu.
      Renal ischemia-reperfusion injury (IRI) is a leading trigger of acute kidney injury (AKI), a syndrome with high incidence and mortality worldwide. The kidney is among the most energy-demanding organs; its mitochondrial content is second only to the heart, rendering renal function highly contingent on mitochondrial integrity. Accumulating evidence places mitochondria at the center of IRI pathogenesis. During ischemia, ATP depletion, ionic disequilibrium, and Ca2+ overload set the stage for injury; upon reperfusion, a burst of mitochondrial reactive oxygen species (mtROS), collapse of the mitochondrial membrane potential (ΔΨm), aberrant opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA (mtDNA) damage, and release of mitochondrial damage-associated molecular patterns (mtDAMPs) further amplify inflammation and drive regulated cell-death programs. In recent years, the centrality of mitochondrial bioenergetics, quality control, and immune signaling in IRI-AKI has been increasingly recognized. Building on advances from the past five years, this review synthesizes mechanistic insights into mitochondrial dysfunction in renal IRI and surveys mitochondria-targeted therapeutic strategies-including antioxidant defenses, reinforcement of mitochondrial quality control (biogenesis, dynamics, mitophagy), and modulation of mtDAMP sensing-with the aim of informing future translational efforts in AKI.
    Keywords:  AKI; antioxidant defenses; mitochondria; mitochondria-targeted therapy; mitochondrial DNA; mitochondrial quality control; mtDAMPs; renal ischemia–reperfusion injury
    DOI:  https://doi.org/10.3390/biomedicines14020310
  68. Cell Mol Life Sci. 2026 Feb 27.
    IMP2 enhances M2 macrophage polarization via LKB1-AMPK-mediated mitochondrial dynamics and fatty acid β-oxidation to ameliorate diabetic osteoporosis.
    Lingshuang Li, Yajun Cui, Yu Ji, Ke Ma, Xuejie Lin, Ting Liu, Junyang Sun, Hongrui Liu, Jie Guo, Minqi Li.
      
    Keywords:  AMPK; Diabetic osteoporosis; Fatty acid β-oxidation; IMP2; LKB1; M6A; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s00018-026-06093-5
  69. Research (Wash D C). 2026 ;9 1125
    Targeting a Shared Mitophagy Regulator: The SIRT1-FOXO3-DEPP1 Axis Underpins the Dual Bone and Brain Benefits of Total Flavonoids from Drynaria fortunei.
    Yili Zhang, Xiangyun Guo, Qing Wang, Long Xiao, Qingqing Liu, Yiwen Gan, Yunning Li, Chuanrui Sun, Zhiwen Luo, Kai Sun, Weiwei Tao, Xu Wei.
      Postmenopausal osteoporosis and depression often occur together, but a single treatment that improves both conditions is currently lacking. The loss of estrogen can trigger oxidative stress, damage mitochondria, and drive dysregulated autophagy with impaired flux, simultaneously harming bone and the brain. We evaluated whether total flavonoids from Drynaria fortunei (TFDF) could counter these problems by activating sirtuin-1 (SIRT1), a protein that supports autophagy and mitochondrial health. In menopausal and chronic stress model mice and in cultured bone-forming cells and hippocampal neurons exposed to oxidative injury, we measured bone structure and strength indicators, mood-related behaviors, mitochondrial function, and gene activity patterns. The flavonoids preserved bone density and fine bone structure, shifted bone turnover toward formation, and improved depression-like behaviors (greater exploration and sucrose preference, less immobility). Across bone and the brain, TFDF modulated SIRT1-FOXO3-DEPP1 signaling and FOXO-linked oxidative stress and autophagy programs, thereby normalizing autophagic recycling and mitochondrial function. In cellular models, TFDF preserved mitochondrial function and restored autophagic recycling, and the loss or gain of SIRT1 function abolished or enhanced these benefits, respectively, indicating that SIRT1 activity is necessary for the effects of TFDF. These findings identify TFDF as a single, mechanism-based strategy that addresses both skeletal deterioration and depressive symptoms after menopause by engaging SIRT1-dependent stress autophagy pathways to restore cellular recycling and energy control.
