bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–01–25
sixty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
  2. Acetyl-CoA as a metabolic switch for selective mitophagy.
  3. Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.
  4. Mitochondrial dynamics in cisplatin resistance: molecular mechanisms and therapeutic targeting.
  5. EBV-Driven Rewiring of Drp1-Mediated Mitophagy Exacerbates Trichloroethylene-Induced Hypersensitivity Syndrome.
  6. Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.
  7. Lonp1 expression and correlation with mitophagy and immune infiltration markers in colon adenocarcinoma.
  8. Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice.
  9. Geniposide Attenuates Post-Myocardial Infarction Cardiac Remodeling via Parkin-Dependent Suppression of Hyperactivated Mitophagy.
  10. Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.
  11. [Electroacupuncture improves learning-memory ability following cerebral ischemia-reperfusion in rats by regulating mitochondrial fission/fusion of hippocampal neurons].
  12. TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
  13. Mitophagy and Mitochondrial Function Regulation by Traditional Chinese Medicine Small Molecules in Cancer Therapy: Mechanisms, Challenges, and Translational Opportunities.
  14. MTP18 as a prognostic biomarker and therapeutic target in lung adenocarcinoma.
  15. Mitochondrial Dynamics-Related Gene Regulation by Epigenetic Suppression of GCN5 Exerts Neuroprotective Effects in Rotenone-Induced Parkinson's Disease Model.
  16. Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
  17. The Synthetic Cannabinoid ADB-FUBINACA Disrupts Mitochondrial Morphology and Dynamics during Neuronal Differentiation of NG108-15 Cells.
  18. Targeting MFF succinylation: a novel therapeutic strategy for premature ovarian insufficiency by restoring mitochondrial dynamics in granulosa cells.
  19. ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.
  20. Stuxnet balances mitochondria homeostasis by regulating uhg5 and parkin.
  21. Mitochondrial acetyl-CoA reprogramming by the SIRT3-ACSS2-OPA1 axis confers resistance to ferroptosis in Parkinson's disease.
  22. Tetramethylpyrazine Targets HDAC6-Mediated PINK1 Degradation to Alleviate Chronic Intermittent Hypoxia-Induced Injury in Human Bronchial Epithelial Cells (16HBE).
  23. [Regulation of PINK1/Parkin-mediated hippocampal neuronal mitophagy with Shugan Tiaoshen acupuncture for alleviating chronic inflammatory pain and depression comorbidity].
  24. TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer.
  25. Interleukin-1β-stimulated macrophage-derived exosomes improve myocardial injury in sepsis via regulation of mitochondrial homeostasis: experimental research: Erratum.
  26. Dynamic stiffness drives BMSC chondrogenesis via Ihh-regulated H3K18 lactylation/Rcan1 axis and mitochondrial fission remodeling.
  27. Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction.
  28. Questions and comments on "ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation," published in Pharmacological Research (2023).
  29. Bushentongluo formula counteracts BMSCs senescence to alleviate postmenopausal osteoporosis by activating mitophagy via the SENP1-SIRT3 pathway.
  30. Levistilide A from Ligusticum chuanxiong alleviates LPS-induced depression- and anxiety-like behaviors by promoting mitophagy through the SIRT3/PINK1/Parkin pathway.
  31. Reply to letter to the editor questions and comments on "ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation".
  32. Harnessing mitochondrial quality control in oxidative stress and environmental resilience in aquaculture.
  33. [Effects of moxibustion on delaying ovarian aging in mice by activating mitochondrial unfolded protein response and enhancing granulosa cell mitochondrial function].
  34. RNA binding motif protein 15 promotes intracerebral hemorrhage progression by regulating mitophagy through E2F transcription factor 1.
  35. Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy.
  36. Nanocatalytic Mitochondrial Oxidative Stress Amplification and Mitophagy Disruption for Efficient Tumor Catalytic Therapy.
  37. Histone Lactylation Couples FSH-Driven Lactate Metabolism to Mitochondrial Biogenesis by Enhancing HDAC4-Mediated Deacetylation of PGC-1α in Granulosa Cells.
  38. CD36 regulates myogenic differentiation via chronic integrated stress response - implications for muscle aging.
  39. The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.
  40. Targeting the ARRDC3-DRP1 Axis via hUMSC-Derived Exosomal CRYAB for Neuroprotection in Cerebral Ischemia/Reperfusion Injury.
  41. Parkin deficiency impairs female fertility, oocyte development, fertilization and mitochondrial function in mice.
  42. Oridonin ameliorates hyperglycemia-induced bladder injury by promoting AMPK/PINK1/Parkin-mediated mitophagy.
  43. Investigating the mechanism by which telomere dysfunction affects mitochondrial homeostasis in anthracosilicosis using a Terc knockout model.
  44. Internal-Friction Network Piezoelectric Hydrogel Microspheres Achieve Physiological Electrical Adaptation to Regulate Mitochondrial Autophagy in Degenerative Tissues.
  45. Total flavonoids isolated from Fructus Mume (Prunus mume Sieb. et Zucc.) mitigate Parkinson's disease progression by promoting neuronal mitophagy via activation of the CaMKKβ/AMPK signaling pathway.
  46. Treadmill Exercise Attenuates CUMS-Induced Depressive Behaviors by Modulating the UPRmt via the Nrf2/Keap1 Pathway.
  47. Exploring biomarkers of mitochondrial dynamics in polycystic ovary syndrome and the effect of mesenchymal stem cell transplantation on ovarian mitochondria.
  48. Narrative review of mitochondrial dysfunction in aging-related salt-sensitive hypertension: outcomes, mechanisms, and therapeutic implications.
  49. Ginsenoside Rg1 ameliorates depression-like behaviors in mice by inhibiting astrocyte pyroptosis via Cx43-dependent restoration of mitophagy flux.
  50. Role of mitochondrial biogenesis in methanol-induced neurobehavioral changes in rats.
  51. Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
  52. Ginsenoside Rb1-enhanced decellularized extracellular matrix hydrogels ameliorates mitochondrial dysfunction and cellular aging in sepsis-induced acute lung injury.
  53. Investigation of the Expression of Bcl-2 Interacting Protein 3 (BNIP3) and Its Molecular Association With Tumor Hypoxia and Immune Response in Breast Cancer.
  54. SENP3/FIS1-regulated PFC neural mitochondrial fragmentation underlies the mechanism of electroacupuncture attenuating depressive behavior in CUMS mice.
  55. Igniting the Tumor: Targeting Mitochondrial Stress to Prime Breast Cancer for Immunotherapy.
  56. Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review).
  57. SRC suppression attenuates vascular aging by activating FUNDC1-dependent mitophagy.
  58. Mitigating psychological stress-induced cardiac injury: The impact of CB2R agonists on endoplasmic reticulum stress and mitophagy.
  59. Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
  60. Low-dose Simvastatin protects pancreatic cancer cells by promoting mitochondrial autophagy through TFEB.
  61. The mechanism of selenomethionine alleviating fluoride-induced brain injury in carp by regulating mitochondrial dynamics, oxidative stress and neuroinflammation: Integrated analysis of transcriptomics and metabolomics.
  62. The herbal compound miltirone from Salvia miltiorrhiza targets DJ-1 to induce mitophagic dysfunction and ROS-dependent hippo activation in gastric cancer.
  63. UBR4 Attenuates Cisplatin-Induced Acute Kidney Injury by Regulating the HRI-ISR Axis.
  64. β-Hydroxybutyric Acid Inhibits Mitochondrial Biogenesis via the HDAC2/SIRT7 Signaling Pathway After Intestinal Ischemia-Reperfusion.
  65. The dual role of TRPC channel-mediated dysregulation of calcium signaling in regulating mitophagy in early brain injury after subarachnoid hemorrhage.
  66. Mitophagy in gastrointestinal tumors: mechanisms and new targets for immunotherapy.
  67. Unraveling the role of mitochondrial dysfunction in diabetic kidney disease: insights and interventions.
  68. Exposure to 77PD quinone inhibits longevity and healthspan via affecting mitochondrial signals in Caenorhabditis elegans.
  69. Protopanaxatriol restores cognitive function in okadaic acid-treated mice via direct inhibition of pathological CDK5 activity.
  1. Autophagy. 2026 Jan 22.
    C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
    Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.
      Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.
    Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2621110
  2. Autophagy. 2026 Feb;22(2): 235-237
    Acetyl-CoA as a metabolic switch for selective mitophagy.
    Daolin Tang, Rui Kang, Daniel J Klionsky.
      A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.
    Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2593032
  3. bioRxiv. 2025 Dec 07. pii: 2025.12.03.692150. [Epub ahead of print]
    Neddylation Regulates Mitochondrial Dynamics and Turnover in the Adult Heart.
    Jianqiu Zou, Wenjuan Wang, Chen Qu, Lingxian Zhang, Josue Zambrano-Carrasco, Yilang Li, Yi Lu, Hongyi Zhou, Kunzhe Dong, Tohru Fukai, Masuko Ushio-Fukai, Dawn Bowles, Michelle Mendiola Pla, Ryan Gross, Weiqin Chen, Jiliang Zhou, Jie Li, Huabo Su.
       BACKGROUND: Disruption of mitochondrial homeostasis drives cardiomyopathy and heart failure, yet upstream regulatory mechanisms remain poorly defined. Neddylation, a reversible post-translational conjugation of the ubiquitin-like protein NEDD8 by E1/E2/E3 enzymes, is essential for cardiac morphogenesis, but its role in the adult heart is unknown.
    METHODS: We assessed the relevance of neddylation to human cardiac disease by gene set enrichment analysis of ischemic (ICM) and non-ischemic cardiomyopathy (NICM) datasets and by immunoblotting and qPCR of ventricular tissue from patients with ICM or dilated cardiomyopathy (DCM). In adult mice, we induced cardiomyocyte-restricted deletion of the NEDD8-activating enzyme 1 (NAE1) by tamoxifen injection and monitored cardiac function at baseline and after transverse aortic constriction (TAC). Bulk RNA-seq 4 weeks post-tamoxifen was combined with bioenergetic, biochemical, and ultrastructural analyses. To assess mitochondrial dynamics, we generated NAE1/MFN2 and NAE1/DRP1 double-knockout mice. Cullin activity, mitochondrial ubiquitination, and mitophagy were measured in hearts and cultured cardiomyocytes.
    RESULTS: Neddylation pathways were dysregulated in human ICM and NICM datasets and in failing ICM/DCM myocardium. Cardiomyocyte-specific NAE1 deletion caused systolic dysfunction and heart failure by 10 weeks post-tamoxifen, culminating in premature death and exacerbating TAC-induced pressure-overload heart failure. At 4 weeks, NAE1 loss repressed metabolic and mitochondrial bioenergetic programs, reduced ATP production, and impaired respiration. Electron microscopy revealed elongated mitochondria and accumulated mitophagic vesicles, with dysregulation of DRP1, MFN2, PINK1, LC3-II, and p62. DRP1/NAE1 co-deletion accelerated systolic failure relative to either single knockout, whereas MFN2/NAE1 co-deletion did not alter early disease progression, implicating pathogenic mitochondrial hyperfusion. Genetic NAE1 depletion in vivo and pharmacologic NAE1 inhibition in vitro impaired mitophagic vesicle formation and flux, inactivated cullin scaffold proteins, reduced mitochondrial ubiquitination, and blunted mitophagic clearance.
    CONCLUSIONS: Cardiac neddylation preserves adult heart function by coordinating mitochondrial fusion-fission dynamics and sustaining cullin-dependent ubiquitination and turnover of damaged mitochondria. These findings identify neddylation as a key regulator of mitochondrial quality control and link its disruption to human cardiomyopathy. Therapeutically, targeting the neddylation-cullin axis may limit mitochondrial dysfunction, enhance mitophagy, and improve energetic reserve in failing hearts, while neddylation signatures in patient myocardium may help guide stratification and precision therapy for cardiomyopathy.
    Clinical Perspective: What Is New?: • Demonstrates for the first time that the NEDD8-activating enzyme (NAE1)driven neddylation pathway is indispensable for maintaining mitochondrial quality control in the adult heart.• Links loss of neddylation to mitochondrial hyperfusion, impaired mitophagy, and rapid progression to heart failure.• Reveals that neddylation promotes cullin-RING ligase-mediated ubiquitination of damaged mitochondria, coupling mitochondrial dynamics with turnover.What Are the Clinical Implications?: • Restoring or enhancing cardiac neddylation may represent a novel therapeutic avenue for cardiomyopathies characterized by mitochondrial dysfunction.• Pharmacologic agents that bolster DRP1-dependent fission or activate cullin neddylation could potentially normalize mitochondrial dynamics and improve myocardial energetics.• Conversely, systemic neddylation inhibitors now in oncology trials warrant careful cardiac monitoring, as they may precipitate mitochondrial injury and heart failure.• Circulating or tissue markers of neddylation might help stratify patients at heightened risk for mitochondrial-driven cardiac disease and guide precision therapy.
    DOI:  https://doi.org/10.64898/2025.12.03.692150
  4. Front Oncol. 2025 ;15 1736487
    Mitochondrial dynamics in cisplatin resistance: molecular mechanisms and therapeutic targeting.
    Wei Huang, Wei Sun, Zhiyuan Yang, Yiwen Li, Ziliang Wang.
      Cisplatin remains a cornerstone of chemotherapy for numerous cancers, despite the persistent challenges of toxicity and the development of drug resistance. Therefore, a deeper understanding of the mechanisms behind cisplatin resistance and the development of strategies to counter it are of critical importance. This review systematically examines the pivotal role of mitochondrial dynamics in cisplatin resistance and discusses emerging therapeutic strategies that target these processes. Mitochondrial dynamics regulate the structure and function of the mitochondrial network through a balance of fusion and fission. Dysregulation of this process directly contributes to cisplatin resistance by maintaining cellular energy homeostasis, inhibiting apoptosis, and enhancing oxidative phosphorylation (OXPHOS). Furthermore, mitophagy, metabolic reprogramming, and the tumor immune microenvironment converge on mitochondrial dynamics to drive the acquisition of drug resistance. Consequently, targeting mitochondrial dynamics presents a promising approach to overcome cisplatin resistance. Potential strategies include restoring the balance of fusion and fission, intervening in mitophagy, disrupting OXPHOS metabolism, and developing mitochondrial-targeted nanodrug delivery systems. However, despite this promising outlook, significant challenges remain, including the heterogeneity of resistance mechanisms, a lack of reliable biomarkers, and the need for selective targeting to minimize off-target effects.
    Keywords:  cisplatin resistance; immune microenvironment; metabolic reprogramming; mitochondrial dynamics; mitophagy; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2025.1736487
  5. Environ Pollut. 2026 Jan 20. pii: S0269-7491(26)00086-2. [Epub ahead of print] 127716
    EBV-Driven Rewiring of Drp1-Mediated Mitophagy Exacerbates Trichloroethylene-Induced Hypersensitivity Syndrome.
    Yuyan Xu, Shuai Liu, Mengnan Yi, Wen Gu, Yican Wang, Guoyong Mei, Jun Han, Yufei Dai.
      The environmental pollutant trichloroethylene (TCE) can induce T-cell-mediated hypersensitivity syndrome. Clinical evidence closely links Epstein-Barr virus (EBV) reactivation to aggravated disease severity, yet the mechanism underlying this chemical-viral synergy remains unknown. Based on the view that hypersensitivity essentially involves sustained activation of effector T-cells and disruption of immune homeostasis, this study aims to investigate how EBV reactivation cooperates with TCE metabolite trichloroethanol (TCOH) to regulate the T-cell apoptosis process by affecting mitochondrial dynamics and autophagy, thereby exacerbating trichloroethylene-induced hypersensitive syndrome (TIHS). Results show that TCOH exposure induces mitochondrial damage and apoptosis in T-cells. However, co-exposure with EBV significantly alleviates TCOH-induced mitochondrial damage by enhancing Drp1-mediated mitochondrial fission and promoting subsequent PINK1/Parkin pathway-dependent mitophagy, which in turn suppresses T-cell apoptosis. In an animal model, administration of the Drp1 inhibitor Mdivi-1 inhibited mitophagy, increased T-cell apoptosis, and effectively alleviated skin and hepatic immune injury in TCE-sensitized mice. This confirms that Drp1 is a key molecular target regulating the T-cell apoptosis program and influencing the progression of TIHS. The study reveals that during TIHS development, EBV reactivation exploits Drp1 to promote mitochondrial fission and mitophagy, thereby hindering the normal apoptotic clearance of activated effector T-cells, leading to their sustained activation and immune attack, which exacerbates tissue inflammation and injury. This finding provides a new scientific perspective for understanding the mechanism by which viral co-exposure aggravates TIHS.
    Keywords:  Drp1; Trichloroethylene; Trichloroethylene-induced hypersensitivity syndrome; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.1016/j.envpol.2026.127716
  6. Redox Biol. 2026 Jan 17. pii: S2213-2317(26)00027-3. [Epub ahead of print]90 104029
    Upregulated GBP2 exacerbates Parkinson's disease pathogenesis by impairing NIX-dependent mitophagy.
    Wenqi Cui, Tianlu Wang, Juan Feng.
      Parkinson's disease (PD), characterized by dopaminergic neuron loss, still lacks disease-modifying therapies due to incompletely understood mechanisms. Guanylate-binding proteins (GBPs) are well-known immune regulators, but their roles in PD are largely unknown. In this study, we identify GBP2 as a critical driver of PD pathogenesis by impairing mitophagy. We found that GBP2 was significantly upregulated in the substantia nigra of PD patients, and in both MPTP-induced and A53T transgenic mouse models, as well as in MPP+-treated or A53T α-synuclein-overexpressing SH-SY5Y cells. Both in vivo and in vitro, genetic knockdown of GBP2 robustly alleviated the MPTP/MPP+-induced motor deficits, dopaminergic neuron loss, and apoptosis. Mechanistically, PD-related stress promotes GBP2 geranylgeranylation, driving its mitochondrial accumulation. At mitochondria, GBP2 directly binds the mitophagy receptor NIX via its large GTPase domain and targets it for ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy. Accordingly, GBP2 knockdown enhanced mitophagy, improved mitochondrial homeostasis, and protected against neuronal apoptosis. The neuroprotective effects of GBP2 knockdown were abolished by either pharmacological inhibition of mitophagy or genetic knockdown of NIX, indicating a linear pathway. Importantly, therapeutically targeting geranylgeranylation with GGTI298 significantly attenuated MPTP-induced neurotoxicity. Our study unveils a novel, druggable axis in PD pathogenesis where GBP2 disrupts mitochondrial quality control. Targeting GBP2 geranylgeranylation with GGTI298 presents a promising therapeutic strategy.
