bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–08–30
fifty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Delay Differential Equation Approach to Oligomerization Reveals the Delay Dynamics Underlying Oscillations in Mitochondrial Fission.
  2. SREBF2 promotes mitophagy and protects against ferroptosis via Cav-1-regulated PINK1/Parkin signaling in ischemic heart failure.
  3. Mitochondrial Homeostasis Mediates the Sustained Neuroprotection of CNTF-Chitosan Hydrogel Against NMDA-Induced Retinal Ganglion Cell Excitotoxicity.
  4. Enhanced mitochondrial fission promotes chemosensitivity via SHP-1 activity in triple-negative breast cancer.
  5. Redox-Mediated Mitochondrial Dysfunction as a Common Pathogenic Axis in Acute Kidney Injury and Chronic Kidney Disease.
  6. A Function-Centric Framework for Mitochondrial Quality Control.
  7. POU2F1 promotes hypertensive cardiac fibrosis by regulating mitochondrial homeostasis through PINK1/Parkin‑dependent mitophagy.
  8. Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
  9. NSUN4-dependent m5C modification facilitates mitochondrial fission to accelerate diabetic nephropathy process via regulating SMURF1/CAMK1 axis.
  10. Astaxanthin alleviates dibutyl phthalate-induced cardiotoxicity in zebrafish larvae by regulating mitophagy.
  11. A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation.
  12. Core-shell lycopene-loaded nanoparticle-modified intraocular lens for posterior capsule opacification prevention via mitochondrial homeostasis.
  13. Targeting FUNDC1 Enhances Radiosensitivity of Esophageal Squamous Cell Carcinoma by Suppressing Mitochondrial Function.
  14. Inhibition of Mitochondrial Fission by Mdivi-1 Alleviates Doxorubicin-Induced Nephrotoxicity in a Rat Model of D-Galactose-Induced Accelerated Renal Aging.
  15. Fragile mitophagy in long COVID: a proposed recovery-failure endotype for post-exertional malaise.
  16. Ginsenoside Rh1 Modulates GABAergic Inhibitory Homeostasis and Mitochondrial Quality Control During Lead (Pb)-Associated Neuronal Dysfunction.
  17. Mfn2-related mitochondrial dysfunction regulates renal fibrosis through ferroptosis in chronic kidney disease.
  18. Exercise-Induced Regulation of Bone Remodeling via Mitophagy: A Review of Current Evidence.
  19. Mitochondrial Ca2+ Influx via MCU-1 Contributes to Oxidative Mitochondrial Defects in PDR-1/Parkin-Deficient Caenorhabditis elegans Body-Wall Muscle.
  20. Propofol regulates SLC6A2 expression via NAT10-mediated ac4C modification to modulate excessive mitophagy and hippocampal neuron dysfunction in aged postoperative cognitive dysfunction.
  21. Mitochondria-centered signalling in pulmonary hypertension: From metabolic reprogramming to vascular remodeling and right ventricular failure.
  22. Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.
  23. Electroacupuncture Prevents TBI-Induced Synaptic Loss by Inhibiting CaMKII/Drp1-Dependent Mitochondrial Fission.
  24. Gastrodia elata Blume-Acorus tatarinowii Schott herb pair alleviates seizures and hippocampal injury in TLE rats with alterations in mitophagy and NLRP3 inflammasome pathways.
  25. Berberine Modulates Mitophagy-Related Gene Expression and Suppresses Breast Cancer Cells: A Multi-Omics and Experimental Study.
  26. A Purified Lycii Fructus Polysaccharide Fraction Extends Healthspan in Caenorhabditis elegans with an ATFS-1/UBL-5-Associated Mitochondrial Unfolded Protein Response.
  27. KLF5 Downregulation Links Impaired BNIP3-Mediated Mitophagy to Inflammatory Valve Remodeling in Calcific Aortic Valve Disease.
  28. NAD⁺ or β-Hydroxybutyrate Each Protects Against Tachypacing-induced Metabolic Remodeling Through Regulation of Mitophagy in HL-1 Cardiomyocytes.
  29. Remimazolam Attenuates Neurological Injury After TBI: A Potential Role of α7nAChR-Associated Mitophagy Enhancement and Pyroptosis Suppression in BV2 Cells.
  30. The role of Mfn2/PERK mediated ER-mitochondrial communication in autophagy induced by silica nanoparticles in HT22 cells.
  31. Aging-Related Myocardial Susceptibility Lowers Cardiac Tolerance to Chronic Intermittent Hypoxia Through Dynamin-Related Protein 1-Associated Mitochondrial Vulnerability.
  32. Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.
  33. Correction: Silencing ATF3 mediates mitochondrial homeostasis and improves ischemic stroke through regulating the MAPK signaling pathway.
  34. Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.
  35. Prunasin alleviates OGD/R-induced injury in H9c2 cardiomyocytes via SRC/EGFR-AKT-FoxO-mediated mitochondrial quality control.