    DOI:  https://doi.org/10.34133/research.1125
  70. Antioxidants (Basel). 2026 Jan 28. pii: 174. [Epub ahead of print]15(2):
    The Gut-Extracellular Vesicle-Mitochondria Axis in Reproductive Aging: Antioxidant and Anti-Senescence Mechanisms.
    Efthalia Moustakli, Christina Messini, Anastasios Potiris, Athanasios Zikopoulos, Ioannis Arkoulis, Alexios Kozonis, Theodoros Karampitsakos, Pavlos Machairoudias, Nikolaos Machairiotis, Panagiotis Antsaklis, Periklis Panagopoulos, Sofoklis Stavros, Ekaterini Domali.
      Cellular senescence, mitochondrial dysfunction, and cumulative oxidative stress (OS) are the main causes of the progressive decreases in oocyte and sperm quality that define reproductive age. There is growing evidence that these processes are controlled by systemic variables, such as metabolites produced from the gut microbiome and extracellular vesicle (EV)-mediated intercellular communication, rather than being exclusively regulated at the tissue level. Antioxidant enzymes, regulatory microRNAs, and bioactive lipids that regulate mitochondrial redox balance, mitophagy, and inflammatory signaling are transported by EVs derived from reproductive organs, stem cells, immune cells, and the gut microbiota. Concurrently, microbiome-derived metabolites such as urolithin A, short-chain fatty acids, and polyphenol derivatives enhance mitochondrial quality control, activate antioxidant pathways, and suppress senescence-associated secretory phenotypes. This narrative review integrates the most recent research on the relationship between redox homeostasis, mitochondrial function, gut microbiota activity, and EV signaling in the context of male and female reproductive aging. We propose an emerging gut-EV-mitochondria axis as a unified framework through which systemic metabolic and antioxidant signals affect gamete competence, reproductive tissue function, and fertility longevity. Finally, we discuss therapeutic implications, including microbiome modulation, EV-based interventions, and senotherapeutic strategies, highlighting key knowledge gaps and future research directions necessary for clinical translation.
    Keywords:  antioxidants; cellular senescence; extracellular vesicles; fertility; gut microbiome; mitochondrial function; mitophagy; oxidative stress; reproductive aging; reproductive longevity
    DOI:  https://doi.org/10.3390/antiox15020174
  71. Biochemistry. 2026 Feb 26.
    Characterization of Conformational Dynamics and Structural Plasticity of the Catalytic Domain of Human Mitochondrial YME1L Protease.
    Megan K Black, Angelina Kim, Ching Y Chen, Monica M Goncalves, Simrah Waseem, Siavash Vahidi, Rui Huang.
      Mitochondrial proteostasis is essential to maintain cellular function and survival. YME1L is a membrane-anchored AAA+ (ATPases Associated with diverse cellular Activities) family protease and plays a pivotal role in mitochondrial proteostasis by selectively degrading misfolded and native proteins. The precise mechanisms by which nucleotide binding and hydrolysis influence YME1L's conformational dynamics, proteolytic activity, and stability remain unclear. Here, we characterize the conformational dynamics of the YME1L catalytic domain. Using a hexameric soluble YME1L construct, we employ hydrogen/deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) spectroscopy to demonstrate that nucleotide binding reduces the backbone flexibility and modulates the side-chain dynamics of the AAA+ domain, while Zn2+ binding stabilizes the protease domain. We also reveal long-range functional crosstalk between the AAA+ and protease domains of YME1L. We use functional assays to show the importance of a salt bridge between the AAA+ and protease domains in facilitating ATP-dependent substrate degradation by YME1L. Additionally, we show that ATP binding stabilizes the structure of the catalytic domain of YME1L and protects it from chemical- and heat-induced aggregation. These findings explain the nucleotide-driven regulation of YME1L and provide insights into our understanding of its proteolytic activity and structural stability under stress conditions.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00535
  72. Genes (Basel). 2026 Jan 31. pii: 177. [Epub ahead of print]17(2):
    VPS35 Deficiency Markedly Reduces the Proliferation of HEK293 Cells.