    Keywords:  GBP2; Geranylgeranylation; Mitochondrial dysfunction; Mitophagy; NIX; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.redox.2026.104029
  7. Histol Histopathol. 2026 Jan 22. 25037
    Lonp1 expression and correlation with mitophagy and immune infiltration markers in colon adenocarcinoma.
    Giada Zanini, Valentina Selleri, Giorgia Sinigaglia, Giulia Micheloni, Isabella Martusciello, Stefania Caramaschi, Milena Nasi, Luca Reggiani Bonetti, Marcello Pinti.
      LONP1, a mitochondrial ATP-dependent protease, plays a crucial role in mitochondrial homeostasis by regulating protein turnover and mitophagy. Recent studies have highlighted its upregulation in various cancers, including colorectal cancer (CRC). This study investigates the expression of LONP1 in colon adenocarcinoma (COAD) and its correlation with mitophagy-related proteins and immune infiltration markers. Using publicly available databases and immunohistochemical analysis of 50 COAD patient samples, we confirmed that LONP1 expression is significantly elevated in COAD compared with normal tissue. High LONP1 levels were associated with tumor progression, TP53 mutation status, and poor prognosis. Correlation analyses revealed that LONP1 is closely linked to mitochondrial dynamics, mitophagy regulators (PINK1, AMBRA1, FUNDC1), and metabolic reprogramming. Additionally, LONP1 expression positively correlated with tumor-infiltrating lymphocytes, particularly CD8+ T cells, suggesting a potential role in immune evasion. Immunohistochemical analysis distinguished two patterns: high LONP1/low TOMM20 expression associated with aggressive tumors and low LONP1/high TOMM20 expression linked to better outcomes and stronger immune infiltration. These findings suggest that LONP1 contributes to tumor progression through mitochondrial regulation and immune modulation, highlighting its potential as both a prognostic biomarker and a therapeutic target in COAD.
    DOI:  https://doi.org/10.14670/HH-25-037
  8. Life Sci Space Res (Amst). 2026 Jan;pii: S2214-5524(25)00127-0. [Epub ahead of print]48 156-165
    Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice.
    Carla Mc Nascimento, James D Fluckey, Florence Lima, Brandon R Macias, Yasaman Shirazi-Fard, Elizabeth S Greene, Leslie A Braby, Susan A Bloomfield, Michael P Wiggs.
      Spaceflight places astronauts under both reduced mechanical loading and ionizing radiation, each of which can compromise skeletal muscle health. We investigated whether 21 days of simulated lunar gravity (one sixth G) with or without a single 0.5 Gy dose of 28Si heavy ion radiation alters transcriptional regulators of mitochondrial quality control in mouse gastrocnemius muscle. Female BALB/cByJ mice were assigned to four groups: Sham + 1 G (SHAM+CC), Rad + 1 G (RAD+CC), Sham + G/6 (SHAM+G/6), Rad + G/6 (RAD+G/6) and relative mRNA levels of key regulators of mitochondrial biogenesis, mitophagy, dynamics and electron transport chain content were measured by quantitative RT-PCR. Radiation significantly suppressed PGC-1α (p = 0.035) and TFAM (p = 0.051) transcripts and reduced LC3b (p = 0.033) and Park2 (p = 0.007) expression; no effects of simulated lunar gravity or interaction effects were detected. Composite scores confirmed suppression of biogenesis (p = 0.029) and a trend toward reduced mitophagy (p = 0.057). Transcripts encoding oxidative phosphorylation subunits and fusion and fission factors remained unchanged, suggesting preserved mitochondrial content and network homeostasis at day 21. These findings indicate that a single space relevant heavy ion exposure selectively disrupts early transcriptional steps of mitochondrial turnover without immediately altering organelle abundance of transcripts for electron transport chain or dynamics; in contrast simulated lunar gravity alone did not elicit changes in these pathways.
    Keywords:  Autophagy; Biogenesis; Dynamics; Fission; Fusion; Spaceflight
    DOI:  https://doi.org/10.1016/j.lssr.2025.10.008
  9. Curr Med Chem. 2026 Jan 13.
    Geniposide Attenuates Post-Myocardial Infarction Cardiac Remodeling via Parkin-Dependent Suppression of Hyperactivated Mitophagy.
    Yang Wei, Qian Zhou, Dan Li, Honghong He, Yao Su, Guanglei Chang, Youqin Jiang.
       BACKGROUND: Cardiac remodeling Post-Myocardial Infarction (MI) drives heart failure. Geniposide (GP), a traditional Chinese medicine-derived compound, exhibits cardioprotective potential, yet its mechanisms remain unclear. This study explored the GP's role in post-MI remodeling via Parkin-dependent mitophagy.
    METHODS: Murine MI and cardiomyocyte Chronic Hypoxia (CH) models were established. MI mice received GP; cardiac function, histopathology, apoptosis, fibrosis/autophagy markers, and mitochondrial clearance were assessed. in vitro, Parkin-silenced hypoxic cardiomyocytes were used to evaluate GP's effects on viability, oxidative stress, mitochondrial function, autophagy proteins, and autophagosome formation.
    RESULTS: in vivo, GP improved cardiac function, reduced fibrosis/apoptosis, and suppressed fibrosis-related genes (Col1a1, Col3a1, Tgfb1, Mmp9). GP enhanced clearance of damaged mitochondria via autophagy, mitigating oxidative stress. in vitro, GP's protection against hypoxia required Parkin: it preserved mitochondrial homeostasis, inhibited ROS-mediated apoptosis, and reduced autophagosome accumulation. Mechanistically, GP attenuated excessive mitophagy by modulating Parkin, thereby maintaining mitochondrial quality and reducing oxidative injury.
    CONCLUSION: GP alleviates post-MI remodeling by suppressing Parkin-dependent hyperactivated mitophagy, reducing cardiomyocyte loss and fibrosis. Parkin is central to GP's therapeutic effects, highlighting its potential as a target for MI-related heart failure. This study elucidates GP's cardioprotective mechanism and proposes Parkin pathway modulation as a novel strategy to counteract pathological cardiac remodeling.
    Keywords:  Geniposide; Parkin; cardiac fibrosis.; cardiac remodeling; mitophagy; myocardial infarction
    DOI:  https://doi.org/10.2174/0109298673402330251125051751
  10. Aging Adv. 2025 Dec 18.
    Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.
    C Nivedya, Prasanna Venkhatesh, Benjamin I Rodriguez, Han Le, Jeremiah Afolabi, Andrea Marshall, Kit Neikirk, Sepiso K Masenga, Muhammad Aftab, Leo Jake Kazma, Prasanna Katti, Antentor Hinton.
      Mitochondrial function is crucial in regulating cellular activity and determining cell fate. The replication and transcription of mitochondrial DNA are essential for maintaining mitochondrial integrity. These processes are governed by mitochondrial fission and fusion, which play a vital role in energy distribution, quality control, and metabolic regulation. Mitochondrial fission relies on the coordinated actions of mitochondria-endoplasmic reticulum contact sites, actin filaments, and dynamin-related protein 1, which collectively mediate mitochondrial constriction and fission. This interplay is fundamental to mitochondrial homeostasis and, critically, to the functionality of skeletal muscle. In this review, we explore the complex interactions among dynamin-related protein 1, mitochondria-endoplasmic reticulum contact sites, and actin and their significance for skeletal muscle function. Additionally, we discuss potential strategies to preserve these interactions, supporting optimal muscle performance in skeletal muscle aging. This review provides key insights and outlines future research directions to advance our understanding of this essential yet widely studied relationship.
    Keywords:  dynamin-related protein 1 (DRP1); exercise interventions; fission and fusion; mitochondria quality control; mitochondrial dynamics; mitochondria–endoplasmic reticulum contact sites (MERCs); mitophagy; posttranslational modifications; sarcopenia; skeletal muscle aging
    DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00013
  11. Zhen Ci Yan Jiu. 2026 Jan 25. pii: 1000-0607(2026)01-0011-10. [Epub ahead of print]51(1): 11-20
    [Electroacupuncture improves learning-memory ability following cerebral ischemia-reperfusion in rats by regulating mitochondrial fission/fusion of hippocampal neurons].
    Lu-Lu Chen, Kai-Qi Su, Bo-Fei Chen, Ya-Min Wang, Guang-Hua Liu, Yi-Bo Wang, Yu-Qi An, Nan-Nan Liu, Hao Liu, Jing Gao, Xiao-Dong Feng.
       OBJECTIVES: To observe the effect of electroacupuncture (EA) on mitochondrial fission/fusion in rats with learning-memory impairment induced by cerebral ischemia-reperfusion (CI/R), so as to explore its potential neuroprotective mechanisms against the ischemic reperfusion injury of hippocampal neurons.
    METHODS: Male SD rats were randomly divided into normal, sham-operation, model, and EA groups, with 12 rats in each group. The CI/R model was established by middle cerebral artery occlusion and reperfusion by using the intraluminal suture method. After successful modeling, rats in the EA group received EA (2 Hz/10 Hz, 6 V) at "Shenting"(GV24) and "Baihui" (GV20) for 30 min, once daily for 14 consecutive days. The rats' learning-memory ability was evaluated using the novel object recognition test and Morris water maze test. The cerebral infarct volume was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. Hippocampal neuronal morphology was examined by HE staining, and the mitochondrial morphology and structure of hippocampal neurons were observed using transmission electron microscopy. The adenosine triphosphate (ATP) content in the hippocampal tissue was measured using colorimetry, and mitochondrial DNA (mtDNA) copy number was detected by qPCR. The relative protein and mRNA expression levels of mitochondrial fusion proteins 1/2 (MFN1/2), optic atrophy protein 1 (OPA1), dynamin-related protein 1 (DRP1), and fission protein 1 (FIS1) in the hippocampal tissue were detected by Western blot and qPCR respectively.
    RESULTS: No significant differences were found between the normal and sham-operation groups in all the indices. Compared with the sham-operation group, the model group exhibited a significant increase in the escape latency of Morris water maze test from the 3rd to the 5th day, brain infarction volume, expression levels of DRP1 and FIS1 protein and mRNA (P<0.01, P<0.05), and a significant decrease in the novel object recognition index, crossing number of the original target platform in Morris water maze test, copy number of mtDNA, ATP content, and the expression levels of MFN1, MFN2, and OPA1 protein and mRNA (P<0.01, P<0.05). In comparison with the model group, both the increased levels of the escape latency, brain infarction volume, expressions of DRP1 and FIS1 protein and mRNA, and the decreased levels of the novel object recognition index, crossing number of the original target platform, copy number of mtDNA, ATP content, and the expressions of MFN1, MFN2, and OPA1 protein and mRNA were reversed in the EA group (P<0.01, P<0.05). Histological examination showed that in the model group, the hippocampal neurons were loosely arranged, with extensive vacuolar degeneration and necrosis, swollen and ruptured mitochondria, irregular mitochondrial membrane, and disappearance of cristae, while in the EA group, hippocampal neurons were closely arranged and relative intact in the morphology, with relatively complete mitochondria, and clear cristae.
    CONCLUSIONS: EA can improve the learning-memory ability in CI/R rats which may be related to its functions in inhibiting the mitochondrial fission and promoting mitochondrial fusion, thus maintaining mitochondrial function and structural stability.
    Keywords:  Cerebral ischemia/reperfusion; Electroacupuncture; Hippocampal neuron; Learning-memory ability; Mitochondrial fission/fusion
    DOI:  https://doi.org/10.13702/j.1000-0607.20241223
  12. FASEB J. 2026 Jan 31. 40(2): e71467
    TFAM-Associated Mitochondrial Dynamics and Metabolic Reprogramming Regulate Microglial Polarization: Temporal and Causal Perspectives.
    Yuxuan Zhang, Ximeng Wang, Dachuan Li, Xiao Lu, Zhaoyang Gong, Zhidi Lin, Hanqiu Sun, Hongli Wang, Zian Lu, Xiaosheng Ma, Guangyu Xu, Jianyuan Jiang.
      The polarization state of microglia exerts an influence on neuroinflammation and neural tissue repair after injury. Modulating microglial polarization is emerging as a potential therapeutic strategy for various types of neural injuries and neurodegenerative diseases. However, the causal relationship between microglial polarization and mitochondrial dynamics, which include mitochondrial fusion and fission, remains to be fully clarified. Our study demonstrates that mitochondrial fusion promoter M1 promotes mitochondrial fusion in mouse microglial cells, leading to reduced glycolysis and increased fatty acid oxidation, and this metabolic reprogramming impacts microglial polarization. Additionally, in both cellular and animal experiments, it was observed that knocking down mitochondrial transcription factor A (TFAM) results in increased mitochondrial fission, decreased fatty acid β-oxidation, enhanced glycolysis, and promotes the polarization of microglia toward the pro-inflammatory M1 phenotype. In conclusion, our study has, for the first time, provided evidence that TFAM may play a role in the regulation of mitochondrial dynamics. Furthermore, we provide a detailed elucidation of the chronological sequence and underlying causal relationships among mitochondrial dynamics, mitochondrial metabolic reprogramming, and microglial polarization. These findings offer novel targets and strategies for the treatment of various neural injuries and neurodegenerative diseases.
    Keywords:  TFAM; cell polarization; fatty acid oxidation; glycolysis; metabolism; microglia; mitochondria
    DOI:  https://doi.org/10.1096/fj.202503182RR
  13. Phytother Res. 2026 Jan 22.
    Mitophagy and Mitochondrial Function Regulation by Traditional Chinese Medicine Small Molecules in Cancer Therapy: Mechanisms, Challenges, and Translational Opportunities.
    Zixuan Shi, Lipeng Wang, Zifan Wang, Yifei Ma, Erling Li, Peirong Xu, Tianli Fan, Guiqin Hou.
      In recent years, small molecules derived from traditional Chinese medicine (TCM) have garnered increasing attention in anticancer research due to their well-defined structures, multi-target regulatory capabilities, and low toxicity. Mitophagy, a critical process for selectively clearing damaged mitochondria and maintaining cellular homeostasis, plays a significant role in tumor development. This review explores the types and molecular mechanisms of mitophagy, its dual role in tumor progression, and its functions across various cancers. We also summarize 21 representative TCM-derived small molecules, such as ginsenosides, oridonin, and sanguinarine, which directly or indirectly regulate key mitophagy-related signaling pathways, including PINK1/Parkin and BNIP3/NIX. These TCM small molecules modulate mitophagy and mitochondrial function, induce tumor cell apoptosis, overcome drug resistance, and improve the tumor microenvironment. This review systematically integrates the molecular mechanisms of mitophagy and its dynamic regulation in cancer, highlighting how TCM small molecules maintain mitochondrial homeostasis, remodel the tumor microenvironment, and reverse therapeutic resistance. It aims to provide a theoretical foundation for future research on anticancer TCM and to inspire the clinical development of effective, low-toxicity, mitochondria-targeted therapies.
    Keywords:  TCM molecules; cancer; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.1002/ptr.70210
  14. Respir Res. 2026 Jan 20.
    MTP18 as a prognostic biomarker and therapeutic target in lung adenocarcinoma.
    Qixuan Li, Yijie Tang, Han Su, Youlang Zhou, Tianyi Wang, Jiahai Shi.
       BACKGROUND: Increasing evidence indicates that tumor cells alter mitochondrial morphology, regulated through fusion, fission, and mitophagy, to meet the demands of rapid proliferation and enhance survival. As a key regulator of mitochondrial dynamics, the biological role and mechanism of MTP18 in lung adenocarcinoma (LUAD) remain unclear.
    METHODS: MTP18 expression and prognostic value were analyzed using TCGA datasets and validated in clinical cohorts via qRT-PCR and IHC. Functional assays (CCK-8, Transwell, flow cytometry) were performed in MTP18-overexpressing or silenced A549 and PC9 cells. The regulatory mechanism involving mitochondrial dynamics, reactive oxygen species (ROS), and the PI3K/AKT pathway was elucidated using specific pharmacological modulators (Mdivi-1, MYLS22, NAC, H2O2, LY294002, 740Y-P) and transmission electron microscopy.
    RESULTS: MTP18 was significantly upregulated in LUAD and correlated with poor patient survival. Functionally, MTP18 overexpression promoted cell proliferation, metastasis, and S-phase entry, while inhibiting apoptosis. Mechanistically, MTP18 induced excessive mitochondrial fission, leading to a robust accumulation of intracellular ROS. This elevated oxidative stress acted as a second messenger to trigger the phosphorylation of PI3K and AKT. Blocking fission or scavenging ROS effectively abrogated MTP18-mediated pathway activation and malignant phenotypes. Additionally, preliminary analysis suggested an association between MTP18 and an immunosuppressive microenvironment.
    CONCLUSIONS: MTP18 functions as a novel oncogenic driver in LUAD by orchestrating a "fission-ROS-PI3K/AKT" signaling axis. Targeting MTP18-mediated mitochondrial dynamics offers a promising therapeutic strategy to disrupt both tumor growth and metabolic adaptation in LUAD.
    Keywords:  Immune microenvironment; MTP18; Mitochondrial dynamics; PI3K/AKT; ROS
    DOI:  https://doi.org/10.1186/s12931-026-03519-3
  15. Mol Neurobiol. 2026 Jan 21. 63(1): 383
    Mitochondrial Dynamics-Related Gene Regulation by Epigenetic Suppression of GCN5 Exerts Neuroprotective Effects in Rotenone-Induced Parkinson's Disease Model.