  36. Curcumin-Loaded Milk-Derived Exosomes Improve the Developmental Competence of Yak Oocytes by Regulating Mitophagy.
  37. ITCH-Mediated Ubiquitination and Degradation of THBS1: A Key Mechanism for Enhancing Mitochondrial Biogenesis and Alleviating Mouse Skeletal Muscle Atrophy.
  38. Mitochondrial regulation of cellular senescence heterogeneity.
  39. Mitochondrial Fusion Protein Mitofusin-2 Mediates the Protection of Fish Oil Against Porcine Intestinal Injury Induced by Deoxynivalenol.
  40. Circulating cell-free mitochondrial DNA as a redox-associated marker of mitochondrial homeostasis disruption during gastric carcinogenesis.
  41. Traffic jam at the powerhouse: restoring protein homeostasis at the mitochondria via MFB1 and HSP31 collaboration with clinical implications. An Educational Primer for use with "Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae".
  42. Transcriptomic and genetic evidence highlights EHHADH in a FUNDC1-associated mitochondrial network in diabetic nephropathy.
  43. Mitochondria as the Hub of Apoptosis: A Comprehensive Insight From Mitochondria to Interactions With Other Organelles.
  44. Oral Colon- and Mitochondria-Targeted Nanoparticles Alleviate Ulcerative Colitis by Reeducating Macrophage Polarization via SIRT3/FOXO3a-Mediated Mitochondrial Restoration.
  45. Bone morphogenetic protein 4-associated mitochondrial dysfunction in diabetic nephropathy involves Parkin downregulation.
  46. Altered TAGLN Expression During HBV Replication Correlates with OPA1 Levels.
  47. Mitochondrial Dysfunction in Renal Cell Carcinoma: A Comprehensive Review of Pathogenic Mechanisms and Emerging Therapeutic Opportunities.
  48. Neonatal Reversible Aortic Constriction Mice Model Unlocks Distinctive Footprints of Young Heart Recovery.
  49. Inflammation-Associated Changes in Piezo1 Expression, Mitophagy-Related Markers, and Matrix Dysregulation in an LPS-Stimulated Co-Culture Organoid System.
  50. AMPK-Orchestrated Metabolic Reprogramming in Some Flavivirus Infections: Mechanisms and Therapeutic Opportunities.
  51. Integrative multi-omics and machine learning analysis identifies candidate biomarkers associated with mitochondrial quality control in major depressive disorder.
  52. IRF1 in Adipocytes Is Associated with Insulin Signaling and Mitochondrial Homeostasis in Diet-Induced Obesity.
  53. Neuromuscular Dysfunction and Charcot-Marie-Tooth Disease Reversal in Mfn2 T105M Knock-In Rats.
  54. Understanding cardiovascular aging as a disorder of mitochondrial network.
  55. Forsythoside A Alleviates Hypertensive Nephropathy by Promoting Mitophagy and Inhibiting Ferroptosis via ASCL1-CCNB1/mTOR Pathway.
  56. Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives.
  57. Adaptor proteins recruit DRP1 into helical assemblies on mitochondria: Insights from super-resolution imaging.
  58. Urolithins: microbial biosynthesis, metabolic pathways and health benefits for functional food and cosmeceutical applications.
  59. Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
  1. Bull Math Biol. 2026 Aug 22. pii: 165. [Epub ahead of print]88(9):
    Delay Differential Equation Approach to Oligomerization Reveals the Delay Dynamics Underlying Oscillations in Mitochondrial Fission.
    Kitrick Fynaardt, Anna K Leinheiser, Colleen C Mitchell, Chad E Grueter.
      Disruptions in the balance of mitochondrial fission and fusion are implicated in a host of diseases including cardiovascular, metabolic, and neurodegenerative, as well as cancer. Leinheiser et al. proposed a mechanistic model for mitochondrial fission which relies on the oligomerization of Dynamin-related protein 1 (Drp1). In this work, we propose an alternative state-dependent delay-differential equation (sdDDE) framework for mitochondrial fission, which reveals that the intrinsic delay dynamics in Drp1 oligomerization can drive oscillations in the rate of mitochondrial fission. To develop this sdDDE model, we generate a simplified model which disallows oligomer disassembly on the mitochondrial membrane. Following homogenization, the simplified model approaches a steady state dominated by oligomers too small to reach the threshold for fission. Therefore, the fission rate approaches zero when initial conditions reside within the basin of attraction of this fission-free equilibrium. We therefore reincorporate oligomer disassembly on the mitochondrial membrane. However, the attracting, fission-free equilibrium persists. To eliminate this fission-free equilibrium, we incorporate an atomization term into the oligomerization mechanism, highlighting the importance of oligomer disassembly in sustaining mitochondrial fission. Using homogenization techniques, we derive an advection PDE with nonlocal interactions and obtain a reduced sdDDE system governing oligomer partial moments. Analysis of this reduced system reveals an analogous Hopf bifurcation to the Leinheiser et al. fission model, demonstrating that intrinsic delays in Drp1 oligomerization are sufficient to generate oscillatory mitochondrial fission dynamics.