    Sujin Lee, Soojin Park, Hyewon Bang, Sun-Uk Kim, Young-Ho Park, Gabbine Wee, Unbin Chae, Ekyune Kim.
      Background/Objectives: The retromer protein complex is involved in various physiological processes, especially endosomal trafficking, and its dysregulation has been linked to Alzheimer's disease and Parkinson's disease, as well as VPS35 knockout (KO), causing early embryonic lethality. We aimed to investigate the cellular consequences of VPS35 deficiency. Methods: To investigate the effects of VPS35 loss, we used CRISPR/Cas9 to generate VPS35 KO human embryonic kidney 293 (HEK293) cells. We analyzed changes in retromer component expression, cell proliferation, apoptosis, and mitochondrial dynamics using Western blotting, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and confocal microscopy. Results: VPS35 KO led to a significant reduction in cell proliferation and decreased expression of VPS29 and VPS26, both essential for retromer complex assembly. Consequently, retromer formation was impaired. Compared to control cells, KO cells exhibited elevated levels of cleaved caspase-3, poly(ADP-ribose) polymerase, cytochrome C, and p21, while the expression of Ki-67, CDK4, and cyclin D was reduced. Additionally, VPS35 deletion also promoted mitochondrial fragmentation, associated with increased expression of mitochondrial fission-related proteins. Finally, the rescue experiment using the human VPS35 gene confirmed that the recovery of VPS35 not only led to the recovery of the essential elements constituting the retromer but also the recovery of molecules related to the cell cycle, restoring cell death to a normal level. Conclusions: These findings suggest that VPS35 plays a critical role in cell growth and survival by modulating apoptosis, mitochondrial dynamics, and cell cycle progression.
    Keywords:  HEK293 cells; VPS35; cell proliferation; endosomal trafficking; mitochondrial dynamics; retromer complex
    DOI:  https://doi.org/10.3390/genes17020177
  73. medRxiv. 2026 Feb 09. pii: 2026.02.06.26345691. [Epub ahead of print]
    Cooperative Architecture of Mitochondrial Proteome Homeostasis.
    Patrick Forny, Merima Forny, Andrew J Smith, Andrew Y Sung, Kaixian Liu, David J Pagliarini.
      Mitochondria are semi-autonomous organelles whose generation and maintenance demand precise expression, processing, and assembly of >1,000 proteins encoded across two genomes. To explore this cooperativity, we performed multiomic analyses on >200 cell lines harboring mitochondrial gene perturbations, generating >26M molecular measurements. Our data reveal that mitochondrial proteome homeostasis is heavily influenced by post-transcriptional processes. Through nearest neighbor analyses, we reveal diverse protein activities undergirding this regulation, including MDH2's regulation of MT-ND3 transcription via FASTKD1 binding and CLPP's processing of the mitoribosomal assembly factor MALSU1, which we establish as a disease gene. Through entropy analysis, we reveal unexpectedly heterogeneous protein-level variability across complexes and use complexome profiling to identify new complex-specific membership, including C15orf61's association with complex V. We further observe substantial mtDNA copy number variation, notably upon disruption of the disease-related cobalamin biosynthesis protein MMADHC. Together, we establish new protein functions and provide a multilayered view into mitochondrial proteome regulation.
    Highlights: Multiomic signatures across perturbations reveal extensive post-transcriptional regulationThe TCA cycle enzyme MDH2 binds FASTKD1 to modulate MT-ND3 transcript levelsMALSU1 is a CLPP protease substrate whose deficiency causes a mitochondrial diseaseC15orf61 binds ATP synthase and negatively regulates its higher order assemblyMMADHC inversely affects mtDNA levels potentially mediated through LONP1.