    Gökçe Ceren Kuşçu, Ezgi Tut, Çevik Gürel, Aylin Buhur, Özgün Selim Germiyan, Çığır Biray Avcı, Cem Güler, Ebru Şancı, Nefise Ülkü Karabay Yavaşoğlu, Altuğ Yavaşoğlu.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and mitochondrial dysfunction. Recent studies implicate the histone acetyltransferase GCN5 in regulating mitochondrial homeostasis and oxidative stress. This study investigated the therapeutic potential of GCN5 silencing via systemically administered siRNA-loaded niosomes in a rotenone-induced rat model of PD. Niosomes were prepared using the thin-film hydration method, and the most effective siRNA sequence was selected through real time quantitative PCR (RT-qPCR) and immunofluorescence in primary mesencephalic neurons. Adult male rats were divided into four groups (n = 24/group), and PD was induced with rotenone (2 mg/kg/day, s.c., for 35 days). Behavioral assessments, biochemical analyses, IVIS imaging, histopathology, immunohistochemistry, and RT-qPCR were conducted. IVIS confirmed brain accumulation of siRNA-niosomes within 3-5 h post-injection. GCN5 siRNA treatment significantly improved locomotor activity (p < 0.05), decreased MDA levels (p < 0.05), and restored SOD and dopamine levels (p < 0.05). Molecular findings showed decreased GCN5 and mitochondrial fission-related gene Drp-1 expression, increased expression of mitophagy and biogenesis markers (↑Parkin, ↑PINK1, ↑Mfn2, ↑PGC-1α), elevated TH expression, and reduced α-synuclein accumulation. Histological analysis revealed preserved midbrain cytoarchitecture and reduced neuronal damage. In conclusion, these findings highlight that epigenetic silencing of GCN5 via siRNA-loaded niosomal delivery provides neuroprotection in PD by modulating the expression of genes involved in mitochondrial dynamics, offering preclinical support for its development as a novel therapeutic strategy.
    Keywords:  GCN5; Mitochondrial dynamics; Niosome; Parkinson’s disease; SiRNA delivery
    DOI:  https://doi.org/10.1007/s12035-026-05700-7
  16. Aging Cell. 2026 Feb;25(2): e70386
    Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
    Wagner S Dantas, Elizabeth R M Zunica, Elizabeth C Heintz, Charles L Hoppel, Cristal M Hill, Christopher D Morrison, Christopher L Axelrod, Gangarao Davuluri, John P Kirwan.
      Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age-related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity-induced cardiac remodeling and inflammaging by activating the AMPK-ULK1 signaling axis and enhancing mitochondrial quality control. In middle-aged male mice with high-fat diet-induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS-STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro-inflammatory mediators, including IRF3 and IFN-γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK-dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.
    Keywords:  bioenergetics; fission; fusion; heart; mitochondria; obesity; quality control
    DOI:  https://doi.org/10.1111/acel.70386
  17. Mol Neurobiol. 2026 Jan 21. 63(1): 382
    The Synthetic Cannabinoid ADB-FUBINACA Disrupts Mitochondrial Morphology and Dynamics during Neuronal Differentiation of NG108-15 Cells.
    Rui Filipe Malheiro, Ana Catarina Costa, Catarina Pereira-Teixeira, Helena Carmo, Félix Carvalho, João Pedro Silva.
      Mitochondria are essential drivers of neuronal growth, differentiation, and overall brain development. Synthetic cannabinoids (SCs) have been shown to enhance neurite outgrowth in NG108-15 neuroblastoma x glioma cells through CB1 receptor activation, while disrupting mitochondrial function. Here, we demonstrated first-hand the impact of biologically-relevant concentrations (< 1μM) of ADB-FUBINACA (an SC commonly identified in drug seizures) on mitochondrial morphology and dynamics (i.e., fusion, fission and mobility) during the neurodifferentiation of NG108-15 cells. Our findings revealed that, during NG108-15 neurodifferentiation, ADB-FUBINACA reduced the mean mitochondrial area and perimeter by around 10%, while increasing mitochondrial circularity, and decreasing network branching and interconnectivity. Specifically, branch length per mitochondrion and branch junctions declined by 17 and 25% in the neurons' soma at the end of NG108-15 differentiation (after 72 h). Moreover, 1 nM and 1 µM ADB-FUBINACA markedly decreased the levels of mitochondrial fusion markers (Opa1 and Mfn2) and increased the levels of fission markers Drp1 and Fis1 at the same time point. The percentage of motile mitochondria in neurites also decreased at 72 h, while average speed and total run length per mobile mitochondrion remained unaffected, resulting in an accumulation of stationary mitochondria which may be important, for example, to support neurite extension. Collectively, these findings suggest that while ADB-FUBINACA promotes mitochondrial accumulation in neurites, potentially supporting the energy demands of developing neurites and influencing neurite outgrowth, in the long-term, the fragmentation of the mitochondrial network in the soma may compromise the maintenance of neurites, in terms of energy requirements.
    Keywords:  Mitochondrial fission and fusion; Mitochondrial network; Mitochondrial transport; Neurodevelopment; New Psychoactive Substances
    DOI:  https://doi.org/10.1007/s12035-026-05699-x
  18. J Ovarian Res. 2026 Jan 19.
    Targeting MFF succinylation: a novel therapeutic strategy for premature ovarian insufficiency by restoring mitochondrial dynamics in granulosa cells.
    Ying Cao, Xiaoyu Tong, Wei Hu, Yicong Wang, Wenhan Lu, Yuning Chen, Junyi You, Yi Feng, Qingxia Song.
      Premature ovarian insufficiency (POI) is a significant clinical disorder characterized by the loss of ovarian function before the age of 40, and its global prevalence is rising. The development of effective therapies is hindered by an incomplete understanding of its pathogenesis. Growing evidence indicates that dysregulated mitochondrial fission in granulosa cells (GCs) is a pivotal contributor to POI, although the upstream regulatory mechanisms remain elusive. This review synthesizes recent findings to propose a novel hypothesis: that aberrant lysine succinylation (Ksucc) of mitochondrial fission factor (MFF) may act as a crucial metabolic switch linking mitochondrial dynamics to ovarian aging. Specifically, hyper-succinylation of MFF at specific residues (e.g., K302) is hypothesized to induce a charge reversal, potentially promoting the excessive recruitment and oligomerization of dynamin-related protein 1 (DRP1) on the mitochondrial membrane. We hypothesize that this leads to mitochondrial fragmentation, bioenergetic deficits, and subsequent apoptosis of GCs and oocytes. This pathogenic cascade is theorized to be driven by a metabolic milieu of elevated succinyl-CoA and diminished desuccinylase activity of SIRT5 in POI. Evidence from related disease models suggests that reversing this imbalance through genetic or pharmacological modulation of SIRT5 can reduce MFF succinylation and restore mitochondrial dynamics. We explore the potential of targeting the SIRT5-MFF axis as a promising therapeutic strategy. Furthermore, detecting elevated MFF succinylation in clinical samples may be explored as a novel diagnostic biomarker for POI, though significant translational hurdles remain.
    Keywords:  Mitochondrial dynamics; Mitochondrial fission factor; Post-translational modification; Premature ovarian insufficiency; Succinylation
    DOI:  https://doi.org/10.1186/s13048-026-01964-8
  19. Sci Rep. 2026 Jan 21.
    ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.
    Saba Qureshi, Stefan Y Kim, Stephanie Lee, Lukas Ritzer, William Steidl, Gayle Joliet Krest, Anisha Kasi, Varun Kumar.
      
    Keywords:  ATF4; Cell survival; ER stress; Mitochondrial stress; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-026-36453-x
  20. Cell Rep. 2026 Jan 17. pii: S2211-1247(25)01627-4. [Epub ahead of print]45(1): 116855
    Stuxnet balances mitochondria homeostasis by regulating uhg5 and parkin.
    Xianguo Zhao, Xingzhuo Yang, Yuansheng Huang, Yifan Zhang, Xiangzhou Cui, Junzheng Zhang, Juan Du.
      Emerging evidence implicates the Stuxnet (Stx) protein in human disease, extending beyond its known role in proteasome-independent degradation. Exploring this further, our investigation into stx downstream targets in Drosophila reveals that loss of the U snoRNA host gene 5 (Uhg5) gene disrupts sleep. This sleep phenotype is linked to inefficient translation of mitochondrial genes, as Uhg5 produces small nucleolar RNAs (snoRNAs) that directly regulate mitochondrial transcripts. Using GoldCLIP technology, we discover that Stx interacts with both Uhg5 and parkin mRNAs. parkin is a key regulator of mitochondrial quality control. Genetic tests confirm functional relationships between stx, Uhg5, and parkin. This study establishes that Uhg5-derived snoRNAs regulate sleep by controlling mitochondrial gene translation. Crucially, our findings propose a model in which Stx coordinates mitochondrial biogenesis (via Uhg5) with mitophagy (via parkin). This provides a molecular link for Stx's potential role in Parkinson's disease pathogenesis.
    Keywords:  CP: molecular biology; CP: neuroscience; Drosophila; RNA binding protein; Uhg5; midnolin; mitochondria; mitochondrial gene translation; parkin; sleep; snoRNA host genes; stuxnet
    DOI:  https://doi.org/10.1016/j.celrep.2025.116855
  21. Redox Biol. 2026 Jan 13. pii: S2213-2317(26)00028-5. [Epub ahead of print]90 104030
    Mitochondrial acetyl-CoA reprogramming by the SIRT3-ACSS2-OPA1 axis confers resistance to ferroptosis in Parkinson's disease.
    Xv-Shen Ding, Bao Wang, Zheng Han, Chen-Xi Feng, Yang-Ni Li, Yu-Fei Wang, Jian-Cai Guru, Jie Cao, Rui-Li Zhang, Xue-Lian Wang, Qian Yang, Yan Qu, Li Gao.
      Mitochondrial dysfunction and ferroptosis have emerged as pivotal contributors to dopaminergic (DA) neuron degeneration in Parkinson's disease (PD). Here, a previously unrecognized SIRT3-ACSS2-OPA1 axis that couples mitochondrial acetyl-CoA (Ac-CoA) metabolism to ferroptosis resistance is identified. Analysis of public human substantia nigra datasets reveals marked reduction in SIRT3 expression, which is further confirmed in 6-OHDA-induced PD models. To establish translational significance, analyses of serum and peripheral blood mononuclear cells (PBMCs) from PD patient cohort demonstrates decreased SIRT3 protein levels and deacetylase activity. Moreover, SIRT3 overexpression inhibits ferroptosis and mitochondrial fragmentation in neurons. Mechanistically, SIRT3 deacetylates and activates acetyl-CoA synthetase 2 (ACSS2), thereby facilitating the redistribution of Ac-CoA from mitochondria to the nucleus, leading to Optic atrophy 1 (OPA1) deacetylation. Meanwhile, this Ac-CoA reprogramming enhances histone H3K27 acetylation at the OPA1 promoter, and thereby drives OPA1 transcriptional upregulation. OPA1 restores mitochondrial homeostasis, alleviates iron accumulation, reduces lipid peroxidation, and ultimately suppresses ferroptosis. In vivo, pharmacological activation of SIRT3 or AAV-mediated Opa1 overexpression mitigates ferroptosis, preserves DA neurons, and improves motor performance in PD mice. This study uncovers mitochondrial Ac-CoA reprogramming as a key defense mechanism against ferroptosis, positioning the SIRT3-ACSS2-OPA1 pathway as a promising therapeutic target for PD.
    Keywords:  Ferroptosis; Mitochondrial acetyl-CoA reprogramming; Mitochondrial dynamics; Parkinson's disease; SIRT3
    DOI:  https://doi.org/10.1016/j.redox.2026.104030
  22. Chem Biol Drug Des. 2026 Jan;107(1): e70236
    Tetramethylpyrazine Targets HDAC6-Mediated PINK1 Degradation to Alleviate Chronic Intermittent Hypoxia-Induced Injury in Human Bronchial Epithelial Cells (16HBE).
    Yanjie Chen, Hongye Chen, Zhixiong Huang, Mulan Deng, Xin Zheng, Qihui Chen.
      Obstructive sleep apnea (OSA) is characterized by recurrent chronic intermittent hypoxia (CIH), which induces oxidative stress, inflammatory responses, and mitochondrial damage in bronchial epithelial cells. Tetramethylpyrazine (TMP) has been shown to exert lung-protective effects in other pathological models, but its role in mitigating CIH-induced 16HBE cell injury and the underlying molecular mechanisms have not been previously investigated. PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy is a critical endogenous mechanism that defends against CIH-induced epithelial damage. However, whether TMP alleviates CIH-induced injury by regulating the PINK1 pathway remains unknown. CIH significantly reduced 16HBE cell viability, increased apoptosis rate, elevated inflammatory responses (IL-6 and TNF-α levels upregulated), and oxidative stress (ROS and MDA levels increased), and inhibited mitophagy (reduced PINK1 and LC3-II/LC3-I ratio, increased p62). TMP treatment improved cell viability in a dose-dependent manner; notably, 20 μg/mL TMP reversed CIH-induced apoptosis, inflammation, and oxidative stress, accompanied by upregulated PINK1 and restored mitophagy. Moreover, HDAC6 knockdown mimicked TMP's benefits (enhanced PINK1 and mitophagy, reduced injury), while concurrent PINK1 silencing reversed this effect. TMP protected 16HBE cells from CIH-induced injury by inhibiting HDAC6-mediated PINK1 deacetylation. This mechanism stabilized PINK1 protein, enhanced mitophagy, and thereby suppressed apoptosis, oxidative stress, and inflammation, identifying the HDAC6/PINK1 axis as a key regulatory pathway in CIH-induced cell injury.
    Keywords:  PTEN‐induced putative kinase 1; chronic intermittent hypoxia; deacetylation; histone deacetylase 6; mitochondrial damage; obstructive sleep apnea; tetramethylpyrazine
    DOI:  https://doi.org/10.1111/cbdd.70236
  23. Zhongguo Zhen Jiu. 2026 Jan 12. 46(1): 85-96
    [Regulation of PINK1/Parkin-mediated hippocampal neuronal mitophagy with Shugan Tiaoshen acupuncture for alleviating chronic inflammatory pain and depression comorbidity].
    Guanghua Liu, Wen Fu, Yisen Wu, Mengyu Wang, Jing Gao, Lihua Wu, Zihua Wang, Dongliang Shi.
       Objective: To observe the effects of Shugan Tiaoshen acupuncture (acupuncture for smoothing liver qi and regulating the mind) on hippocampal neural mitophagy and oxidative stress-related factors in the rats with chronic inflammatory pain and depression comorbidity (CIPDC), and its protective effect on hippocampal neurons; and explore the underlying mechanism of this acupuncture therapy for alleviating CIPDC.
    Methods: Of 60 Sprague-Dawley (SD) rats, 12 rats were randomly selected as the control group. CIPDC models were established by subcutaneous injection with complete Freund's adjuvant (CFA) into the plantar region of the left hind paws of the rest rats. Forty-eight successfully modeled rats were assigned into a model group, an electroacupuncture (EA) group, an inhibitor group and an EA + inhibitor group, 12 rats in each one. In the EA group, EA was applied to "Yintang" (GV24+), "Baihui" (CV20), and bilateral "Hegu" (LI4) and "Taichong" (LR3). Electric stimulation was delivered at "Hegu" (LI4) and "Taichong" (LR3) unilaterally, with disperse-dense wave, a frequency of 2 Hz/10 Hz, and a current of 1 mA. EA was operated for 30 min daily. In the inhibitor group, autophagy inhibitor, 3-methl adenine (3-MA) was injected intraperitoneally. In the EA + inhibitor group, EA was delivered after intraperitoneal injection with 3-MA. The intervention of each group was operated once daily and for 14 consecutive days. Pain threshold was assessed using paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PTWL). Depressive-like behaviors were evaluated using the sucrose preference test, open-field test, and forced swimming test. Hematoxylin and eosin (HE) staining was used to observe the pathological morphology of hippocampal neurons. Fluoro-Jade B staining was performed to assess hippocampal neuronal injury and degeneration. Transmission electron microscopy (TEM) was employed to examine the ultrastructure of hippocampal mitochondria. Hippocampal reactive oxygen species (ROS) expression was detected using flow cytometry. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) in the hippocampus were measured using a colorimetric method. Western blot analysis was conducted to detect the protein expression of sequenstering protein 1 (p62), PTEN induced putative kinase 1 (PINK1), Parkin protein (Parkin), Beclin1, and microtubule-associated protein 1A/1B 1ight chain3 (LC3) in the hippocampus. Real-time PCR was used to detect the mRNA expression of p62, PINK1, Parkin and Beclin1.
    Results: Compared with the control group, in the model group, PWMT, PTWL, sucrose preference rate, total distance traveled in the open field, and time spent in the center area decreased (P<0.05), while the immobility time increased (P<0.05); the mitochondria was ruptured and swollen and the internal crista were broken or disappeared; the content of ROS and MDA elevated (P<0.05) and SOD reduced (P<0.05); the protein and mRNA expression of hippocampal p62, PINK1, Parkin and Beclin 1, as well as the protein expression of LC3 were not different statistically (P > 0.05). Compared with the model group, in the EA group, PWMT, PTWL, sucrose preference rate, total distance traveled in the open field, and time spent in the center area increased (P<0.05), while the immobility time decreased (P<0.05); hippocampal neurons were rounded and neatly arranged, with the number of degenerated neurons declined (P<0.05); the mitochondrial morphology was relatively normal, and the bilayer membrane structure intact, and autophagosomes visible; the content of ROS and MDA reduced (P<0.05) and SOD elevated (P<0.05); the protein and mRNA expression of hippocampal p62 was declined (P<0.05), and the protein and mRNA expression of PINK1, Parkin and Beclin 1 was elevated (P<0.05), and the protein expression of LC3 rose (P<0.05). When compared with the EA group, in the EA + inhibitor group, PWMT, PTWL, sucrose preference rate, total distance traveled in the open field, and time spent in the center area were reduced (P<0.05), while the immobility time was higher (P<0.05); hippocampal neurons were more disarranged, with increased nuclear membrane damage and more degenerated neurons (P<0.05); the damage in mitochondrial bilayers and cristae was obvious; the content of ROS and MDA higher (P<0.05) and SOD lower (P<0.05); the protein and mRNA expression of hippocampal p62 was elevated (P<0.05), and protein and mRNA expression of PINK1, Parkin and Beclin 1 was reduced (P<0.05), and the protein expression of LC3 decreased (P<0.05).
    Conclusion: Shugan Tiaoshen acupuncture presents a protective effect on CIPDC by enhancing hippocampal neuronal mitophagy through regulating the PINK1/Parkin pathway in the model rats.
    Keywords:  PINK1/Parkin pathway; Shugan Tiaoshen acupuncture; chronic inflammatory pain; comorbidity; depression; hippocampal neurons; mitophagy
    DOI:  https://doi.org/10.13703/j.0255-2930.20241115-k0006
  24. Cancer Lett. 2026 Jan 20. pii: S0304-3835(26)00034-0. [Epub ahead of print] 218271
    TMEM11 promotes cisplatin resistance by inhibiting BNIP3-mediated mitophagy in bladder cancer.