    Keywords:  DDE; Delay-differential equation; Delay-differential equation of threshold type; Homogenization; Hopf bifurcation; Mitochondrial dynamics; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s11538-026-01743-y
  2. J Mol Med (Berl). 2026 Aug 27. pii: 103. [Epub ahead of print]104(1):
    SREBF2 promotes mitophagy and protects against ferroptosis via Cav-1-regulated PINK1/Parkin signaling in ischemic heart failure.
    Jia Li, Jia Liu, Fanyan Luo, Chengliang Zhang, Wen Hu, Wei Liu.
      Myocardial infarction-induced heart failure (MI-HF) remains a major contributor to cardiovascular mortality, yet the molecular mechanisms underlying its progression, particularly those involving ferroptosis, are not fully understood. This study aimed to investigate the role of SREBF2 in regulating ferroptosis and mitochondrial homeostasis in MI-HF. Differentially expressed genes were screened from the GSE24519 dataset and overlapped with ferroptosis-related genes, identifying SREBF2 as a potential target. SREBF2 expression was examined in human HF samples, MI-HF mice, and oxygen-glucose deprivation (OGD)-injured cardiomyocytes. Functional roles of SREBF2 were evaluated through in vivo overexpression in mice and in vitro assays in cardiomyocytes. Ferroptosis markers (GPX4, ACSL4, ROS, MDA, Fe²⁺, GSH), mitochondrial membrane potential (ΔΨm), and mitophagy-related proteins (PINK1, Parkin, p62) were assessed. Chromatin immunoprecipitation and rescue experiments were conducted to confirm the transcriptional regulation of Caveolin-1 (Cav-1) by SREBF2. SREBF2 was significantly downregulated in MI-HF tissues and OGD-injured cardiomyocytes. Overexpression of SREBF2 improved cardiac function, reduced infarct size and fibrosis, and enhanced myocardial remodeling in MI-HF mice. SREBF2 suppressed ferroptosis by reducing ROS, Fe²⁺, and MDA levels, restoring GSH and GPX4, and downregulating ACSL4. Mitochondrial dysfunction was alleviated via improved ΔΨm, reduced mitoROS, and balanced mitochondrial dynamics. SREBF2 activated PINK1/Parkin-mediated mitophagy, which was essential for its anti-ferroptotic effects. Mechanistically, SREBF2 directly bound to and transcriptionally activated Cav-1, which mediated downstream mitophagy activation and ferroptosis inhibition. Cav-1 knockdown or mitophagy inhibition abrogated SREBF2-induced mitochondrial protection and cytoprotection. The results of our study demonstrate that SREBF2 mitigates MI-induced HF by activating the Cav-1/PINK1/Parkin axis to promote mitophagy and inhibit ferroptosis. These findings reveal a novel cardioprotective mechanism and identify SREBF2 as a promising therapeutic target in heart failure.
    Keywords:  Ferroptosis; Heart failure; Mitophagy; Myocardial infarction; PINK1/Parkin; SREBF2
    DOI:  https://doi.org/10.1007/s00109-026-02707-4
  3. Int J Mol Sci. 2026 Aug 12. pii: 7200. [Epub ahead of print]27(16):
    Mitochondrial Homeostasis Mediates the Sustained Neuroprotection of CNTF-Chitosan Hydrogel Against NMDA-Induced Retinal Ganglion Cell Excitotoxicity.
    Huiting Jiang, Xunhui Guo, Yuanyuan Bai, Xinyue Ma, Hongmei Duan, Xiaoguang Li, Zhaoyang Yang.
      N-methyl-D-aspartate (NMDA) excitotoxicity drives mitochondrial dysfunction and retinal ganglion cell (RGC) loss in blinding retinal disorders. Ciliary neurotrophic factor (CNTF) is neuroprotective, but its short half-life limits long-term therapy. Here, we investigated whether mitochondrial homeostasis mediates the sustained protection of a CNTF-loaded chitosan hydrogel. In vitro, free CNTF and the hydrogel equally protected RGCs against NMDA, effects completely abolished by the mitochondrial uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP). In vivo, free CNTF provided only transient rescue, whereas the hydrogel sustained RGC survival, mitochondrial integrity, and visual function for 28 days, with persistent upregulation of mitochondrial biogenesis genes. Adeno-associated virus-mediated DRP1 overexpression-induced mitochondrial fission fully reversed the hydrogel's benefits, mirroring CCCP inhibition. Collectively, intact mitochondrial homeostasis is essential for the long-term neuroprotection of the CNTF-chitosan hydrogel, which extends CNTF retention without altering its mitochondrial-dependent mechanism. This hydrogel represents a promising long-acting treatment for retinal excitotoxicity.