    DOI:  https://doi.org/10.64898/2026.02.06.26345691
  74. Mater Today Bio. 2026 Apr;37 102934
    Orchestrating diabetic wound repair via mitochondria-targeted delivery of dihydromyricetin with tailored ADSC-derived biohybrid nanovesicles.
    Guoyong Jiang, Jiahe Guo, Chengqi Yan, Chengcheng Li, Zhichao Ruan, Xiangrui Li, Yingjie He, Siju Liu, Chi Zhang, Yufeng Wang, Xinyu Zeng, Xiang Xu, Sijia Duan, Chunlei Yuan, Zhenbing Chen, Xiaofan Yang.
      The therapeutic failure in diabetic wounds often stems from a pathological disconnect between antioxidant signaling and mitochondrial repair, a core limitation that conventional antioxidative approaches fail to address. Although targeting mitochondrial dysfunction presents a promising therapeutic avenue, conventional strategies often fail to reconcile efficient targeting of impaired organelles with high biocompatibility. To address this limitation, a biohybrid nanovesicle (designated DHM@mtABV) was engineered by fusing ADSC-derived nanovesicles (ANVs) with synthetic liposomes that co-encapsulate the antioxidant dihydromyricetin (DHM) and the mitochondria-targeting ligand TPP (DHM@mtLipo). The resulting DHM@mtABV nanovesicles demonstrated exceptional biocompatibility and pronounced mitochondrial accumulation. Functionally, DHM@mtABV effectively broke the vicious cycle of oxidative stress by simultaneously scavenging mitochondrial ROS and activating the cytoprotective NRF2 signaling pathway. Consequently, DHM@mtABV treatment significantly restored mitochondrial membrane potential and calcium homeostasis, enhanced cellular proliferation and migration under oxidative stress, and markedly accelerated wound closure in a diabetic mouse model. This work not only presents a potent therapeutic but also validates a generalizable biohybrid strategy that reconstitutes the critical link between subcellular targeting and systemic tissue repair, offering a transformative paradigm for treating refractory diabetic wounds.
    Keywords:  Biohybrid nanovesicles; Diabetic wound; Drug delivery; Mitochondrial homeostasis; Mitochondrial targeting; Oxidative stress
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102934
  75. Microvasc Res. 2026 Feb 23. pii: S0026-2862(26)00020-8. [Epub ahead of print] 104920
    Formononetin, an active component of RAS-RH, ameliorates radiation-induced mitochondrial fission dysfunction in endothelial cells via TCs-ECs crosstalk.
    Ai Liu, Weijie Lu, Hugang Jiang, Linchan Li, Zeao Guo, Jiakun Liu, Guoci Lu, Jianfang Yuan, Xinke Zhao, Yingdong Li.
       OBJECTIVE: This study aimed to investigate the mechanisms by which the ultrafiltrate of Radix Angelicae Sinensis and Hedysari (RAS-RH) and its active component formononetin alleviate X-ray radiation-induced injury in rat cardiac microvascular endothelial cells (CMECs) through modulation of cardiac telocytes (TCs)-mediated paracrine signaling.
    METHODS: An in vitro radiation-induced CMEC injury model was established. Mitochondrial function, proliferation, migration, angiogenesis, and apoptosis were assessed using transmission electron microscopy, flow cytometry, mitochondrial probes, 5-ethynyl-2'-deoxyuridine staining, wound-healing and tube-formation assays, Western blotting, and immunofluorescence. Single-cell RNA sequencing, network pharmacology, molecular docking, and molecular dynamics simulations were used to identify formononetin as the key active component of RAS-RH and to predict its regulatory targets. Reverse transcription quantitative real-time polymerase chain reaction and in situ hybridization further validated the underlying mechanisms.