    Yuan Huang, Chen Chen, Mingqiang Su, Wanteng Ye, Shu Wei, Kuangye Long, Yunjie Huang, Haiyong Chen, Zhangfeng Zhong, Lina Hou, Jinge Zhang, Wanlong Tan, Fei Li.
      Cisplatin-based chemotherapy stands as the first-line treatment for metastatic bladder cancer (BCa), yet only 35% of patients show initial responsiveness, with resistance commonly developing. Therefore, investigating cisplatin-sensitizing targets is warranted for overcoming resistance. In this study, the transmembrane protein 11 (TMEM11) was explored for its role in mediating cisplatin resistance in BCa. Single-cell and bulk RNA sequencing, together with assay for transposase-accessible chromatin using sequencing were utilized. The analyses revealed that TMEM11 was upregulated in cisplatin-resistant cells and associated with mitochondrial metabolic reprogramming and poor prognosis. Spatial transcriptomics and proteomics further confirmed the spatial co-localization of TMEM11 with metabolic pathways enriched in resistant tumors. Functional experiments demonstrated that TMEM11 inhibited BNIP3-mediated mitophagy and apoptosis, thereby stabilizing mitochondrial function to promote cisplatin resistance. Mechanistically, TMEM11 suppressed BNIP3 and impaired mitophagy flux, leading to enhanced survival of cancer cells under cisplatin stress. In vivo, TMEM11 knockdown reduced tumor growth and sensitized tumors to cisplatin treatment. Furthermore, molecular docking and experimental validation identified Curcumin as a high-affinity TMEM11 inhibitor capable of restoring cisplatin sensitivity. This study uncovered the TMEM11-BNIP3 axis as a novel driver of cisplatin resistance in BCa, and proposed pharmacological targeting of TMEM11 as a precise therapeutic strategy to overcome cisplatin resistance.
    Keywords:  Bladder cancer; Cisplatin resistance; Mitophagy; TMEM11
    DOI:  https://doi.org/10.1016/j.canlet.2026.218271
  25. Int J Surg. 2026 Jan 01. 112(1): 2203
    Interleukin-1β-stimulated macrophage-derived exosomes improve myocardial injury in sepsis via regulation of mitochondrial homeostasis: experimental research: Erratum.
      
    DOI:  https://doi.org/10.1097/JS9.0000000000004644
  26. Biomed Mater. 2026 Jan 19.
    Dynamic stiffness drives BMSC chondrogenesis via Ihh-regulated H3K18 lactylation/Rcan1 axis and mitochondrial fission remodeling.
    Liyang Chen, Heng'an Ge, Centao Liu, Jun Li, Chenglong Huang, Biao Cheng.
       BACKGROUND: Cartilage defects pose significant clinical challenges due to limited regenerative capacity. Dynamic matrix stiffness, mimicking the physiological mechanical microenvironment, shows promise in directing stem cell chondrogenesis, but its molecular mechanisms remain unclear.&#xD;Methods: Bone marrow mesenchymal stem cells (BMSCs) were cultured on engineered hydrogels with static soft (0.033 kPa), dynamic (0.031-0.126 kPa, time-dependent stiffening), and static stiff (0.126 kPa) conditions. We performed siRNA-mediated Ihh knockdown and Rcan1 overexpression, with chondrogenic differentiation assessed via COL2/SOX9 immunofluorescence. For molecular analyses, we conducted qPCR, CUT&Tag-PCR, Western blot, RNA-seq, H3K18la-targeted CUT&Tag sequencing, and transmission electron microscopy (TEM) for mitochondrial morphology assessment.&#xD;Results: Dynamic stiffness significantly enhanced chondrogenic differentiation, as evidenced by immunofluorescence detection of elevated COL2 and SOX9 expression. Ihh mRNA expression levels were upregulated by dynamic stiffness. Transcriptome profiling analysis revealed that Ihh knockdown disrupted the expression of genes involved in the glycolytic pathway, while Western blot results showed that Ihh knockdown inhibited histone H3 lysine 18 lactylation (H3K18la). CUT&Tag sequencing revealed Ihh-dependent H3K18la enrichment at regulatory regions of mitochondria-associated genes, notably Rcan1. Ihh deficiency promoted mitochondrial fission, as evidenced by increased Drp1 and Fis1 mRNA expression levels and direct observation of enhanced mitochondrial fission via TEM. Crucially, Rcan1 overexpression rescued mitochondrial fusion, downregulated fission markers, and reinstated chondrogenic marker expression. Consistently, the LDHA inhibitor FX11 reduced lactate levels, diminished H3K18la, and downregulated Rcan1, confirming the metabolic dependence of this axis. RNA-seq analysis further established that Rcan1 overexpression reprogrammed signaling pathways critical for cell differentiation, including ECM-receptor interaction.&#xD;Conclusion: Dynamic stiffness promotes BMSC chondrogenesis via the Ihh-H3K18la-Rcan1 axis, linking mechanical cues to epigenetic regulation of mitochondrial remodeling and providing a novel target for cartilage repair.
    Keywords:  Bone marrow mesenchymal stem cells (BMSCs); Cartilage repair; Chondrogenesis; Dynamic stiffness matrix; Histone lactylation; Ihh
    DOI:  https://doi.org/10.1088/1748-605X/ae3a29
  27. Redox Biol. 2026 Jan 19. pii: S2213-2317(26)00038-8. [Epub ahead of print]90 104040
    Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction.
    Zhengyu Yu, Hua Lin, Jingran He, Linfeng Li, Zhongwang Wang, Kun Li, Ting Niu, Bingquan Qiu.
      Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO2) derived from L-cysteine catalysis regulated immune cell functions. However, its role in CAR-T cell exhaustion remained unknown. In this study, we identified that SO2 accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8+ T cell and CAR-T cell infiltration and promoted a transcriptional profile consistent with functional exhaustion, leading to impaired antitumor immunity. Tumor cell derived SO2 altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function. Mechanistically, SO2 enhanced interaction of dynamin-related protein 1 (DRP1) and voltage-dependent anion channel 1 and mitochondrial fission via DRP1 sulphenylation at cysteine 607 (Cys607), with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of Cys607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumor immunity. These findings define a novel redox-mediated mechanism of mitochondrial dysfunction in CAR-T cells exhaustion and identify the SO2-DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.
    Keywords:  CAR-T cell exhaustion; CAR-T therapy; DRP1; Mitochondrial dynamics; Multiple myeloma; Sulfur dioxide
    DOI:  https://doi.org/10.1016/j.redox.2026.104040
  28. Pharmacol Res. 2026 Jan 17. pii: S1043-6618(26)00016-2. [Epub ahead of print] 108101
    Questions and comments on "ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation," published in Pharmacological Research (2023).
    Bing Bai, Wenming Bao, Ling Wang, Ningling Kang.
      
    DOI:  https://doi.org/10.1016/j.phrs.2026.108101
  29. Phytomedicine. 2026 Jan 12. pii: S0944-7113(26)00064-4. [Epub ahead of print]152 157827
    Bushentongluo formula counteracts BMSCs senescence to alleviate postmenopausal osteoporosis by activating mitophagy via the SENP1-SIRT3 pathway.
    Shuai Chen, Lingling Yu, Ningsheng Tian, Qilong Zhao, Miaochao Qin, Liansheng Shao, Pengfei Sun, Peng Ma, Junwu Wang, Penghua Fang, Wen Min.
       BACKGROUND: Senescence and impaired osteogenic capacity of bone marrow mesenchymal stem cells (BMSCs) are pivotal pathogenic drivers in the progression of postmenopausal osteoporosis (PMOP). The Bushentongluo formula (BSTLF) is a traditional Chinese herbal prescription that has shown beneficial clinical outcomes in the treatment of PMOP, yet its underlying mechanisms remain unclear.
    PURPOSE: To elucidate the regulatory function and underlying mechanism of BSTLF in mitigating PMOP.
    METHODS: The active ingredients of BSTLF were identified by LC-MS/MS. The ovariectomized (OVX)-induced osteoporosis in mice was utilized to evaluate the effects of BSTLF on bone mass, trabecular structure, and bone strength through micro-CT, histopathology, and biomechanical testing. For in vitro studies, oxidative stress-induced senescence in BMSCs was modeled using H₂O₂, and the impacts of BSTLF on BMSCs proliferation, differentiation, and senescence were analyzed. Subsequently, proteomic sequencing of BMSCs samples was conducted to elucidate the underlying mechanisms of BSTLF regulating BMSCs osteogenic differentiation and senescence. Additionally, further mechanistic investigations, including molecular docking, flow cytometry, immunofluorescence co-localization, co-immunoprecipitation (CO-IP), and siRNA-mediated gene silencing were performed to confirm the involvement of critical signaling.
    RESULTS: In vivo results verified that BSTLF ameliorates trabecular bone loss, structural failure, and diminishes bone strength in OVX-induced osteoporotic mice. Simultaneously, our findings indicated that BSTLF upregulates the levels of osteogenic-related markers while downregulating those of senescence-associated biomarkers. In vitro, BSTLF alleviated oxidative stress-induced BMSCs senescence, suppressed mitochondrial damage, and enhanced BMSCs osteogenic differentiation. Furthermore, proteomic sequencing and functional gene enrichment analysis revealed that mitophagy might be the key pathway by which BSTLF suppresses BMSCs senescence. Subsequently, both in vitro and in vivo assays confirmed that BSTLF activates the PINK1/Parkin pathway-mediated mitophagy and improves the mitochondrial function. Moreover, immunofluorescence co-localization and CO-IP experiments confirmed that BSTLF prevents SENP1-dependent SUMOylation of SIRT3, leading to enhanced mitophagy and restored mitochondrial homeostasis. Critically, SENP1 knockdown by siRNA promoted SIRT3 SUMOylation and eliminated the beneficial effects of BSTLF on osteogenic differentiation and the suppression of senescence in BMSCs.
    CONCLUSION: These findings elucidated that BSTLF could repair mitophagy deficiency via the SENP1-SIRT3 axis and promote osteogenic differentiation of senescent BMSCs, thereby exerting its anti-osteoporosis effect. Our observation provided experimental validation to support the clinical application of BSTLF in PMOP treatment.
    Keywords:  Bushentongluo formula; Mitophagy; Postmenopausal osteoporosis; SENP1; SUMOylation
    DOI:  https://doi.org/10.1016/j.phymed.2026.157827
  30. J Ethnopharmacol. 2026 Jan 17. pii: S0378-8741(25)01839-2. [Epub ahead of print]361 121146
    Levistilide A from Ligusticum chuanxiong alleviates LPS-induced depression- and anxiety-like behaviors by promoting mitophagy through the SIRT3/PINK1/Parkin pathway.
    Jinni Meng, Ping Wei, Heping Yang, Lin Chen, Cheng Peng, Ou Dai, Qinmei Zhou, Liang Xiong.
       ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticumchuanxiong Hort. (Chuanxiong) is a traditional Chinese medicinal herb whose rhizome has been historically and clinically used to treat conditions such as headache, dizziness, and depression. These traditional application broadly correlate with modern diagnoses of cerebrovascular dysfunction, impaired cerebral blood flow, and neuroinflammation. As a characteristic phthalide dimer and major bioactive constituent of Chuanxiong, levistilide A (LA) has shown significant therapeutic potential. However, its specific antidepressant and anxiolytic properties require further clarification.
    AIM OF THE STUDY: This study aimed to assess the efficacy of LA against depression and anxiety, with the further goal of elucidating its underlying molecular mechanisms.
    MATERIALS AND METHODS: A depression- and anxiety-like state was induced in C57BL/6 mice by LPS challenge after which they received therapeutic intervention with different doses of LA. The therapeutic efficacy was assessed by behavioral tests, histopathological analyses, and enzyme-linked immunosorbent assays (ELISA). Concurrently, we assessed microglial activation via immunofluorescence, along with mitochondrial status by measuring reactive oxygen species (ROS) levels with flow cytometry and examining ultrastructure with transmission electron microscopy (TEM). To investigate the cellular mechanisms, LPS-stimulated BV2 cells was established. In this model, autophagic flux was quantitatively measured using Bafilomycin A1 (Baf A1) inhibition assays combined with Western blot analysis of LC3B-II. And mitophagy was evaluated by co-immunofluorescence LC3B with the mitochondrial marker Tomm40 in both BV2 cells and mouse hippocampal CA3. Building on this, computational approaches, along with experimental methodologies including immunofluorescence and western blotting, were utilized to elucidate the underlying molecular mechanisms. Furthermore, SIRT3-specific siRNA (siRNA-SIRT3) was used for further validation.
    RESULTS: The LA treatment demonstrated a notable protective role against LPS-induced depression and anxiety through ameliorating behaviors accompanied by depression- and anxiety-like behaviors, attenuating neuronal damage, downregulating pro-inflammatory cytokine expression levels, and suppressing microglial overactivation. Mechanistically, LA alleviated oxidative stress and mitochondrial dysfunction by reducing ROS accumulation and mitigating mitochondrial damage. In the LPS-induced BV2 cells, LA treatment significantly enhanced autophagic flux, as evidenced by the further accumulation of LC3B-II upon Baf A1 inhibition, which confirmed the promotion of functional autophagy. Concurrently, the increased co-localization of Tomm40 with LC3B upon LA treatment provided direct evidence for mitophagy activation. Molecular docking combined with molecular dynamics simulation analyses revealed robust binding interactions between LA and SIRT3, as well as between SIRT3 and PINK1. Further investigation into the downstream pathway revealed that LA effectively activated the SIRT3/PINK1/Parkin pathway. This was supported by the Western blot analyses. Specifically, LA treatment increased the SIRT3, PINK1, Parkin, and LC3B-II expression levels, while it decreased p62 levels. This result suggested mitophagy activation. An immunofluorescence analysis corroborated this result and revealed increased cytoplasmic colocalization of Tomm40 with LC3B following the LA treatment. Consistent with these findings, LA significantly suppressed neuroinflammation in LPS-stimulated BV2 microglial cells by inhibiting both NO production and the release of pro-inflammatory cytokines. Importantly, LA recapitulated its favorable impacts on mitochondrial function and the SIRT3/PINK1/Parkin signaling cascade in this cellular model.
    CONCLUSIONS: LA serves as a potential therapeutic agent for depression and anxiety through activating mitophagy mediated by the SIRT3/PINK1/Parkin pathway. The results of this study provide scientific evidence for the clinical application of LA in treating depression and anxiety.
    Keywords:  Depression and anxiety; Levistilide A; Mitophagy; SIRT3/PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.jep.2025.121146
  31. Pharmacol Res. 2026 Jan 19. pii: S1043-6618(26)00017-4. [Epub ahead of print] 108102
    Reply to letter to the editor questions and comments on "ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation".
    Juan Wang, Hui Tao, Chao Lu, Jingjing Yang.
      
    DOI:  https://doi.org/10.1016/j.phrs.2026.108102
  32. Vet Res Commun. 2026 Jan 21. 50(2): 121
    Harnessing mitochondrial quality control in oxidative stress and environmental resilience in aquaculture.
    Shuojia Wu, Md Akibul Hasan Bakky, Ming Zhang, Ngoc Tuan Tran, Shengkang Li.
      Mitochondria, as central hubs of cellular metabolism and signaling, play a pivotal role in mediating the physiological response of aquatic animals to environmental stressors, largely through their involvement in oxidative stress pathway and quality control mechanism. Understanding these molecular pathways is crucial for addressing key challenges in both aquaculture and environmental toxicology. Rather than focusing on the established fact of stress induced mitochondrial damage, this review synthesizes current knowledge to highlighting the emerging role of the mitochondrial quality control (MQC) system as a decisive determinant of stress resilience. A key research evolution is documented, showing a shift from describing oxidative stress towards exploiting MQC for adaptation and performance optimization. Furthermore, a novel theoretical framework is proposed, explaining how aquatic animals perceive and respond to environmental stress through a multi-stage process: 'stress perception-metabolic reprogramming-quality control'. This framework not only integrates a wide range of existing research but also pinpoints key intervention points for enhancing stress resilience. Collectively, these findings provide a significant theoretical foundation and practical guidance for stress tolerance breeding in aquaculture, precise environmental management, and sustainable development.
    Keywords:  Environmental stress; Mitochondria; Mitochondrial quality control; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s11259-025-11051-w
  33. Zhen Ci Yan Jiu. 2026 Jan 25. pii: 1000-0607(2026)01-0087-09. [Epub ahead of print]51(1): 87-95
    [Effects of moxibustion on delaying ovarian aging in mice by activating mitochondrial unfolded protein response and enhancing granulosa cell mitochondrial function].
    Yan-Liang Fan, Hong-Xiao Li, Mei-Hong Shen, Ge Lu.
       OBJECTIVES: To investigate the effect of moxibustion on delaying ovarian aging in naturally aging mice and to explore the underlying mechanisms.
    METHODS: Fifteen 2-month-old female SPF ICR mice with regular estrous cycles were included in a 2-month-old group. Thirty 10-month-old female SPF ICR mice were randomly divided into a 10-month-old group and a moxibustion group, with 15 mice in each group. The moxibustion group received alternating moxibustion on bilateral "Shenshu"(BL23) and "Zhongwan" (CV12), "Guanyuan" (CV4) for 10 min every other day, for 21 consecutive days. The vaginal smears were used to observe the estrous cycle irregularities of mice. The serum contents of estradiol (E2), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH) were measured by ELISA. The ovarian morphology was observed by hematoxylin-eosin staining. The contents of adenosine triphosphate (ATP) in granulosa cells were measured by luminescence-based ATP assay. The levels of mitochondrial membrane potential (MMP) of granulosa cells were measured by JC-1 staining. The real-time fluorescence quantitative PCR, Western blot, and immunohistochemistry were used to assess the mRNA and protein expression levels of mitochondrial unfolded protein response (UPRmt)-related signaling pathway components, including activating transcription factor 5 (ATF5), caseinolytic protease P (ClpP), and Lon protease 1 (LONP1) in the ovarian tissues.