    Keywords:  NMDA excitotoxicity; chitosan hydrogel; ciliary neurotrophic factor; mitochondrial dynamics; mitochondrial homeostasis; retinal ganglion cells
    DOI:  https://doi.org/10.3390/ijms27167200
  4. Mol Biol Rep. 2026 Aug 25. pii: 1459. [Epub ahead of print]53(1):
    Enhanced mitochondrial fission promotes chemosensitivity via SHP-1 activity in triple-negative breast cancer.
    Elizabeth K Croom, Lillian E Walton, Alessandro J Bono, Anne Zhang, Brock A Humphries.
       BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with high chemoresistance and poor survival rates. While mitochondrial dynamics, fission and fusion, are implicated in chemoresistance, their precise roles remain largely unexplored. This study investigates how cytoplasmic phosphatases SHP-1 and SHP-2 regulate chemotherapeutic response in TNBC cells with altered mitochondrial dynamics.
    METHODS: We utilized click beetle green luciferase-expressing SUM149 and SUM159 TNBC cells engineered to stably express mitochondrial dynamics modulators (PISD, Drp1, MFN2). SHP-1/2 activity was further manipulated using either the inhibitor NSC87877 or stable shRNA knockdown, confirmed by qRT-PCR and Western Blotting. Cell growth and cytotoxicity were evaluated through bioluminescence imaging and drug assays using doxorubicin, paclitaxel, and salinomycin.
    RESULTS: We show that SUM149 and SUM159 TNBC cells engineered to exhibit enhanced mitochondrial fission via increased PISD and Drp1 expression are more sensitive to doxorubicin and salinomycin, but not paclitaxel. SHP-1/2 inhibition attenuated doxorubicin and salinomycin sensitivity specifically in mitochondrial fission-enriched cells, with minimal effects in fusion-enriched cells and no effect on paclitaxel response. Notably, only SHP-1 knockdown reduced drug sensitivity in cells with enhanced mitochondrial fission, highlighting SHP-1 as a key regulator of chemoresistance. Conversely, enhanced mitochondrial fusion conferred resistance to cytotoxic agents.
    CONCLUSIONS: Our in vitro findings demonstrate that mitochondrial fission sensitizes TNBC cells to certain chemotherapeutics, and that SHP-1 critically regulates this response. This newly identified mechanism links mitochondrial dynamics to chemotherapeutic sensitivity, offering a potential pathway to overcome TNBC chemoresistance through targeted therapies.
    Keywords:  Cell signaling; Drug resistance; Mitochondrial dynamics; SHP-1 (PTPN6); SHP-2 (PTPN11); Triple-negative breast cancer
    DOI:  https://doi.org/10.1007/s11033-026-12615-y
  5. Biomolecules. 2026 Aug 07. pii: 1148. [Epub ahead of print]16(8):
    Redox-Mediated Mitochondrial Dysfunction as a Common Pathogenic Axis in Acute Kidney Injury and Chronic Kidney Disease.
    Ewelina Młynarska, Kinga Bojdo, Katarzyna Hossa, Wiktoria Lisińska, Katarzyna Krawiranda, Natalia Krupińska, Natalia Kustosik, Anna Wieczorek, Jacek Rysz, Beata Franczyk.
      Acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic kidney disease (DKD) are interconnected disorders linked by shared mechanisms involving redox imbalance and mitochondrial dysfunction. This review summarizes current evidence on the role of excessive reactive oxygen species (ROS) production, impaired oxidized nicotinamide adenine dinucleotide (NAD+) metabolism, altered mitochondrial bioenergetics, disrupted mitochondrial dynamics, and defective mitochondrial quality control pathways, including mitophagy and the mitochondrial unfolded protein response (UPRmt), in kidney disease progression. Experimental and clinical studies indicate that these mechanisms contribute to inflammation, fibrosis, apoptosis, and maladaptive repair, promoting progression from AKI to CKD and worsening DKD. The review also discusses emerging biomarkers and therapeutic strategies targeting oxidative stress and mitochondrial dysfunction. Overall, redox-mediated mitochondrial injury represents a shared pathogenic axis and a potential therapeutic target across kidney diseases.
    Keywords:  acute kidney injury; biomarkers; chronic kidney disease; diabetic kidney disease; mitochondrial bioenergetics; mitophagy; reactive oxygen species; reductive stress; targeted therapies
    DOI:  https://doi.org/10.3390/biom16081148
  6. Biomolecules. 2026 Jul 30. pii: 1116. [Epub ahead of print]16(8):
    A Function-Centric Framework for Mitochondrial Quality Control.
    Fulya Ozcan, Filip Vujovic, Ramin M Farahani.