    RESULTS: X-ray radiation decreased the mitochondrial membrane potential, increased reactive oxygen species levels, and upregulated the expression of mitochondrial fission-related proteins: mitochondrial fission 1 protein (Fis1), dynamin-related protein 1,and mitochondrial fission factor, thereby inducing mitochondrial dysfunction. These changes suppressed endothelial cells (ECs) proliferation, migration and tube formation and downregulated the expression of endothelial growth factors, such as vascular endothelial growth factor, basic fibroblast growth factor, and angiopoietin-2. In contrast, formononetin, as the active component of RAS-RH upregulated androgen receptor (AR) transcription in TCs and enhanced the expression and paracrine release of TCs-derived miR-151a-5p, which subsequently downregulated Fis1 expression in ECs and inhibited Fis1-mediated excessive mitochondrial fission. Through these mechanisms, formononetin attenuated X-ray-radiation-induced endothelial dysfunction.
    CONCLUSION: Formononetin, the active component of RAS RH, mediates TCs-ECs crosstalk through the AR/miR-151a-5p/Fis1 axis, which represents the core mechanism for inhibiting excessive mitochondrial fission in ECs and alleviating EC injury.
    Keywords:  Formononetin; Mitochondrial fission; RAS-RH; TCs-ECs crosstalk; miR-151a-5p
    DOI:  https://doi.org/10.1016/j.mvr.2026.104920
  76. Phytomedicine. 2026 Feb 21. pii: S0944-7113(26)00234-5. [Epub ahead of print]153 157997
    Ginsenoside Rg2 ameliorates acute cold exposure/rewarming-induced myocardial injury via modulating HMGB1/TLR4/NF-κB and PGC-1α signaling pathways: Role of SIRT1.
    Shunfang Zuo, Wenwen Fu, Wenli Ma, Huifeng Wang, Shuting Feng, Han Sun, Zihao Zhang, Linyu Li, Yan Xue, Huali Xu.
       BACKGROUND: Acute cold exposure (ACE) is a significant environmental stressor that markedly increases the risk of cardiovascular complications; however, the precise mechanisms underlying the resultant myocardial injury remain incompletely understood. Ginsenoside Rg2 (Rg2), a key bioactive component of Panax ginseng, confers significant cardioprotective benefits. Despite this, the therapeutic potential and specific mechanisms of Rg2 in attenuating acute cold exposure/rewarming (ACE/R)-induced myocardial injury require further clarification.
    PURPOSE: The objective of this study was to clarify the cardioprotective efficacy of Rg2 and delineate the underlying molecular mechanisms in rats with ACE/R-induced myocardial injury.
    METHODS: In vivo and in vitro models of cold-induced injury were established, including an ACE/R rat model and a mild hypothermia (MH) model utilizing primary rat cardiomyocytes. The cardioprotective effects of Rg2 were evaluated in vivo using functional assessments (echocardiography and hemodynamics), histological analysis (H&E staining), ultrastructural examination (transmission electron microscopy), and hemorheological, biochemical, and ELISA analyses. In vitro, cell viability and cytotoxicity were assessed using CCK-8 and LDH release assays. An integrated approach was employed to elucidate the mechanisms underlying Rg2 action. Initially, proteomics, molecular docking, molecular dynamics simulations, and CETSA were performed to verify the direct interaction between Rg2 and SIRT1. Subsequently, immunohistochemistry, RT-qPCR, western blot, and Co-IP assays were conducted to evaluate pathway activation in both rat myocardial tissue and primary cardiomyocyte samples. Finally, the indispensable role of SIRT1 in mediating the therapeutic effects of Rg2 was definitively established by integrating genetic ablation (mediated by AAV9 and siRNA) and pharmacological inhibition (using EX527) strategies across both in vitro and in vivo experimental systems.
    RESULTS: Rg2 treatment significantly attenuated ACE/R-induced cardiac injury, as evidenced by improved cardiac function, diminished myocardial inflammation, and mitigated mitochondrial damage. Mechanistically, Rg2 upregulated SIRT1 expression, which suppressed inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway and concurrently ameliorated mitochondrial dysfunction by enhancing mitochondrial biogenesis involving the PGC-1α pathway. Furthermore, both pharmacological inhibition and genetic knockdown of SIRT1 significantly abrogated the cardioprotective effects of Rg2 against ACE/R-induced myocardial injury.