    RESULTS: Compared with the 2-month-old group, the 10-month-old group exhibited an increased rate of estrous cycle irregularity (P<0.01), elevated serum FSH contents (P<0.01), decreased E2 and AMH contents (P<0.01), reduced number of follicles at all stages (P<0.01), reduced granulosa cell ATP content and MMP level (P<0.01), decreased positive expression levels of ATF5, ClpP, and LONP1 protein, and diminished expression levels of ATF5, ClpP, and LONP1 mRNA and protein in ovarian tissue (P<0.01). Compared with the 10-month-old group, the moxibustion group showed a lower rate of estrous cycle irregularity (P<0.01), decreased serum FSH content (P<0.01), increased E2 and AMH contents (P<0.01), increased the number of primordial, growing and antral follicles (P<0.05, P<0.01), elevated granulosa cell ATP content and MMP level (P<0.01), increased ATF5, ClpP, and LONP1 protein positive expression levels, and enhanced ATF5, ClpP, and LONP1 mRNA and protein expression levels in the ovarian tissue (P<0.01, P<0.05).
    CONCLUSIONS: Moxibustion can delay ovarian dysfunction related to natural aging in mice and modulate hormonal levels. Its mechanism may involve regulating the expressions of UPRmt-related signaling molecules such as ATF5, ClpP and LONP1, and enhancing mitochondrial function in granulosa cells.
    Keywords:  Activating transcription factor 5; Mitochondrial function; Mitochondrial unfolded protein response; Moxibustion; Ovarian aging
    DOI:  https://doi.org/10.13702/j.1000-0607.20241300
  34. Arch Biochem Biophys. 2026 Jan 20. pii: S0003-9861(26)00017-2. [Epub ahead of print] 110746
    RNA binding motif protein 15 promotes intracerebral hemorrhage progression by regulating mitophagy through E2F transcription factor 1.
    Jiwei Sun, Ning Li, Yesen Zhang, Jian Song, Yi Han.
      RNA binding motif protein 15 (RBM15) has been implicated in the progression of various diseases. However, its role in intracerebral hemorrhage (ICH) remains inadequately understood. To investigate RBM15's involvement in ICH, an ICH model was established using HT-22 cells and C57BL/6 mice. Elevated RBM15 expression levels were observed, suggesting its critical role in ICH pathogenesis. Our study further revealed that RBM15 depletion significantly mitigated ICH-induced brain injury and enhanced neurological function. Furthermore, RBM15 was found to mediate the N6-methyladenosine (m6A) methylation of E2F transcription factor 1 (E2F1) mRNA, thereby enhancing its stability. Further analysis confirmed that RBM15 regulates mitophagy via E2F1, with E2F1 overexpression effectively counteracting mitophagy in the absence of RBM15. Collectively, these findings indicate that targeting RBM15 may offer a promising therapeutic strategy for ICH.
    Keywords:  E2F transcription factor 1; RNA binding motif protein 15; intracerebral hemorrhage; mitophagy
    DOI:  https://doi.org/10.1016/j.abb.2026.110746
  35. Cell Commun Signal. 2026 Jan 22.
    Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy.
    Fuli Li, Qing Huang, Naisheng Zheng, Wenyu Zhang, Shan Luo, Ruowen Wang, Thulasiram Bathini, Pengkai Sun, Xinjian Li, Xian Huang, Tomasz Maj.
      
    Keywords:  Autoimmunity; Immunometabolism; Itaconate; Mitophagy; Th17 lymphocytes
    DOI:  https://doi.org/10.1186/s12964-025-02621-1
  36. Small. 2026 Jan 23. e08146
    Nanocatalytic Mitochondrial Oxidative Stress Amplification and Mitophagy Disruption for Efficient Tumor Catalytic Therapy.
    Yuemei Wang, Jiadie Yu, Xi Cheng, Qiu-Yi Duan, Penghao Ji, Shuwen Qiu, Dongliang Huo, Minfeng Huo, Jianlin Shi.
      Despite its attractive therapeutic potentials, nanocatalytic cancer therapy faces substantial challenges in delivery efficiency and target specificity. Organelle-targeted approaches, particularly those focusing on mitochondria, offer enhanced therapeutic precision. In this study, we have developed a mitochondria-targeted nanotherapeutic platform based on ultrasmall cobalt single-atom nanocatalysts functionalized with triphenylphosphine (TPP) and co-loaded with chloroquine (CQ) (Co-SA-TPP@CQ) for enhanced tumor catalytic therapy. Following precise mitochondrial localization, the nanocatalysts could catalyze the in situ generation of superoxide anions (•O2 -) and molecular oxygen (O2). The produced oxidative stress disrupts mitochondrial electron transport chain (ETC) function, which serves as an endogenous electron donor to further reduce O2 to •O2 -, thereby establishing a self-sustaining oxidative stress amplification cascade. Simultaneously, the released CQ effectively inhibits protective mitophagy, preventing the clearance of accumulating dysfunctional mitochondria. This dual-functional mechanism combines the amplified oxidative damage with the blockade of mitophagy flux, ultimately triggering efficient tumor cell apoptosis. Our findings provide a robust paradigm in precision nanocatalytic medicine for harnessing intrinsic mitochondrial biochemistry while evading cellular defense mechanisms.
    Keywords:  catalytic therapy; mitophagy disruption; oxidative stress amplification; single‐atom catalyst; tumor therapy
    DOI:  https://doi.org/10.1002/smll.202508146
  37. Research (Wash D C). 2026 ;9 1045
    Histone Lactylation Couples FSH-Driven Lactate Metabolism to Mitochondrial Biogenesis by Enhancing HDAC4-Mediated Deacetylation of PGC-1α in Granulosa Cells.
    Gang Wu, Min Chen, Chengyu Li, Mengli Wei, Yitong Pan, Tong He, Zhaojun Liu, Hongmin Li, Chunlei Zhang, Jia-Qing Zhang, Yanan Sheng, Yang Liu, Honglin Liu, Ming Shen.
      Follicle-stimulating hormone (FSH) coordinates ovarian follicle development by aligning mitochondrial biogenesis with increased metabolic demand. Although FSH is known to stimulate glycolysis in granulosa cells (GCs), the mechanism by which glycolytic flux coupled to mitochondrial biogenesis remains unclear. Here, we demonstrate that histone lactylation functions as a lactate-sensitive epigenetic mediator linking FSH-driven metabolic alterations to mitochondrial biogenesis in GCs. Mechanistically, FSH increases intracellular lactate levels through glycolytic activation, thereby promoting P300/CBP-dependent lactylation of histone H4 at lysine 5 (H4K5la). H4K5la directly enhances HDAC4 expression, and HDAC4 subsequently deacetylates PGC-1α at lysine residues 329/330. Deacetylated PGC-1α cooperates with nuclear respiratory factors NRF1/2 to drive transcription of key mitochondrial regulators (TFAM, TFB1M, TFB2M), ultimately promoting mitochondrial biogenesis. Disruption of the H4K5la/HDAC4/PGC-1α axis markedly impaired mitochondrial biogenesis and follicular development, evidenced by reduced ovarian weight, smaller follicle size, decreased antral follicle number, and impaired GC proliferation and estradiol (E2) production in FSH-treated mice. These findings identify a metabolic-epigenetic regulatory pathway in which histone lactylation links glycolysis to mitochondrial adaptation, providing mechanistic insight into FSH-dependent reproductive physiology.
    DOI:  https://doi.org/10.34133/research.1045
  38. J Muscle Res Cell Motil. 2026 Jan 22. 47(1): 2
    CD36 regulates myogenic differentiation via chronic integrated stress response - implications for muscle aging.
    Xin Ye, He-Qiang Jia, Chen Yuan, Hui Sun, Ying Dong, Dan Wang, Zhen-Jiang Wang, Zhi Chen, Chun-Yan Yu.
      The integrated stress response (ISR) and mitochondrial unfolded protein response (UPRmt) plays a vital role in myogenic differentiation of muscle satellite cells. In this study, chronic ISR and UPRmt was induced with impaired myogenic differentiation and cluster of differentiation 36 (CD36) was highly expressed and localized on the mitochondria in aging muscle. Little is known about the interplay of CD36 and ISR during differentiation. Knocking down CD36 expression at day 3 in differentiated C2C12 myoblasts indicated that the expression levels of Activating transcription factor 4 (ATF4), and other ISR - related proteins decreased, but the expression levels of UPRmt - related proteins Activating transcription factor 5 (ATF5), Heat Shock Protein 60(HSP60) and Heat Shock Protein 10(HSP10) increased with mRNA level of HSP60 increased. Meanwhile Myogenin (MyoG) expression level was increased but Myosin heavy chain 1 (Myh1) expression level was decreased. Following CD36 knockdown, mito-nuclear protein imbalance and mitochondrial dysfunction occurred. Interaction between CD36 and Mammalian Target of Rapamycin (mTOR) was observed in aging muscle. Collectively, CD36 was localized on the mitochondria in aging muscle, while CD36 was associated with ISR and UPRmt early during myogenic differentiation in C2C12 myoblasts, which could have implications for the development of new strategies to treat sarcopenia.
    Keywords:  CD36; ETC; ISR; Sarcopenia; UPRmt ; mTOR
    DOI:  https://doi.org/10.1007/s10974-025-09719-6
  39. Mol Neurobiol. 2026 Jan 19. 63(1): 372
    The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.
    Simranjeet Kaur, Ashi Mannan, Thakur Gurjeet Singh.
      The transcription factor Nurr1 (NR4A2) serves as an essential element in dopaminergic neuron development since it functions predominantly in the substantia nigra, which becomes severely affected during Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 regulates dopamine synthesis, survival-promoting, and oxidative stress genes that affect mitochondrial formation. Nurr1 binds to PGC-1α, allowing for mitochondrial activity regulation. This relationship supports mitochondrial biogenesis. Post-translational changes, including phosphorylation and acetylation, modify Nurr1 transcriptional regulation in order to enhance its ability to regulate mitochondrial genes. The assessment examines Nurr1's involvement in dopaminergic neuron development and mitochondrial formation while showing its role in reducing oxidative damage for an extensive understanding of its neurological disease functionality. Nurr1 serves as a therapeutic candidate for analysis, while the review explores obstacles and potential paths for using Nurr1-based treatments against Parkinson's disease alongside Alzheimer's disease and other neurodegenerative disorders. The extensive research utilized multiple databases, PubMed, Scopus, Medline, and EMBASE, with keywords "Nurr1," "NR4A2," "Neurodegenerative disorders," "Mitochondrial biogenesis," "Oxidative stress," "Parkinson's disease," "Alzheimer's disease," and "Therapeutic target." The analysis examined published research regarding Nurr1-mediated control of dopaminergic function and survival and mitigation of neurological and mitochondrial deficits within the past decade. Nurr1's interactions with important co-regulators like PGCα, its post-translational changes, and its effects on neuroinflammation have also received particular focus. In neurodegenerative illnesses, mitochondrial dysfunction adds to neuronal damage. Nurr1's regulation of mitochondrial biogenesis helps recover mitochondrial function, alleviate oxidative stress, and sustain neuronal survival. Dysregulation of Nurr1 expression is connected to decreased mitochondrial activity and accelerated neurodegeneration.
    Keywords:  Alzheimer’s disease; Mitochondrial biogenesis; Neurodegeneration; Nurr1; Oxidative stress; PGC-1α; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-025-05633-7
  40. Adv Healthc Mater. 2026 Jan 19. e03803
    Targeting the ARRDC3-DRP1 Axis via hUMSC-Derived Exosomal CRYAB for Neuroprotection in Cerebral Ischemia/Reperfusion Injury.
    Rong Ji, Zengyu Zhang, Zhuohang Liu, Kaicheng Yang, Xueyu Mao, Min Chu, Yong Wang, Jing Zhao.
      Cerebral ischemia/reperfusion injury (CIRI) remains a major clinical challenge due to the lack of effective neuroprotective strategies. Here, hUMSC-derived exosomes (H-Exo) were isolated and administered intranasally (15 µg/mouse/day for 3 days) in a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model. Animals were randomly assigned to three groups: Sham, MCAO/R, and H-Exo-treated MCAO/R mice. H-Exo efficiently penetrated the blood-brain barrier, accumulated within the ischemic penumbra, and was internalized by neurons and glial cells. Treatment with H-Exo markedly improved neurological function both in vivo and in vitro. Mechanistically, H-Exo inhibits neuronal ferroptosis by preserving mitochondrial dynamics and alleviating oxidative stress. Transcriptomic analysis identified ARRDC3 as a previously unrecognized ferroptosis-associated gene that was upregulated after ischemia but suppressed by H-Exo treatment. ARRDC3 exacerbates neuronal ferroptosis by promoting Drp1-dependent mitochondrial fragmentation. Proteomic profiling further identified CRYAB as an abundant exosomal cargo mediating the neuroprotective effects of H-Exo. Pharmacological inhibition of CRYAB with NCI-41356 partially reversed the anti-ferroptotic effects of H-Exo, confirming its essential role. Collectively, this study reveals the CRYAB-ARRDC3-Drp1 axis as a key regulator linking mitochondrial dynamics to ferroptosis and highlights H-Exo as a promising non-invasive therapeutic approach for ischemic stroke.
    Keywords:  ARRDC3/DRP1 axis; cerebral ischemia‐reperfusion injury; exosomes; ferroptosis; mitochondrial dynamics
    DOI:  https://doi.org/10.1002/adhm.202503803
  41. NPJ Aging. 2026 Jan 22.
    Parkin deficiency impairs female fertility, oocyte development, fertilization and mitochondrial function in mice.
    Michelle Volovsky, Adolfo Rodríguez-Eguren, Yagmur Ergun, Raziye Melike Yildirim, Gizem Nur Sahin, Rolando Garcia Milian, Sameet Mehta, Lavinia Turanli, Irene Cervelló, Richard Scott, Emre Seli.
      Parkin, a mitochondrial E3 ubiquitin ligase, plays a central role in mitophagy and cellular homeostasis. Although well studied in neurobiology, its role in female reproduction remains unclear. This study investigated the role of Parkin on female fertility using young (2-3 months old) and older (9-10 months old) mice with a global germline Parkin deletion. Parkin knockout (KO) females exhibited significantly reduced fertility with total pups per female lower in KO mice (16.0 ± 1.53) compared to wild type (WT) (22.33 ± 0.67; p = 0.02). In young mice, GV oocyte yield was significantly reduced in KO (30.0 ± 1.53) compared to WT (52.7 ± 6.96; p = 0.03), as was MII oocyte count (7.7 ± 0.67 vs. 22.3 ± 0.88; p = 0.0002). In older mice, similar trends were observed. Fertilization rates were significantly lower in KO mice compared to WT (36.2 ± 8.1% vs. 61.2 ± 5.5%; p = 0.03). RNA sequencing identified multiple differentially expressed genes between KO and WT, with associated pathway changes. These findings indicate that Parkin deficiency impairs oocyte yield, fertilization capacity, and overall fertility, suggesting that Parkin plays a key role in reproductive competence.
    DOI:  https://doi.org/10.1038/s41514-026-00332-6
  42. Eur J Pharmacol. 2026 Jan 16. pii: S0014-2999(26)00041-5. [Epub ahead of print] 178559
    Oridonin ameliorates hyperglycemia-induced bladder injury by promoting AMPK/PINK1/Parkin-mediated mitophagy.
    Kang-Jing Li, Zhenhua Qiu, Tongduan Li, Hongjun Zhao, Xiaoping Liu, Longchen Zhao, Chubiao Zhuo, Runqi Luo, Yujie Yang, Xiangmao Lai, Jianwen Zeng.
      Diabetic bladder dysfunction (DBD), characterized by impaired detrusor contractility, decreased bladder sensation, and increased bladder compliance, remains difficult to treat due to its complex and multifactorial pathogenesis, including chronic inflammation. Oridonin (ORI), known for its strong anti-inflammatory properties, may offer therapeutic benefits for DBD. This study investigated the effects and underlying mechanisms of ORI on hyperglycemia-induced bladder injury. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to evaluate potential mechanisms. The function and molecular events of ORI in DBD were explored using both rat and cell models. GO analysis revealed that ORI primarily regulates inflammatory processes, while KEGG analysis identified the AMPK pathway as a key mechanism. Additionally, molecular docking demonstrated strong interactions between ORI and AMPK. In vivo experiments showed that ORI significantly reduced hyperglycemia-induced inflammation and mitochondrial damage, promoted AMPK phosphorylation, and increased the expression of contraction- and mitophagy-related factors. These findings were further validated in human bladder smooth muscle cells (HBSMCs) exposed to high glucose. Notably, after inhibiting AMPK-mediated mitophagy using compound C or cyclosporine A in vitro, the anti-inflammatory effects of ORI were inhibited and the expression of contraction-related proteins were down-regulated. In conclusion, ORI alleviates inflammation and reverses changes in contraction-related proteins in HBSMCs in association with changes in AMPK/PINK1/Parkin-related mitophagy markers, suggesting its potential as a novel candidate for preventing or attenuating hyperglycemia-induced bladder injury and for further investigation in the management of DBD.
    Keywords:  AMPK; PINK1/Parkin; diabetic bladder dysfunction; mitophagy; oridonin
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178559
  43. Int Immunopharmacol. 2026 Jan 16. pii: S1567-5769(26)00033-0. [Epub ahead of print]172 116190
    Investigating the mechanism by which telomere dysfunction affects mitochondrial homeostasis in anthracosilicosis using a Terc knockout model.
    Qiufang Qu, Yiming Zhang, Qingnan Zhou, Shuhan Guo, Qiang Zhou, Meiyu Chang, Zhenlin He, Le Liu, Yuke Wang, Jing Li, Hong Cao, Xiangwei Zhao, Zhiheng Li, Sanqiao Yao.