      Mitochondrial quality control (QC) comprises interconnected pathways that preserve organelle function by detecting damage and mediating repair, remodelling, or elimination of defective components. Although many sub-organellar QC mechanisms are well characterised, stress is often sensed first at the level of mitochondrial function rather than at individual molecular targets. Functional domains such as oxidative folding, bioenergetics, redox balance, pH, and thermogenesis act as sensory portals that detect perturbations and trigger adaptive reprogramming of mitochondrial activity. In this perspective, we provide a conceptual perspective for mitochondrial QC as a mechanistically integrated network, emphasising how changes in these functional states couple diverse QC modules-including proteases, antioxidant systems, mitochondrial dynamics, mitophagy, and mitochondrial-derived vesicles-into a unified surveillance system. We propose that primary stressors, such as redox imbalance, are progressively converted into secondary stress signals, including reactive oxygen species accumulation, membrane depolarisation, metabolite redistribution, and altered lipid or nucleic-acid structure. These secondary signals propagate across mitochondrial and cytosolic compartments, amplifying QC by coordinating the engagement of repair, remodelling, and organelle-elimination pathways. This cascading transformation of stress signals not only limits the impact of the initial insult but also enhances adaptive capacity by driving synergistic deployment of QC processes across multiple mechanistic layers.
    Keywords:  cell cycle; electron transport chain; mitochondria; quality control; signalling pathways
    DOI:  https://doi.org/10.3390/biom16081116
  7. Mol Med Rep. 2026 Oct;pii: 290. [Epub ahead of print]34(4):
    POU2F1 promotes hypertensive cardiac fibrosis by regulating mitochondrial homeostasis through PINK1/Parkin‑dependent mitophagy.
    Yongbo Ma, Xiaozhe Chen, Zixian Liu, Yulong Ma, Chunlei Hou, Yunfeng Li, Mingtai Gui, Bo Lu, Deyu Fu, Mingzhu Wang.
      Hypertension‑induced cardiac fibrosis is a major risk factor for heart failure; although disrupted mitochondrial homeostasis has been confirmed to serve a critical role in the pathological process, its upstream regulatory factors remain incompletely understood. In the current study, RNA sequencing and bioinformatics analyses identified POU domain class 2 transcription factor 1 (POU2F1) as a hub transcriptional regulator in the fibrotic cardiac tissues of spontaneously hypertensive rats (SHRs). The expression levels of POU2F1 were associated with the severity of myocardial fibrosis, and cardiac expression of PTEN‑induced kinase 1 (PINK1) and Parkin in SHRs. Complementing these in vivo observations, angiotensin II stimulation significantly upregulated POU2F1 expression in cardiac fibroblasts (CFs) in vitro. Furthermore, POU2F1 expression exhibited a positive correlation with fibroblast activation, as indicated by α‑smooth muscle actin fluorescence intensity. Mechanistically, POU2F1 knockdown attenuated CF activation, improved mitochondrial structure and energy metabolism, and restored PINK1/Parkin‑mediated mitophagy balance in vivo and in vitro. Conversely, POU2F1 overexpression was associated with enhanced PINK1/Parkin‑mediated mitophagy signaling. Crucially, through chromatin immunoprecipitation‑quantitative PCR, electrophoretic mobility shift assay and dual‑luciferase reporter assay, it was demonstrated that POU2F1 can directly bind to the PINK1 promoter to activate its transcription. In conclusion, the present study identified a novel role for POU2F1 in hypertensive cardiac fibrosis, demonstrating that it exacerbates disease progression by disrupting mitochondrial homeostasis through transcriptional activation of PINK1, accompanied by alterations consistent with enhanced PINK1/Parkin‑mediated mitophagy.
    Keywords:  PINK1; POU2F1; cardiac fibrosis; hypertension; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2026.14001
  8. J Biomed Sci. 2026 Aug 27. pii: 86. [Epub ahead of print]33(1):
    Rebalancing mitochondrial dynamics restores succinate dehydrogenase activity and reduces succinate release in hepatocellular carcinoma.
    Jing-Yiing Wu, Tzu-Ching Chang, Mei-Jen Chen, Shih-Han Cho, Jun-Yang Liou, Cheng-Chin Kuo, Kenneth K Wu.
       BACKGROUND: Dysregulated mitochondrial dynamics in cancer cells perturbs mitochondrial function and metabolism and promotes cancer progression. Its impacts on the electron transport chain, oxidative phosphorylation, redox balance, and glycolysis are well recognized. However, its influence on tricarboxylic acid (TCA) cycle activity is less clear. In this study, we hypothesized that excessive mitochondrial fragmentation suppresses the expression of succinate dehydrogenase (SDH), resulting in the accumulation and secretion of succinate.
    METHODS: We tested this hypothesis in human hepatocellular carcinoma (HCC) cell model, murine xenograft tumor model, human HCC tumor tissues, and serum samples from patients with HCC. Genetic suppression and pharmacological inhibition of dynamin-related protein 1 (Drp1) were employed to examine their effects on SDH expression and succinate levels. The effects of Mdivi-1, a pharmacological inhibitor of Drp1-mediated mitochondrial fission, were evaluated in the xenograft tumor model, and the impact of succinate on mitochondrial dynamics was assessed in Huh7 cells.