    CONCLUSION: This study provides the first evidence that ginsenoside Rg2 has considerable cardioprotective effects against ACE/R. The cardioprotective mechanism is mediated through SIRT1 activation, which subsequently suppresses the HMGB1/TLR4/NF-κB-mediated inflammatory cascade and enhances PGC-1α-driven mitochondrial biogenesis. By clarifying the pharmacological actions of Rg2 and presenting a fresh perspective on the pathophysiology of ACE/R-induced cardiovascular injury, these results underscore the compound's promise as a treatment.
    Keywords:  Acute cold exposure; Ginsenoside Rg2; HMGB1/TLR4/NF-κB; Mitochondrial biogenesis; Myocardial injury; SIRT1
    DOI:  https://doi.org/10.1016/j.phymed.2026.157997
  77. J Neurochem. 2026 Feb;170(2): e70387
    Integrated Bioinformatics Analysis of Screen Mitochondrial Autophagy-Related Core Genes and Construct Diagnostic Model for Alzheimer's Disease.
    Zhe Gao, Yun Wang, Yanfeng Ren, Juncheng Lyu.
      Identify mitochondrial autophagy genes associated with Alzheimer's disease (AD) and elucidate its underlying pathogenesis and explore potential therapeutic targets. Alzheimer's disease related gene expression data were obtained from the Gene Expression Omnibus database. Mitochondrial autophagy-related genes with a relevance score > 1 were screened based on the GeneCards database. We identified differentially expressed genes using R, followed by functional enrichment and immune cell infiltration analyses. A protein-protein interaction network was constructed based on the STRING database, and key genes were identified by Cytoscape software. A diagnostic model for Alzheimer's disease was subsequently developed based on these key genes. Nine key genes were identified for Alzheimer's disease. Gene Ontology enrichment analysis revealed that the differentially expressed genes (DEGs) were primarily involved in mitochondrial function and nucleotide metabolism. Immune infiltration analysis showed negative correlations between YWHAG and VPS35 expression and M1 macrophage abundance, while RTN4 expression positively correlated with follicular helper T cell abundance. Using logistic regression analysis, a diagnostic model for AD was constructed based on three of the key genes. The model was validated by independent external samples, where area under the curve (AUC) demonstrated its robust and excellent diagnostic performance. The nine key genes identified in this study provide new insights and potential therapeutic targets for elucidating how mitochondrial autophagy influences Alzheimer's disease. The established diagnostic model provides a theoretical basis for personalized diagnosis and treatment of Alzheimer's disease.
    Keywords:  Alzheimer's disease; diagnostic model; differential expression analysis; key genes; mitochondrial autophagy
    DOI:  https://doi.org/10.1111/jnc.70387
  78. Trends Mol Med. 2026 Feb 26. pii: S1471-4914(25)00289-8. [Epub ahead of print]
    Rethinking mitochondria as a target for cancer therapy.
    Lucia Minarrieta, Julie St-Pierre.
      In recent years, numerous studies have highlighted the crucial role of mitochondrial metabolism in cancer progression. This sparked interest in its potential as a target for cancer therapy and prompted the clinical evaluation of multiple drugs targeting mitochondrial metabolism. Regrettably, most have showed limited efficacy and safety, raising concerns about the viability of mitochondrial inhibitors in cancer treatment. However, emerging evidence suggests that shifting the focus away from mitochondrial bioenergetics and targeting other aspects of mitochondrial biology, may have a meaningful impact on cancer progression with milder side effects. In this review, we discuss emerging actionable targets and strategies to tailor the administration of inhibitors of mitochondrial pathways for cancer therapy.
    Keywords:  cancer; metabolism; metastasis; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.molmed.2025.12.002
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