      Anthracosilicosis, a type of coal workers' pneumoconiosis, exhibits pathological features of both coal workers' pneumoconiosis and silicosis. Its pathogenesis remains incompletely understood. Growing evidence suggests that telomere dysfunction and mitochondrial homeostasis play critical roles in the development of pulmonary fibrosis. This study aimed to investigate the regulatory role of telomere function in mitochondrial homeostasis and its impact on pulmonary fibrosis in anthracosilicosis, using a telomerase RNA component (Terc) knockout mouse model. Terc knockout mice and an anthracosilicosis mouse model were established to explore the effects of telomere function on mitochondrial homeostasis. Lung tissues were subjected to histopathological analysis via H&E and Masson staining. Deposition of COL1a1 and COL1a3 was detected using immunofluorescence. Telomere length was measured by quantitative fluorescence in situ hybridization (Q-FISH) and qPCR. Subcellular localization of telomerase reverse transcriptase (TERT) to mitochondria was observed via immunofluorescence colocalization. Mitochondrial ultrastructural changes were assessed using transmission electron microscopy (TEM). Oxidative stress levels were evaluated by ELISA and ferric reducing antioxidant power (FRAP) assays. Expression levels of six telomere-binding proteins and mitochondrial homeostasis-related markers were analyzed by Western blot and qPCR. Compared with control and coal-silica dust (CSD)-exposed wild-type mice, Terc-/- control and Terc-/- CSD-exposed mice exhibited significantly shortened telomeres, severe dysregulation of six telomere-binding proteins, and exacerbated telomere dysfunction. These mice also showed enhanced oxidative damage, abnormal mitochondrial morphology and quantity under TEM, significantly reduced ATP levels, and disrupted mitochondrial dynamic balance. Our findings demonstrate that coal-silica dust exposure aggravates telomere shortening and disrupts mitochondrial homeostasis in Terc-/-mice, leading to exacerbated pulmonary fibrosis and promoting the initiation and progression of anthracosilicosis. These results provide valuable insights for developing precise prevention and treatment strategies for pneumoconiosis.
    Keywords:  Anthracosilicosis; Mitochondrial homeostasis; Telomere dysfunction; Terc knockout
    DOI:  https://doi.org/10.1016/j.intimp.2026.116190
  44. Adv Mater. 2026 Jan 21. e19152
    Internal-Friction Network Piezoelectric Hydrogel Microspheres Achieve Physiological Electrical Adaptation to Regulate Mitochondrial Autophagy in Degenerative Tissues.
    Huzhe Liu, Fan Wang, Weiwei Yi, Siyuan Huang, Zixiang Tang, Bo Liao, Zhenming Hu, Wenguo Cui, Jieliang Shen.
      Mitochondrial autophagy imbalance critically drives apoptosis and tissue degeneration, requiring physiological electrical adaptation to meet cellular thresholds. However, degenerative tissues exhibit deficient endogenous electrical signals, disrupting cellular energy transfer. Using supramolecular engineering and microfluidic strategies, we constructed an internal-friction network hydrogel microsphere system through synergistic assembly of piezoelectric bismuth ferrite nanoparticles (BF) and sliding-ring-functionalized methacrylated hyaluronic acid (HAMA), achieving physiological electrical adaptation in degenerative tissues. BF convert mechanical stimuli into electrical signals, while the stress-dependent internal-friction network regulates energy dissipation. Under low stress, sliding-ring movement produces low friction with mechanoelectrical conversion loss of 61.5 kJ/m3, enhancing electrical generation. Under high stress, main chain straightening increases friction to 78.3 kJ/m3, suppressing excessive signals and restoring physiological electrical adaptation. The microspheres generate stable electric fields (95-110 mV/mm) under dynamic loading, promoting mitochondrial autophagy via PINK1/Parkin pathway activation, maintaining stable mitochondrial membrane potential (compared with OS group, the JC-1 ratio increases by 49.2%), and reducing nucleus pulposus apoptosis by 75%. In vivo experiments demonstrated that microsphere implantation restored the physiological electrical environment, enhanced mitochondrial autophagy, inhibited apoptosis, and delayed intervertebral disc degeneration progression, providing new insights for treating degenerative tissues through electrical adaptation restoration.
    Keywords:  hydrogel microspheres; internal‐friction network; intervertebral disc degeneration; mitochondrial autophagy; piezoelectricity
    DOI:  https://doi.org/10.1002/adma.202519152
  45. J Ethnopharmacol. 2026 Jan 19. pii: S0378-8741(26)00095-4. [Epub ahead of print] 121244
    Total flavonoids isolated from Fructus Mume (Prunus mume Sieb. et Zucc.) mitigate Parkinson's disease progression by promoting neuronal mitophagy via activation of the CaMKKβ/AMPK signaling pathway.
    Chunling Wang, Xiaotao Feng, Wentao Zhang, Lizhen Huang, Xiangdong Lu, Mengjie Sun, Mengyuan Gao, Xiaodong Wen.
       ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Mume (FM) is derived from the nearly ripe fruit of Prunus mume Sieb. et Zucc., and widely used as a traditional medicine in Asian countries. FM has the effect of calming Liver to stop endogenous Wind, and has been used for thousands of years in the treatment of Parkinson's disease (PD), as recorded in ancient formulas such as Wumei Pills. However, the specific mechanism by which it treats PD remains larger unclear.
    PURPOSE: The aim of this study was to investigate the effects and mechanisms by which the active ingredients of FM (Fructus Mume flavonoids, FMF) mitigate the progression of PD.
    METHODS: We isolated FMF from FM and explored its chemical composition and active compound content. In vivo and in vitro PD models were employed to investigate the alleviative effects of FMF on PD and its underlying mechanisms.
    RESULTS: We identified 193 compounds and quantified 154 flavonoid compounds in the FMF. Six compounds were present at concentrations exceeding 100 μg/g, namely Isorhamnetin (1287.0639 μg/g), Narcissin (764.9639 μg/g), Nicotiflorin (613.8568 μg/g), Quercetin (435.5215 μg/g), Nepitrin (295.4833 μg/g), and Kaempferol (241.9767 μg/g). Moreover, FMF alleviated behavioral deficits in PD rats. FMF also inhibited the loss of neurons and the formation of α-synuclein aggregates, and promoted the expression of tyrosine hydroxylase in the substantia nigra pars compacta in PD rats. In vivo and in vitro PD models demonstrated that autophagy inhibition significantly abolished the neuroprotective effects of FMF. Mechanically, FMF could enhance mitophagy to attenuate the mitochondrial dysfunction by activating the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMP-activated protein kinase (AMPK) signaling pathway.
    CONCLUSION: FMF promotes neuronal mitophagy to exert the neuroprotective effects by activating the CaMKKβ/AMPK signaling pathway. These findings provide a theoretical foundation for the application of FM in the treatment of PD and promote the clinical application of FM.
    Keywords:  CaMKKβ/AMPK signaling pathway; Fructus Mume flavonoids; Mitophagy; Neuroprotective; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.jep.2026.121244
  46. Brain Res Bull. 2026 Jan 17. pii: S0361-9230(26)00024-9. [Epub ahead of print] 111738
    Treadmill Exercise Attenuates CUMS-Induced Depressive Behaviors by Modulating the UPRmt via the Nrf2/Keap1 Pathway.
    Yang Wang, Mingshi Peng, Tongxi Zhou, Juncheng Si, Yuwen Shangguan, Jingfeng Wang, Siyun Lei, Li Li.
       INTRODUCTION: Depression is a very common brain disorder worldwide. It is associated with damaging behaviors such as self-harm and suicide that hurt the brain and body. Mitochondrial dysfunction and dysregulation of the mitochondrial unfolded protein response (UPRmt) are increasingly seen as playing a key role in chronic stress-induced pathophysiology of depression. Aerobic exercise is a very effective non-pharmacological intervention, however, the specific mechanisms of how it modifies hippocampal UPRmt is poorly understood. This effect may be attributed to the Nrf2/Keap1 pathway, a master regulator of cellular antioxidant defense that mediates exercise-induced neuroprotection. This study aimed to investigate whether treadmill exercise modulates UPRmt dysregulation in CUMS-induced depressive mice by activating the hippocampal Nrf2/Keap1 signaling pathway, thereby ameliorating mitochondrial dysfunction and depression-like behaviors.
    METHODS: Male C57BL/6J mice were subjected to a chronic unpredictable model of stress for the induction of a depression model which through exercise on a treadmill for 6 weeks was tested for therapeutic effects. Behaviors consistent with a model of depressive behavior were assessed by OFT, SPT, and TST. Hippocampal mitochondrial function was assessed by transmission electron microscopy, flow cytometry, biochemical, and ELISA. Oxidative stress markers were assessed with biochemical kits and ELISA. The mRNA and protein levels of key markers in the Nrf2/Keap1 pathway and UPRmt were analyzed using RT-qPCR, Western blotting, and immunofluorescence. Pathway dependence was determined using the Nrf2 inhibitor, ML385 and the Nrf2 activator Bardoxolone methyl.
    RESULTS: The six-week treadmill exercise program significantly reduced depression-like behaviors (e.g., anxiety-like behaviors, anhedonia, and behavioral despair), restored mitochondrial functions (mitochondrial cristae morphology, Δψm, ATP, and ROS levels) and eliminated oxidative stress (SOD, T-AOC, and MDA levels). Moreover, treadmill exercise significantly increased the expression of proteins in the Nrf2/Keap1 pathway (Nrf2, Keap1, NQO1, and HO-1), which attenuated CUMS-induced UPRmt markers (HSP60, ClpP, HSP70, LONP1, and ATF5) and the associated stress transcription factor CHOP.
    CONCLUSION: The treadmill exercise activates the Nrf2/Keap1 pathway in the hippocampus, thereby reducing CUMS-induced excessive and dysregulated endoplasmic reticulum stress (UPRmt) in an Nrf2-dependent manner, which leads to a recovery of mitochondrial function, suppression of oxidative stress, and improvement of depressive-like behaviors.
    Keywords:  CUMS; Depression; Nrf2/Keap1; Treadmill exercise; UPRmt
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111738
  47. J Ovarian Res. 2026 Jan 21.
    Exploring biomarkers of mitochondrial dynamics in polycystic ovary syndrome and the effect of mesenchymal stem cell transplantation on ovarian mitochondria.
    Na Tang, Ou Chai, Dongqing Cui, Wei Zhang, Wenyan Tian, Yurong Wang, Yuwei Chen, Jinyue Fan, Zhimin Hou.
      
    Keywords:  Granulosa cells; Mesenchymal stem cells; Mitochondrial dynamics; Polycystic ovary syndrome; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s13048-026-01974-6
  48. Aging Adv. 2025 Nov 24.
    Narrative review of mitochondrial dysfunction in aging-related salt-sensitive hypertension: outcomes, mechanisms, and therapeutic implications.
    Sepiso K Masenga, Joreen P Povia, Bislom C Mweene, Ronald McMillian, Claude Albritton, Taneisha Gillyard, Jeremiah Afolabi, Edgar Garza Lopez, Benjamin Rodriguez, Amber Crabtree, Salma AshShareef, Margaret Mungai, Han Le, Andrea Marshall, Prasanna Katti, Kit Neikirk, Annet Kirabo, Antentor Hinton.
      Salt sensitivity of blood pressure is prevalent in the aging population, characterized by an exaggerated hypertensive response to dietary sodium intake. Emerging evidence implicates mitochondrial dysfunction as a central contributor to salt sensitivity of blood pressure with mechanistic involvement of oxidative stress, endoplasmic reticulum stress, disrupted mitochondrial-endoplasmic reticulum contacts, and impaired autophagy. This review explores the interplay between aging, mitochondrial dysfunction, and salt sensitivity of blood pressure. Morphological mitochondrial changes including mitochondrial fragmentation due to fission-fusion imbalances, cristae remodeling leading to bioenergetic deficits, and mitochondrial-endoplasmic reticulum contact disruptions affecting calcium homeostasis across aging are contextualized in salt sensitivity of blood pressure. Alongside these changes, age-associated impairments in mitophagy result in the accumulation of defective mitochondria, exacerbating oxidative stress and inflammation. Understanding these pathways offers potential therapeutic avenues to attenuate salt sensitivity of blood pressure in older adults.
    Keywords:  aging; cristae remodeling; fission; fusion; mitochondria-endoplasmic reticulum contact; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial-targeted therapies; oxidative stress; salt-sensitive hypertension
    DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00018
  49. Int Immunopharmacol. 2026 Jan 21. pii: S1567-5769(26)00086-X. [Epub ahead of print]172 116243
    Ginsenoside Rg1 ameliorates depression-like behaviors in mice by inhibiting astrocyte pyroptosis via Cx43-dependent restoration of mitophagy flux.
    Zan Xing, Xin-Mu Li, Yuan-Chun Wang, Peng-Yu Chen, Xue-Ying Yang, Hui-Qin Wang, Meng Zhang, Ai-Ping Chen, Shi-Feng Chu, Zhen-Zhen Wang, Nai-Hong Chen.
       BACKGROUND: Ginsenoside Rg1 (GRg1), a principal neuroactive constituent of ginseng, has demonstrated promising antidepressant potential. Beyond its well-documented roles in mitigating oxidative stress, suppressing neuroinflammation, and protecting mitochondrial function, our study further demonstrates that GRg1 exerts its protective effects on the organism by upregulating the expression of connexin 43 (Cx43) in astrocytes. However, it remains unknown whether Cx43 mediates the antidepressant effects of GRg1 by regulating astrocyte pyroptosis.
    OBJECTIVE: This study aimed to elucidate the role of the Cx43-mitophagy-pyroptosis axis in the antidepressant mechanism of GRg1.
    METHODS: The model of depression was established using an 8-week chronic unpredictable stress (CUS). The optimal therapeutic dose of GRg1 was determined in vivo. Subsequently, we employed Western blotting, immunofluorescence, and fMRI to assess the effects of GRg1 on Cx43 expression and its protective effects on astrocytes. The causal role of Cx43 was verified using Cx43flox/flox mice. Furthermore, we used corticosterone (CORT) to stimulate primary mouse astrocytes and conducted in vitro studies on the relationship between the "Cx43-mitophagy-pyroptosis" pathway and depression.
    CONCLUSION: GRg1 exerts its antidepressant effects by upregulating Cx43 expression, which restores mitophagy flux and facilitates the clearance of damaged mitochondria. This process, in turn, suppresses NLRP3 inflammasome activation and subsequent GSDMD-N-mediated astrocyte pyroptosis.
    Keywords:  Cx43; Depression; GRg1; Mitophagy flux; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2026.116243
  50. Toxicol Lett. 2026 Jan 20. pii: S0378-4274(26)00018-4. [Epub ahead of print] 111835
    Role of mitochondrial biogenesis in methanol-induced neurobehavioral changes in rats.
    Guoping Li, Xiaohong Du, Xinqiao Wang, Xiaojie Han, Mengnan Peng, Chen Nan.
       OBJECTIVE: This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure.
    METHODS: Forty-eight healthy Sprague-Dawley rats (200 ± 20g), equally stratified by sex, were randomized into four groups: a control group (0g/m³) and low- (25.344g/m³), medium- (50.688g/m³), and high-dose (101.376g/m³) methanol exposure groups. Rats were exposed via inhalation for 2h/day, 7 days/week for 4 weeks. Neurobehavioral changes were evaluated using the Morris water maze (MWM) and open field test (OFT). Cortical histopathology was examined via H&E staining. Mitochondrial DNA (mtDNA) content was quantified by qPCR, and ATP levels were measured using a commercial assay kit. Western blotting was performed to assess the expression of mitochondrial biogenesis-related proteins (COX IV, PGC-1α, NRF1, and TFAM).
    RESULTS: Methanol-exposed rats exhibited significantly prolonged escape latency and fewer platform crossings in the MWM (P < 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P < 0.05). H&E staining revealed neuronal loss and structural disorganization in the cortex. Additionally, mtDNA content and ATP levels were significantly decreased in medium- and high-dose groups (P < 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P < 0.05), indicating suppressed mitochondrial biogenesis.
    CONCLUSION: Methanol exposure disrupts mitochondrial biogenesis in rat cortical neurons, leading to reduced mitochondrial content and ATP production, which may contribute to the observed neurobehavioral deficits. These findings provide mechanistic insights into methanol-induced neurotoxicity.
    Keywords:  ATP; PGC-1α; methanol; mitochondrial biogenesis; neurobehavior
    DOI:  https://doi.org/10.1016/j.toxlet.2026.111835
  51. Sci Rep. 2026 Jan 17.
    Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
    Olivier Reynaud, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marc P Lussier, Sabah Na Hussain, Gilles Gouspillou.
      Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.
    DOI:  https://doi.org/10.1038/s41598-025-34223-9
  52. J Ginseng Res. 2026 Jan;50(1): 100906
    Ginsenoside Rb1-enhanced decellularized extracellular matrix hydrogels ameliorates mitochondrial dysfunction and cellular aging in sepsis-induced acute lung injury.
    Linlin Gao, Fushuang Zheng, Zhiling Fu, Wei Wang.
       Background: Sepsis-induced acute lung injury (ALI) is a life-threatening condition with high mortality and limited effective treatments. Aging of alveolar type II (AT2) epithelial cells and mitochondrial dysfunction are key contributors to ALI pathogenesis. Ginsenoside Rb1, a major bioactive component of ginseng, has shown potential in modulating cellular senescence and mitochondrial health. This study aimed to evaluate the therapeutic efficacy of Rb1-loaded lung tissue-derived decellularized extracellular matrix hydrogel (dECM-gel) in alleviating sepsis-induced ALI.
    Methods and results: Rb1-loaded dECM-gel was formulated and characterized for its rheological properties. In vitro, primary AT2 cells were treated with lipopolysaccharide (LPS) to mimic ALI conditions. The impact of Rb1-loaded dECM-gel on cellular senescence, mitochondrial function, and oxidative stress was assessed using β-galactosidase staining, JC-1 dye for mitochondrial membrane potential, ATP quantification assays, and transmission electron microscopy. Results demonstrated that Rb1-loaded dECM-gel significantly reduced AT2 cell senescence, improved mitochondrial function via activation of the mitochondrial unfolded protein response (mtUPR), and alleviated mitochondrial structural damage. In vivo, a murine model of sepsis-induced ALI was used to evaluate therapeutic outcomes. Treatment with Rb1-loaded dECM-gel improved lung histopathology, decreased oxidative stress, and reduced apoptosis, largely through activation of the AMPK/SIRT1 signaling pathway.
    Conclusion: Rb1-loaded dECM-gel mitigates sepsis-induced ALI by enhancing mtUPR and activating the AMPK/SIRT1 pathway, offering a promising therapeutic strategy for lung injury. These findings underscore the potential of ginsenoside-based biomaterials in the clinical management of ALI.
    Keywords:  AMPK/SIRT1 pathway; Decellularized extracellular matrix hydrogel; Ginsenoside Rb1; Mitochondrial unfolded protein response; Sepsis-induced acute lung injury
    DOI:  https://doi.org/10.1016/j.jgr.2025.10.003
  53. Asia Pac J Clin Oncol. 2026 Jan 22.
    Investigation of the Expression of Bcl-2 Interacting Protein 3 (BNIP3) and Its Molecular Association With Tumor Hypoxia and Immune Response in Breast Cancer.