    RESULTS: The results reveal imbalance of mitochondrial fission and fusion proteins and increase in mitochondrial fragmentation which was associated with reduced expression of SDH and increased succinate. Succinate dehydrogenase B subunit (SDHB) mRNA levels were reduced in human HCC tumor tissues, and higher SDHB expression was associated with improved overall and relapse-free survival. Serum succinate levels were increased in patients with HCC. Genetic suppression and pharmacological inhibition of Drp1 resulted in restoration of SDH and reduction of succinate. Administration of Mdivi-1 reduced tumor growth and lung metastasis in the xenograft tumor model, which was associated with reduced p-Drp1 and increased SDHB. Addition of succinate to Huh7 cells enhanced Drp1-mediated mitochondrial fragmentation while succinate antibodies abrogated it. Overexpression of SDHB in Huh7 cells suppressed Drp1 activation and mitochondrial fragmentation through reduction of succinate. By contrast, SDHB silencing with SDHB siRNA enhanced Drp1 activation and mitochondrial fragmentation. These results suggest a positive feedback regulation of mitochondrial fragmentation by SDH/succinate.
    CONCLUSIONS: These findings indicate that the mitochondrial fragmentation-SDH-succinate regulatory loop plays an important role in HCC growth and metastasis and may represent a potential target for new drug development.
    Keywords:  Cancer metabolism; Dynamin-related protein 1; Hepatocellular carcinoma; Mitochondrial dynamics; Succinate; Succinate dehydrogenase
    DOI:  https://doi.org/10.1186/s12929-026-01289-0
  9. Clin Transl Med. 2026 Sep;16(9): e70783
    NSUN4-dependent m5C modification facilitates mitochondrial fission to accelerate diabetic nephropathy process via regulating SMURF1/CAMK1 axis.
    Danyi Yang, Yinyin Chen, Hao Li, Guoyong Liu, Yang Gao, Liyu He.
       BACKGROUND: NOP2/Sun RNA methyltransferase family member 4 (NSUN4)-mediated 5-methylcytosine (m5C) modification has been implicated in diabetes-related diseases. However, its role and molecular mechanism in diabetic nephropathy (DN) remain unclear.
    METHODS: DN mouse model was constructed by injecting with streptozotocin (STZ). High glucose (HG)-induced HK-2 cells were used to establish a cellular model of DN. The levels of NSUN4, SMAD ubiquitination regulatory factor 1 (SMURF1), calcium/calmodulin-dependent protein kinase 1 (CAMK1), and mitochondrial-related proteins were analyzed using qRT-PCR, western blot, or immunohistochemical staining. Renal injury in mice was evaluated using relevant kits and histological staining. Cell apoptosis, ROS production and proliferation were examined by TUNEL, dihydroethidium, MitoSOX Red and EdU staining. The interaction between SMURF1 and Aly/REF export factor (ALYREF) or CAMK1 was confirmed by RNA immunoprecipitation, Co-IP and ubiquitination assay.
    RESULTS: Upregulation of NSUN4 increased the m5C level in DN. Knockout of NSUN4 alleviated STZ-induced renal injury in mice by repressing renal tubule cell mitochondrial fission and promoting mitochondrial fusion. NSUN4 downregulation reduced mitochondrial fission and promoted mitochondrial fusion to relieve HG-induced HK-2 cell apoptosis. NSUN4-mediated m5C modification promoted SMURF1 mRNA stability by regulating ALYREF. SMURF1 overexpression rescued the suppressive effect of NSUN4 knockdown on cell mitochondrial fission and apoptosis. Besides, SMURF1 facilitated the ubiquitination and degradation of CAMK1. Furthermore, sh-CAMK1 abolished the inhibitory effect of sh-SMURF1 on cell mitochondrial fission and apoptosis. Meanwhile, downregulation of NSUN4 relieved STZ-induced renal injury in DN mice by reducing mitochondrial fission via the SMURF1/CAMK1 axis.
    CONCLUSION: NSUN4-mediated upregulation of SMURF1 promoted mitochondrial fission to accelerate DN progression via increasing CAMK1 ubiquitination. The discovery of the NSUN4/SMURF1/CAMK1 axis provides new insights into DN pathogenesis.
    Keywords:  CAMK1; NSUN4; SMURF1; diabetic nephropathy; m5C modification; mitochondrial
    DOI:  https://doi.org/10.1002/ctm2.70783
  10. Comp Biochem Physiol C Toxicol Pharmacol. 2026 Aug 24. pii: S1532-0456(26)00223-1. [Epub ahead of print]310 110665
    Astaxanthin alleviates dibutyl phthalate-induced cardiotoxicity in zebrafish larvae by regulating mitophagy.
    Jing Gao, Jinxing Wu, Jiachun Hu, Chunyan Li, Hao Ji.
      Dibutyl phthalate (DBP), an environmental endocrine disruptor, has been shown to pose potential risks for inducing cardiotoxicity, although its precise mechanism remains incompletely understood, and effective preventive strategies are lacking. Astaxanthin (AST), known for its potent antioxidant properties and potential cardiovascular protective effects, has garnered widespread attention. This study demonstrates that environmental concentrations of DBP cause cardiac dysfunction in zebrafish and reduce viability while increasing apoptosis in human cardiomyocytes (AC16), accompanied by elevated cardiac injury markers. Mechanistically, DBP induces mitochondrial oxidative stress (including increased ROS production, impaired antioxidant systems, and mitochondrial membrane potential and function disruption), leading to activation of the PINK1/Parkin pathway and excessive mitophagy. Intervention with AST alleviates oxidative stress, enhances mitochondrial function, and normalizes the overactivated mitophagy. Both in animal and cell models, AST exhibits significant cardioprotective effects. This study is the first to reveal that AST mitigates DBP-induced cardiotoxicity by regulating mitochondrial autophagy homeostasis, providing new insights into the molecular mechanisms of environmental pollutants-induced cardiovascular injury and potential therapeutic strategies.
    Keywords:  Astaxanthin; Cardiotoxicity; Dibutyl phthalate; Mitophagy; Zebrafish
    DOI:  https://doi.org/10.1016/j.cbpc.2026.110665
  11. Autophagy. 2026 Aug 28.
    A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation.
    Ian Collinson, Robin A Corey, Adam G Grieve.
      The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) - followed by PARL-mediated cleavage and degradation. This happens in healthy mitochondria with a high membrane potential (ΔΨ) across the inner-membrane - required for passage of proteins into or across the inner-membrane. The second being surface stabilization, Parkin activation and initiation of mitophagy upon membrane depolarization. But what if PINK1 acts in active mitochondria as well? Our recent work identifies a third fate - matrix entry! The findings expand the biology of PINK1 beyond mitochondrial surveillance for quality control alone. They suggest an additional mitophagy-independent regulatory role within the matrix, which turns out to be governed by the unusual properties of its TMD for the conferral of a decisive conformational switch.
    Keywords:  Mitochondria; PARL; PINK1; Parkinson’s disease; transmembrane
    DOI:  https://doi.org/10.1080/15548627.2026.2726091
  12. J Control Release. 2026 Aug 23. pii: S0168-3659(26)00696-6. [Epub ahead of print] 115292
    Core-shell lycopene-loaded nanoparticle-modified intraocular lens for posterior capsule opacification prevention via mitochondrial homeostasis.
    Jian-Ying Liu, Shi-Chao Zhao, Jing-Shang Zhang, Jin-Fei Wei, Chun-Bo Dong, Hui-Cong Zheng, Tao Jiang, Meng Li, Ying-Yan Mao, Xiu-Hua Wan.
      Posterior capsule opacification (PCO) develops when residual lens epithelial cells (LECs) proliferate, migrate, and undergo epithelial-mesenchymal transition (EMT) after cataract surgery. Because mitochondrial dysfunction may promote EMT-associated cellular remodeling, modulation of mitochondrial quality control could provide a complementary strategy for PCO prevention. Lycopene (LYC) is a natural antioxidant capable of regulating mitochondrial homeostasis. Here, we developed a microfluidic-engineered LYC-eluting intraocular lens (IOL) modified with poly(lactic-co-glycolic acid) (PLGA)-shelled LYC-loaded liposome-core nanoparticles (LYC@Lip@PLGA-IOL). This dual-encapsulation design improved LYC formulation stability, reduced the initial burst release, and enabled sustained LYC release over a 14-day period in vitro. In SRA01/04 lens epithelial cells, LYC attenuated PI3K/AKT activation, activated mitophagy, restored mitochondrial membrane potential and ATP production, reduced reactive oxygen species (ROS) accumulation, and consequently inhibited EMT and migration. In a rabbit PCO model, LYC@Lip@PLGA-IOL reduced posterior capsule opacity, capsular thickening, and EMT-associated fibrotic remodeling, while exhibiting favorable ocular and systemic biocompatibility over 28 days. These findings support sustained local delivery of LYC as a mitophagy-activating strategy for restoring mitochondrial homeostasis and preventing PCO.
    Keywords:  Core–shell nanoparticles; Intraocular lens; Lycopene; Mitochondrial homeostasis; Posterior capsule opacification
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115292
  13. Curr Gene Ther. 2026 Aug 12.
    Targeting FUNDC1 Enhances Radiosensitivity of Esophageal Squamous Cell Carcinoma by Suppressing Mitochondrial Function.
    Weinan Yao, Dong Guo, Xueyuan Zhang, Xingyu Du, Wenbin Shen, Shuchai Zhu.