    Khalidha Noordeen, B S Lakshmi.
       BACKGROUND: BNIP3 is a crucial gene involved in mitophagy that modulates mitochondrial and cellular homeostasis. However, there is limited research examining its biological regulation. The current study investigates the expression of BNIP3 in breast cancer, and its relationship with hypoxia and immune response.
    METHODS: BNIP3 expression and its effect on clinical prognosis was assessed using TCGA database. Immunohistochemistry was used to identify the expression of BNIP3 in 50 cases of invasive breast carcinomas. Gene expression of BNIP3 was assessed in breast cancer cell lines exposed to hypoxia. The expression levels of BNIP3 were correlated with multiple clinicopathologic variables, HIF-1α and NF-κB (p65). The association between BNIP3 and cancer immune infiltration was investigated using the TIMER database.
    RESULTS: In breast cancer, an overexpression of BNIP3 has been substantially linked to a poor survival rate. Immunohistochemical analysis showed a repression of BNIP3 in patient samples tested. An increase in the gene expression of BNIP3 was observed in breast cancer cell lines exposed to hypoxic conditions. Our results demonstrate a positive correlation between expression of BNIP3 and the expression of hypoxia and immune response markers, as well as the lobular subtypes of invasive breast cancer.
    CONCLUSION: According to the study findings, BNIP3 expression is lower in breast cancer and may influence the prognosis and play a role in immune modulation. Our findings suggest that hypoxia and immune response regulate the expression of BNIP3 in breast cancer. Hence the results signify the importance of BNIP3 as a prognostic marker in breast tumor progression.
    Keywords:  BNIP3; HIF‐1α; NF‐kB; breast cancer; hypoxia; mitophagy
    DOI:  https://doi.org/10.1111/ajco.70061
  54. Front Psychiatry. 2025 ;16 1645757
    SENP3/FIS1-regulated PFC neural mitochondrial fragmentation underlies the mechanism of electroacupuncture attenuating depressive behavior in CUMS mice.
    Shaoda Lai, Xiaoke Qiu, Peilin Lin, Jiayi Wu, Feifei Li, Ningjing Lai, Xin Li, Ting Tu, Jiping Zhang, Yong Huang, Zhinan Zhang.
       Objective: Electroacupuncture (EA) is a common alternative treatment for depression, but its underlying mechanism remains unclear. Research suggests that its therapeutic effect may involve reducing SENP3/FIS1-regulated mitochondrial fragmentation, thereby mitigating neuronal damage in the prefrontal cortex. This study aimed to evaluate the efficacy of EA at Baihui (GV20) and Yintang (GV29) on SENP3/FIS1-regulated mitochondrial fragmentation in prefrontal cortex neurons of depressive animals.
    Methods: Twenty-eight 6-8-week-old male C57BL/6 mice were randomly divided into normal control, depression, and EA groups. Following depression modeling, the EA group received EA at GV20 and GV29. The effects of EA on neuronal mitochondrial fragmentation and the SENP3/FIS1 pathway were evaluated using transmission electron microscopy, western blotting, and immunofluorescence assays.
    Results: EA at GV20 and GV29 notably reduced depression-like behaviors in animals and exerted neuroprotective effects on prefrontal cortical neurons. It also inhibited FIS1-mediated mitochondrial fragmentation in the prefrontal cortex and enhanced SUMOylation. Further investigation of SENP3, the key regulatory enzyme for FIS1 SUMOylation, revealed that EA downregulated the SENP3-FIS1 interaction.
    Conclusions: These evidences suggested that the antidepressant effects of EA may involve modulation of mitochondrial fragmentation regulated by the SENP3/FIS1 pathway in prefrontal cortex neurons.
    Keywords:  SENP3/FIS1; depression; electroacupuncture; mitochondrial fragmentation; prefrontal cortex
    DOI:  https://doi.org/10.3389/fpsyt.2025.1645757
  55. Eur Cytokine Netw. 2026 Jan 19. 36(3): 0
    Igniting the Tumor: Targeting Mitochondrial Stress to Prime Breast Cancer for Immunotherapy.
    Hung-Yu Lin, Hsing-Ju Wu, Pei-Yi Chu.
      Immunotherapy has demonstrated limited efficacy in immunologically "cold" breast cancers characterized by absent T-cell infiltration and inadequate interferon signaling. The purpose of this work is to propose and articulate a mechanistic and therapeutic framework in which mitochondrial stress is deliberately harnessed to convert immunologically "cold" breast tumors into "hot," T cell-inflamed, immunotherapy-responsive lesions. This review synthesizes emerging evidence positioning mitochondrial stress as a strategic lever to transform these immune-excluded tumors into inflamed, therapy-responsive lesions. We examine how mitochondrial dysfunction triggers cytosolic release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern that activates the cGAS-STING pathway, initiating type I interferon responses and secretion of T-cell-recruiting chemokines such as CCL5 and CXCL10. This axis functions as a "double-edged sword"-while acute activation converts "cold" tumors into "hot" immune-responsive states, chronic engagement drives immunosuppressive cytokine networks and therapeutic resistance, with outcomes varying across breast cancer subtypes. We explore six combination therapeutic strategies: mitochondrial poisons, radiotherapy/chemotherapy, PARP/ATR inhibitors, metabolic reprogramming agents, mitochondrial quality control modulators, and localized mitochondrial stress induction, each paired with immune checkpoint blockade. The review emphasizes "controlled ignition" as a paradigm whereby precisely dosed mitochondrial stress amplifies tumor antigenicity and favorable cytokine landscapes while avoiding chronic immunosuppression. Cytokine networks emerge as both integrators and therapeutic targets of mitochondrial-immune crosstalk. Future advances require mapping subtype-specific thresholds, developing tumor-restricted delivery systems, and implementing biomarker-guided trials to safely harness mitochondrial stress, potentially redefining these organelles as programmable immunological adjuvants in breast cancer therapy.
    Keywords:  breast cancer; cgas; cytokines; immunotherapy; mitochondrial stress; sting; tumor microenvironment
    DOI:  https://doi.org/10.1684/ecn.2025.0504
  56. Biomed Rep. 2026 Feb;24(2): 26
    Targeting mitochondrial oxidative stress: A novel therapeutic strategy for degenerative joint diseases (Review).
    Yang Hou, Xiaolei Yang, Tianyi Zhao, Yongfei Guo, Jiangang Shi.
      Degenerative joint diseases, such as osteoarthritis (OA), intervertebral disc degeneration (IVDD) and rheumatoid arthritis (RA), cause pain and disability worldwide. Globally, OA affects >500 million individuals, IVDD affects 40-60% of adults and RA affects 0.5-1% of the global population. Current treatments (such as non-steroidal anti-inflammatory drugs and corticosteroids for OA, conservative management and spinal surgery for IVDD, and disease-modifying anti-rheumatic drugs/biologics for RA) focus on symptom relief and inflammation control, but they do not prevent disease progression nor restore damaged tissue. Furthermore, these treatments are often associated with risks of systemic side effects (such as gastrointestinal bleeding, cardiovascular events and immunosuppression) or surgical complications (such as infection and implant failure). Although accumulating evidence implicates mitochondrial dysfunction and excessive reactive oxygen species (ROS) in the pathogenesis of these disorders, strategies that directly target mitochondrial oxidative stress are yet to be developed and translated into the clinic. In the present study this gap in the knowledge was addressed by systematically reviewing mitochondria-targeted antioxidant therapies and mitochondrial quality-control mechanisms due to their potential as novel, disease-modifying approaches for degenerative joint diseases. The preclinical efficacy of mitochondria-directed antioxidants (such as mitoquinone, MitoTEMPO, 10-(6'-plastoquinonyl) decyltriphenylphosphonium and Szeto-Schiller-31) in alleviating ROS-induced cellular damage, inhibiting apoptosis/pyroptosis and preserving extracellular matrix integrity in OA, IVDD and RA models were summarized. Additionally, strategies to enhance mitophagy (such as through PTEN-induced kinase 1/Parkin), rebalance mitochondrial dynamics (such as through the dynamin-related protein 1/mitofusin 1/2) and activate antioxidant signaling pathways (such as nuclear factor erythroid 2-related factor 2 and sirtuin 3) were highlighted. The present study identified key translational challenges (such as optimal delivery systems, long-term safety and clinical validation) and suggested integrated therapeutic frameworks that combine targeted antioxidants with advanced drug carriers and adjunctive treatments. Mitochondria-focused interventions may have potential as the next generation of disease-modifying treatments for OA, IVDD and RA.
    Keywords:  intervertebral disc degeneration; mitochondria-targeted antioxidants; mitophagy; osteoarthritis; oxidative stress
    DOI:  https://doi.org/10.3892/br.2025.2099
  57. Mech Ageing Dev. 2026 Jan 15. pii: S0047-6374(26)00008-4. [Epub ahead of print]230 112156
    SRC suppression attenuates vascular aging by activating FUNDC1-dependent mitophagy.
    Linghuan Wang, Yan Ma, Tianhu Wang, Weiwei Zhang, Zhiyi Fang, Tingting Lu, Yingjie Zhang, Yan Fang, Ting Sun, Dong Han, Feng Cao.
      Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using in vitro and in vivo models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE-/- mice, while senescence in mouse aortic vascular smooth muscle cells (MOVASs) was induced by doxorubicin. Elevated expression of SRC and phosphorylated SRC (Tyr418) was confirmed in both models. Pharmacological inhibition of SRC with KX2-391 partially mitigated features of vascular aging, improved mitochondrial morphology, reduced plaque burden, and enhanced fibrous cap stability. In senescent MOVASs, SRC knockdown decreased FUNDC1 Tyr18 phosphorylation, enhanced mitophagic flux, and reduced senescence, whereas SRC overexpression produced opposite effects and impaired KX2-391-mediated protection. Moreover, FUNDC1 knockdown abolished the anti-senescence effects of KX2-391, confirming that FUNDC1 is essential for SRC-mediated regulation. Together, these findings establish the SRC-FUNDC1 axis as an important regulator of mitophagy and vascular aging, suggesting that SRC inhibition may offer therapeutic benefit against vascular senescence and atherosclerosis.
    Keywords:  Autophagy; FUNDC1; Mitochondrial dysfunction; SRC; Vascular aging
    DOI:  https://doi.org/10.1016/j.mad.2026.112156
  58. Biochem Biophys Rep. 2026 Mar;45 102425
    Mitigating psychological stress-induced cardiac injury: The impact of CB2R agonists on endoplasmic reticulum stress and mitophagy.
    Chenke Ma, Wenbin Gai, Kan Zhang, Cheng Qin.
       Background: Psychological stress is a recognized contributor to cardiac injury and disease; however, the molecular mechanisms underlying this relationship remain incompletely understood, and effective therapeutic strategies are still limited.
    Materials and methods: DEGs were identified from our sequencing data and GEO datasets, intersected with ER stress/mitophagy-related genes, and then prioritized by machine-learning and network analyses; pathway activity, immune signatures, molecular subtypes, and miRNA-mRNA interactions (DIANA-TarBase) were further characterized and experimentally validated.
    Results: In cardiac injury induced by psychological stress, 38 differentially expressed ER stress- and mitophagy-related genes were identified. Through methods such as LASSO regression, four key genes-Foxo3, Pparg, Sirt1, and Stat3-were selected. ROC analysis of the four-gene phenotype score showed strong discrimination in the test dataset (AUC = 0.917 for control vs. stress; AUC = 0.938 for stress vs. CB2R-agonist treatment) and moderate discrimination in the external validation cohort GSE68077 for the comparison of controls versus 5dayStress-1dayRest samples (AUC = 0.720). Correlation analysis revealed that Sirt1 exhibited significant positive correlations with CD56bright natural killer cells, MDSCs, and Type 1 T helper cells. Pparg showed a notable positive association with Type 1 T helper cells, while γδ T cells showed significant negative correlations with Stat3, Sirt1, Pparg, anRd Foxo3. Treatment with a cannabinoid type 2 receptor (CB2R) agonist notably downregulated the expression of these four key genes.
    Conclusion: This study provides mechanistic insight into molecular processes underlying psychological stress-induced cardiac injury. The identified four-gene module may serve as an exploratory molecular signature and a starting point for evaluating CB2R agonism as a modulator of ER stress and mitophagy.
    Keywords:  Cannabinoid type 2 receptor agonist; Cardiac injury; Endoplasmic reticulum stress; LASSO regression; Mitophagy; Psychological stress; WGCNA
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102425
  59. Protein Sci. 2026 Feb;35(2): e70445
    Recognition of small Tim chaperones by the mitochondrial Yme1 protease.
    Mariella Quispe-Carbajal, Lauren Todd, Steven E Glynn.
      Yme1 is a conserved ATP-dependent protease that maintains mitochondrial function by degrading proteins in the intermembrane space. However, how Yme1 selects substrates within the crowded mitochondrial environment is poorly understood. An established substrate of Yme1 in yeast is the Tim10 subunit of the small Tim9-Tim10 protein chaperone complex, which is degraded following disruption of the subunit's internal disulfide bonds. Here, we use biochemical and biophysical approaches to examine initial substrate binding and degradation of small Tim proteins by Yme1 and shed light on the molecular mechanism of substrate selection. We show that Yme1 preferentially binds Tim10 over other small Tim proteins by forming a strong interaction with the subunit irrespective of the presence of its disulfide bonds. This interaction is primarily mediated by Tim10's flexible N-terminal "tentacle," though substrate unfolding exposes additional contact sites that enhance engagement. Notably, the human ortholog TIMM13 is also recognized by yeast Yme1, suggesting conservation of recognition strategy across species. Yme1 also binds to the assembled Tim9-Tim10 chaperone but independently of the Tim10 N-terminal tentacle. These findings suggest that Yme1 interacts with both the functional chaperone complex and the disassembled Tim10 monomers but only commits to degradation after disruption of its disulfide bonds.
    Keywords:  AAA+ proteases; intermembrane space; i‐AAA; mitochondrial proteostasis
    DOI:  https://doi.org/10.1002/pro.70445
  60. Cell Oncol (Dordr). 2026 Jan 19. 49(1): 28
    Low-dose Simvastatin protects pancreatic cancer cells by promoting mitochondrial autophagy through TFEB.
    Zhiliang Wang, Di Wu, Yue Zhang, Weibo Chen, Shupei Fan, Yang Yang, Yue Yang, Guangchen Zu, Yong An, Yuchi Jin, Aining Kang, Yanxun Zou, Yi Liu, Xianjun Yu, Yi Qin, Xiaowu Xu, Xuemin Chen.
       BACKGROUND: Pancreatic cancer is typically accompanied by fibrosis, forming a dense stromal matrix. This dense matrix restricts drug penetration, making it difficult for drugs to effectively reach tumor cells. Additionally, pancreatic cancer has inadequate local blood supply and "vascular irregularity," which makes it challenging for drugs to reach the core of the tumor. Even if some drugs reach the pancreas through systemic circulation, poor vascular permeability prevents them from effectively entering tumor cells, resulting in suboptimal therapeutic effects. Statins were initially used to treat high cholesterol levels and prevent cardiovascular diseases, but recent studies suggest that they may also have potential therapeutic effects on cancer, particularly certain types of cancer such as pancreatic cancer. However, clinical research on the use of statins for pancreatic cancer treatment is still ongoing, and the results are inconsistent. The effects of statins on pancreatic cancer may vary depending on the dose. Due to the aforementioned limitations of fibrosis and lack of blood supply in pancreatic cancer, simvastatin only exerts its effect on pancreatic cancer cells at low doses.
    PURPOSE: This study aimed to explore the effects of low-dose simvastatin on pancreatic cancer cells and the underlying mechanisms. We investigated the effects of different concentrations of simvastatin on pancreatic cancer cells.
    METHODS: The vitality of the cells was evaluated by CCK8, EDU staining, and the level of ferroptosis in pancreatic cancer cells was detected by flow cytometry detection of C11, MDA, ROS.
    RESULTS: We found that small doses of simvastatin can resist the toxicity of Erastin against pancreatic cancer cells. Under the transmission electron microscope, more mitophagosomes were produced in pancreatic cancer cells treated with small dose of simvastatin, and immunofluorescence revealed increased co-localization of lysosomes and mitochondria, indicating that simvastatin promoted the occurrence of mitophagy. At the same time, immunofluorescence confirmed that simvastatin promoted the nuclear translocation of TFEB, and chromatin immunoprecipitation and dual-luciferase gene report confirmed that TFEB is the transcription factor of P62/SQSTM1. This study clarified that a small dose of simvastatin, in the event of mitochondrial stress in pancreatic cancer cells, induces mitophagy to clear damaged mitochondria, protecting pancreatic cancer cells from ferroptosis and apoptosis, by promoting the transcription of P62/SQSTM1 through the nuclear translocation of TFEB.
    CONCLUSION: These findings may explain one of the reasons for the suboptimal efficacy of simvastatin in the treatment of pancreatic cancer, while also providing new insights for research on the antitumor effects of statins.
    Keywords:  Mitochondrial autophagy; P62; Simvastatin; TFEB
    DOI:  https://doi.org/10.1007/s13402-026-01164-y
  61. Aquat Toxicol. 2026 Jan 16. pii: S0166-445X(26)00018-4. [Epub ahead of print]292 107722
    The mechanism of selenomethionine alleviating fluoride-induced brain injury in carp by regulating mitochondrial dynamics, oxidative stress and neuroinflammation: Integrated analysis of transcriptomics and metabolomics.
    Wenjie Wang, Mengyan Xu, Yongju Luo, Wenxuan Wang, Lijing He, Qianxi Han, Bo Liu, Lijuan Li, Jianjie Chen, Jinling Cao.
      This study was designed to clarify the protective effect of selenomethionine (Se-Met) and the underlying molecular mechanism on brain injury induced by fluoride (F) in carp. Using carp as the model organism, F injury model and Se-Met intervention models were established. Physiological and biochemical indicators (antioxidant enzyme activities, ATP synthesis efficiency, etc.), molecular biological analysis (apoptosis- and inflammation- related gene expression) and as well as transcriptomics and metabolomics technology were integrated to comprehensively investigate the pathological process of F-induced brain injury and the protective mechanism of Se-Met. The results showed that F significantly activated the NF-κB signaling pathway, induced mitochondrial dynamics imbalance (DRP1 up-regulation/MFN1 down-regulation), oxidative stress (decreased activities of GSH, SOD; increased MDA) and neuroinflammation (up-regulation of IL-1β, TNF-α; down-regulation of IL-10), eventually leading to neuronal apoptosis and behavioral disorders. Se-Met intervention effectively reversed these toxic effects through multiple pathways, specifically by restoring antioxidant enzyme activities (T-SOD, CAT, GSH-Px, GSH); Se-Met up-regulated the expression of anti-apoptotic gene Bcl-2 and down-regulated the expression of pro-apoptotic genes Bax and caspase-3 to inhibit neuronal apoptosis; Se-Met inhibited NLRP3 inflammasome activation and reduced the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-1α, IL-10, TGF-β); Se-Met balanced mitochondrial dynamics protein (DRP1/MFN1) expression and restored mitochondrial function (ATP and membrane potential recovery); Se-Met reversed abnormal expression of neuropeptides (GnRH-II, vip, PDYN). The integrated analysis of metabolomics and transcriptomics further revealed that Se-Met exerted neuroprotective effects by regulating calcium signaling pathway, arachidonic acid metabolism and neuroactive ligand-receptor interaction pathway. However, long-term exposure to Se-Met alone may also cause mild toxicity, indicating that its application requires strict control of dosage and exposure duration. This study elucidates the molecular mechanisms by which Se-Met mitigates F neurotoxicity and provides a theoretical basis for aquatic ecological risk assessment and selenium nutrition intervention strategies.
    Keywords:  Fluoride; Inflammatory response; Mitochondrial dysfunction; Neurotoxicity; Oxidative stress; Selenomethionine
    DOI:  https://doi.org/10.1016/j.aquatox.2026.107722
  62. Phytomedicine. 2026 Jan 14. pii: S0944-7113(26)00058-9. [Epub ahead of print]152 157821
    The herbal compound miltirone from Salvia miltiorrhiza targets DJ-1 to induce mitophagic dysfunction and ROS-dependent hippo activation in gastric cancer.
    Chuhang Wang, Xiaochen Ni, Xiaojuan Liu, Kaiyuan Zhang, Wei Fan, Jianing Guo, Mingsi Zhang, Yunhai Wei, Linfeng Zheng, Tao Jiang, Guangji Zhang.
       BACKGROUND: The protein DJ-1/PARK7 is highly expressed in various cancers and is involved in oxidative stress and mitophagy, making it a potential anti-cancer target. Salvia miltiorrhiza Bunge, a traditional Chinese herb, exhibits significant anti-tumor activity through its ethanol extract, though its specific active components and molecular mechanisms remain largely unknown.
    PURPOSE: This study aims to screen the active components from the ethanol extract of Salvia miltiorrhiza, elucidate the molecular mechanism underlying its anti-gastric cancer effects.
    METHODS: Liquid chromatography-mass spectrometry was employed to construct a compound library of SME, and limited proteolysis-mass spectrometry was employed for the screening of potential targets. The binding between compounds and DJ-1 was validated through surface plasmon resonance and molecular docking. In vitro experiments, including CCK-8, EdU, flow cytometry, Western blot, immunofluorescence, and transmission electron microscopy, were conducted to assess cell proliferation, apoptosis, autophagy, and mitochondrial function. In vivo anti-tumor efficacy was evaluated by the nude mouse xenograft model. Mechanistic studies involved ROS detection, kinase activity analysis, and gene knockdown.
    RESULTS: A total of 596 compounds were identified from SME, among which Miltirone directly bound to the DJ-1 protein (KD = 3.89 μM) and inhibited its antioxidant function. Miltirone significantly suppressed gastric cancer cell proliferation and induced apoptosis both in vitro and in vivo, while also causing mitochondrial dysfunction, autophagy impairment, and ROS accumulation. Furthermore, Miltirone activated the CBP/MOB1 axis in a ROS-dependent manner, promoting MOB1 phosphorylation and subsequently activating the Hippo pathway, leading to YAP phosphorylation and degradation. Inhibition of the Hippo pathway reversed the anti-tumor effects of Miltirone, indicating that activation of the Hippo signaling pathway is responsible for Miltirone-mediated anti-gastric cancer activity.
    Keywords:  DJ-1/PARK7; Gastric cancer; Hippo signaling; Limited proteolysis-mass spectrometry; Miltirone; Mitophagy; Reactive oxygen species; Salvia miltiorrhiza ethanol extract
    DOI:  https://doi.org/10.1016/j.phymed.2026.157821
  63. Free Radic Biol Med. 2026 Jan 16. pii: S0891-5849(26)00033-X. [Epub ahead of print]
    UBR4 Attenuates Cisplatin-Induced Acute Kidney Injury by Regulating the HRI-ISR Axis.
    Zeyu Tang, Chen Li, Cheng Yang, Xinghua Chen, Maoqing Tian, Liwen Qiao, Jiefei Zeng, Wenjing Zhen, Wei Liang, Lunzhi Liu, Huiming Wang, Xiangyou Li, Lu Zhang.
      Cisplatin is widely used in treating solid tumors, but its dose-limiting nephrotoxicity, which manifests as acute kidney injury (AKI), remains a major clinical challenge. The molecular pathways determining proximal tubular epithelial cell (PTEC) susceptibility during cisplatin-induced injury are not fully elucidated. Here, we identify ubiquitin protein ligase E3 component n-recognin 4 (UBR4) as a key regulator of the integrated stress response (ISR), which plays an important role in regulating reactive oxygen species (ROS) accumulation and mitophagy in the kidney. UBR4 expression was markedly upregulated in PTECs of mice with cisplatin-induced AKI. Tubule-specific Ubr4 deficiency exacerbated kidney dysfunction, tubular damage, and cell death. Mechanistically, UBR4 promoted ubiquitination and degradation of the kinase HRI, thereby constraining ISR overactivation and alleviating its inhibitory effect on mitophagy. Consistent with this mechanism, both genetic enhancement of UBR4 and pharmacological inhibition of the ISR with ISRIB significantly mitigated cisplatin-induced nephrotoxicity. Together, our findings uncover a previously unrecognized UBR4-HRI-ISR regulatory axis that serves as an intrinsic protective mechanism in the kidney and highlight UBR4 as a promising therapeutic target for preventing cisplatin-induced tubular injury.
    Keywords:  HRI; UBR4; acute kidney injury; integrated stress response; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.025
  64. FASEB J. 2026 Jan 31. 40(2): e71495
    β-Hydroxybutyric Acid Inhibits Mitochondrial Biogenesis via the HDAC2/SIRT7 Signaling Pathway After Intestinal Ischemia-Reperfusion.
    Ruoshi Shi, Yiguo Zhang, Lele Zhang, Ke Ding, Yixin Jing, Yu Shi, Rong Chen, Qingtao Meng.
      β-hydroxybutyric acid (BHB), a key ketone body with energy substrate and epigenetic regulatory roles, has contradictory effects in pathological contexts. Intestinal ischemia-reperfusion (IIR) is a life threatening perioperative complication characterized by metabolic disorders and mitochondrial dysfunction, yet BHB's role in IIR remains unclear. Using C57BL/6 mouse IIR models and Caco2 cell hypoxia-reoxygenation (HR) models, we identified a pathogenic mechanism: IIR induced nearly 10-fold elevation of intestinal BHB, while ketolytic enzymes 3-hydroxybutyrate dehydrogenase 1 (BDH1) and 3-oxoacid CoA-transferase 1 (OXCT1) were significantly downregulated, blocking BHB's metabolic pathway. Exogenous BHB administration failed to protect the intestine; instead, it selectively inhibited expression of histone deacetylase 2 (HDAC2) (by 30%) and disrupted its nuclear binding to the Sirt7 promoter, promoting Sirt7 gene transcriptional activation (mRNA upregulated by 2-fold). This cascade exacerbated oxidative stress (reactive oxygen species increased by 2.7-fold), reduced adenosine triphosphate levels (by 20%), impaired mitochondrial biogenesis (decreased mitochondrial DNA copy number and mitochondrial transcription factor A (TFAM)/mitochondrial ribosomal proteins (MRPs) expression), and aggravated intestinal barrier dysfunction (Claudin-1 reduced and D-lactate elevated). Notably, HDAC2 overexpression or SIRT7 knockdown reversed these impairments. Our findings uncover a previously unrecognized role of BHB in exacerbating IIR injury via the HDAC2/SIRT7 pathway, providing new insights for protecting pathological intestinal tissues at ischemic risk and targeting mitochondrial biogenesis.
    Keywords:  intestinal ischemia–reperfusion; mitochondrial biogenesis; mitochondrial dysfunction; protein acetylation; β‐Hydroxybutyric acid
    DOI:  https://doi.org/10.1096/fj.202502616R
  65. Rev Neurosci. 2026 Jan 22.
    The dual role of TRPC channel-mediated dysregulation of calcium signaling in regulating mitophagy in early brain injury after subarachnoid hemorrhage.
    Jieqiong Yang, Yan Zou, Xudong Zhao.
      Subarachnoid hemorrhage (SAH) induces early brain injury (EBI) through mechanisms involving mitochondrial dysfunction and dysregulated calcium signaling. Transient receptor potential canonical (TRPC) channels are critical mediators of calcium homeostasis and have emerged as key players in SAH pathophysiology. This review explores the interconnected roles of TRPC channel-mediated calcium dyshomeostasis and mitophagy in EBI. We summarize how mitochondrial damage post-SAH triggers mitophagy via ubiquitin-dependent and -independent pathways, a process with dual effects on neuronal survival. We then detail the dual-phase roles of TRPC subtypes: early neuroprotection via TRPC1/4 and later exacerbation of injury via TRPC3/6/7, linking their activation to vascular dysfunction and inflammation. Crucially, we propose and discuss the mechanistic links through which TRPC-mediated calcium signals may directly regulate mitophagic flux, thereby influencing EBI outcomes. Targeting this TRPC-mitophagy axis with subtype- and temporal-specific strategies holds therapeutic promise for SAH.
    Keywords:  calcium dyshomeostasis; early brain injury; subarachnoid hemorrhage; transient receptor potential channel
    DOI:  https://doi.org/10.1515/revneuro-2025-0115
  66. Front Oncol. 2025 ;15 1717138
    Mitophagy in gastrointestinal tumors: mechanisms and new targets for immunotherapy.
    Tao Zhang, Zhetan Ren, Bowen Tang, Ru Man, Lin Wang, Qingyan Wang, Jirun Peng, Yongduo Yu.
      Gastrointestinal tumors (GITs), particularly gastric and colorectal cancers, are the leading causes of cancer-related deaths worldwide. Despite advances in screening technologies and the continuous development of treatments, which have improved early diagnosis and therapeutic interventions, the morbidity and mortality rates remain high, presenting a significant challenge to global public health. While existing treatments can extend patient survival to some degree, they are often accompanied by substantial side effects. In recent years, immunotherapy has yielded positive outcomes for some patients. However, the emergence of immune escape mechanisms has hindered treatment effectiveness. As a result, there is an urgent need for new therapeutic strategies that can address the limitations of current approaches. mitophagy, a key cellular process, has gained significant attention in cancer research. It plays an essential role in maintaining cellular energy balance and metabolic stability, and is intricately linked to crucial biological processes such as drug resistance, metastasis, invasion, and the tumor microenvironment. This article aims to provide a comprehensive review of the mechanisms underlying mitophagy, examining its role in gastrointestinal cancers, particularly in relation to cellular metabolism, apoptosis, drug resistance, metastasis, invasion, and the tumor microenvironment. Additionally, it will explore the potential of mitophagy as a therapeutic target and address current clinical challenges. It is hoped that this research will offer new insights and directions for the treatment of GITs.
    Keywords:  drug resistance; gastrointestinal tumors; immune escape; immunotherapy; mitophagy
    DOI:  https://doi.org/10.3389/fonc.2025.1717138
  67. Front Pharmacol. 2025 ;16 1618418
    Unraveling the role of mitochondrial dysfunction in diabetic kidney disease: insights and interventions.
    Zhenliang Fan, Puchang Luo, Yuancheng Gao, Hongzhen Ma, Junfen Fan, Shriya Sanan, Peipei Zhang, Keda Lu, Hong Xia.
      The incidence of Diabetic Kidney Disease (DKD) is rising globally, paralleling the increasing prevalence of diabetes mellitus (DM). As DM spreads worldwide, DKD becomes a significant and growing complication, challenging healthcare systems. DKD is a leading cause of end-stage renal disease (ESRD), requiring costly renal replacement therapies. Mitochondria are vital for cellular energy production via oxidative phosphorylation (OXPHOS), playing a pivotal role in DKD pathogenesis through dysfunction in energy metabolism, reactive oxygen species (ROS) generation, and mitochondrial dynamics. Emerging evidence highlights the crucial role of mitochondrial dysfunction in the pathogenesis and progression of DKD. This review elucidates the intricate relationship between mitochondrial dysfunction and DKD pathophysiology, emphasizing mechanisms such as impaired OXPHOS, excessive ROS production, and disrupted mitochondrial biogenesis. We critically analyze therapeutic interventions, including preclinical compounds, repurposed clinical drugs, and experimental molecules, highlighting their efficacy, limitations, and clinical translation challenges. Emerging evidence suggests novel mitochondrial-targeted therapies may mitigate DKD progression, though controversies, such as inconsistent PGC-1α expression, warrant further investigation. By integrating molecular insights with clinical perspectives, this review aims to guide future research and therapeutic development for DKD.
    Keywords:  clinical translation; diabetic kidney disease; mitochondrial biogenesis; mitochondrial dysfunction; oxidative stress; therapeuticinterventions
    DOI:  https://doi.org/10.3389/fphar.2025.1618418
  68. Ecotoxicol Environ Saf. 2026 Jan 19. pii: S0147-6513(26)00096-5. [Epub ahead of print]310 119767
    Exposure to 77PD quinone inhibits longevity and healthspan via affecting mitochondrial signals in Caenorhabditis elegans.
    Chengjie Shu, Dayu Hu, Shengqi Cao, Beiwei Hou, Shunlin Gu, Lei Fu, Fenglun Zhang, Dayong Wang.
      The 77PD quinone (77PDQ), a member of PPDQs family, can be frequently detected in environment and bioavailable to organisms. In nematodes, toxicity of 77PDQ on longevity and healthspan and underlying mechanism were determined. Exposure to 0.1-10 μg/L 77PDQ reduced lifespan and inhibited healthspan indicated by change of locomotion behavior during the aging. 77PDQ was accumulated in mitochondrion, and caused mitochondrial dysfunction. Activities of mitochondrial complex I/II and expression of component genes for complex I/II were inhibited by 77PDQ, and RNAi of component genes of gas-1 and mev-1 strengthened 77PDQ toxicity on longevity and healthspan. Additionally, expressions of hsp-6/60, mitochondrial UPR (mt UPR) marker genes, were inhibited by 10 μg/L 77PDQ, suggesting induction of suppression in mt UPR. 77PDQ toxicity on longevity and healthspan was also exacerbated by hsp-6/60 RNAi. Pharmacological treatment with cuminaldehyde inhibited 77PDQ toxicity on longevity and healthspan and in causing suppression in mt UPR. This beneficial effect of cuminaldehyde could be disrupted by gas-1, mev-1, hsp-6, and hsp-60 RNAi, which further confirmed role of these mitochondrial signals in controlling 77PDQ toxicity. Therefore, risk of 77PDQ exposure in inhibiting longevity and healthspan was suggested, which was associated with dysregulation of mitochondrial signals.
    Keywords:  77PD quinone; Caenorhabditis elegans; Cuminaldehyde; Mitochondrial dysfunction; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.119767
  69. Acta Pharmacol Sin. 2026 Jan 21.
    Protopanaxatriol restores cognitive function in okadaic acid-treated mice via direct inhibition of pathological CDK5 activity.
    Ye Peng, Sha-Sha Wang, Ke-Dao Lai, Jun-Rui Ye, Wen-Bing He, Xu Yan, Zhao Zhang, Shi-Feng Chu, Nai-Hong Chen.
      Alzheimer's disease (AD), a prevalent neurodegenerative dementia, presents therapeutic challenges due to safety concerns about amyloid-targeting strategies. Traditional Chinese medicine (TCM) may offer alternative avenues for exploration. Ginsenoside Rg1, a key bioactive component of ginseng, has shown neuroprotective potential in okadaic acid (OKA)-induced rat model, its limited brain bioavailability suggests that its metabolite protopanaxatriol (Ppt) may exert these effects. In this study, we investigated the therapeutic effects of Ppt on OKA-induced mice model and the underlying mechanisms. Cultured hippocampal neurons were treated with OKA (0.5 nM) with or without Ppt co-treatment for 24 h. We showed that Ppt (1.25-40 nM) exerted dose-dependent neuroprotection against OKA-induced cytotoxicity, with the maximal protection observed at 10 nM. The suppressed tau aggregation by Ppt was confirmed using a Venus-tau bimolecular fluorescence complementation (BiFC) system. Molecular dynamics simulations and microscale thermophoresis (MST) revealed that Ppt bound to the catalytic domain of CDK5 at Cys83, destabilizing the CDK5/p25 complex. Co-immunoprecipitation (Co-IP) assays with CDK5 mutants (S159T, C83A, F80A and D86A) validated this interaction. In vivo mice were treated with Ppt (10 mg/kg, i.g.) for 25 days. On D8 and D9, the mice were bilaterally microinjected with OKA into the cerebral ventricles. We showed that Ppt administration improved spatial memory deficits in Novel Object Recognition and Barnes Maze tests; these effects were abolished in mice expressing a lentivirus-mediated CDK5[C83A] mutant. Hippocampal transcriptomic profiling in OKA-challenged mice following Ppt intervention revealed that Ppt modulated Drp1-mediated mitochondrial fission/fusion dynamics, mitigating OKA-induced mitochondrial homeostasis disruption. Collectively, these results demonstrate that Ppt attenuates tau pathology by selectively targeting CDK5 at Cys83, thereby reducing pathological kinase activity, rebalancing mitochondrial function, and improving cognitive outcomes in an OKA-induced mice neurodegeneration model. The study underscores the therapeutic potential of Ppt in AD treatment and supports CDK5 modulation as a strategic approach for addressing tau-related neurodegeneration.
    Keywords:  Alzheimer’s disease; CDK5; Drp1; mitochondrial dysfunction; protopanaxatriol; tauopathy
    DOI:  https://doi.org/10.1038/s41401-025-01709-1
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