       INTRODUCTION: As one of the most important treatments of Esophageal Squamous Cell Carcinoma (ESCC), the therapeutic effect of radiotherapy is still limited. FUN14 DomainContaining 1 (FUNDC1), a key regulator of mitophagy, has been implicated in tumor progression in several malignancies. However, its role in ESCC remains unclear. This study investigated the role of FUNDC1 in mitochondrial morphology, mitophagy, and radiosensitivity in ESCC cells.
    MATERIALS AND METHODS: We evaluated FUNDC1 expression in ESCC using bioinformatics and immunohistochemistry. The effects of FUNDC1 knockdown on malignant behavior were assessed through CCK-8, wound healing, and transwell assays. Flow cytometry analyzed cell cycle and apoptosis. Radiosensitivity was determined by colony formation assays with survival curve fitting using the Linear-Quadratic (LQ) model. DNA damage was assessed by γH2AX foci formation. Mitochondrial morphology and mitophagy were examined using live cell staining and immunofluorescence. Western blotting measured protein expression.
    RESULTS: FUNDC1 expression was elevated in multiple cancers. High FUNDC1 expression was associated with advanced tumor stage and showed an unfavorable survival trend in ESCC patients. In our clinical cohort, a significant association with overall survival was observed in the M0 subgroup. FUNDC1 knockdown inhibited proliferation, migration, and invasion, particularly after irradiation. It also enhanced IR-induced G2/M arrest, γH2AX foci formation, and apoptosis. Mechanistically, FUNDC1 knockdown attenuated IR-induced mitochondrial fission and mitophagy-related changes, accompanied by increased cytochrome c release and apoptosis. In addition, FUNDC1 knockdown was associated with reduced total HMGB1 expression, impaired HMGB1 nuclear-to-cytoplasmic translocation, and suppressed RAGE/ERK activation, and these changes were partially reversed by 14-3-3σ overexpression.
    DISCUSSION: Our findings suggest that FUNDC1 promotes malignant behavior and radioresistance in ESCC cells. FUNDC1 knockdown was accompanied by reduced mitochondrial fission, attenuated mitophagy-related changes, and enhanced apoptosis after irradiation. FUNDC1 may also modulate HMGB1/RAGE/ERK signaling through a mechanism involving 14-3-3σ, although the precise causal relationships remain to be established.
    CONCLUSION: FUNDC1 knockdown inhibited malignant behavior and enhanced radiosensitivity in ESCC cells, associated with altered mitochondrial morphology, reduced mitophagy-related changes, and suppression of HMGB1/RAGE/ERK signaling. FUNDC1 may serve as a potential target for radiosensitization in ESCC.
    Keywords:  14-3-3σ; ESCC; FUNDC1; mitochondrial fission; mitophagy; radioresistance
    DOI:  https://doi.org/10.2174/0115665232502208260729114754
  14. Biomolecules. 2026 Jul 29. pii: 1112. [Epub ahead of print]16(8):
    Inhibition of Mitochondrial Fission by Mdivi-1 Alleviates Doxorubicin-Induced Nephrotoxicity in a Rat Model of D-Galactose-Induced Accelerated Renal Aging.
    Anongporn Kobroob, Chayodom Maneechote, Sivaporn Sivasinprasasn, Nipon Chattipakorn, Orawan Wongmekiat.
      The clinical use of doxorubicin (DOX), an effective chemotherapeutic drug for breast cancer, is limited by off-target nephrotoxicity, which is exacerbated in elderly patients. While excessive mitochondrial fission is known to contribute to DOX-induced cardiotoxicity, its role in DOX-induced nephrotoxicity, particularly in the context of renal aging, remains unclear. To explore this and investigate the therapeutic potential of the mitochondrial fission inhibitor Mdivi-1, female Wistar rats with D-galactose-induced accelerated renal aging were allocated into four groups: vehicle, DOX, DOX+Mdivi-1 co-treatment, and DOX+Mdivi-1 post-treatment. DOX administration resulted in significant renal dysfunction, oxidative stress, inflammation, and histopathological damage. Mitochondrial dysfunction along with the increased expression of fission protein, decreased fusion proteins, and activation of apoptotic markers and PINK1 expression were also evident. Remarkably, both co-treatment and post-treatment with Mdivi-1 comparably and significantly attenuated DOX-induced renal damage. This study suggests that Mdivi-1 mitigates DOX-induced nephrotoxicity in the aged kidney by modulating mitochondrial dynamics, suppressing oxidative stress and inflammation, and inhibiting apoptosis. These findings highlight mitochondrial fission as a promising therapeutic target for the treatment of doxorubicin toxicity and provide further support for the possible use of Mdivi-1 as a therapeutic strategy to protect the kidneys of elderly breast cancer patients undergoing chemotherapy.
    Keywords:  Mdivi-1; apoptosis; doxorubicin; inflammation; mitochondrial dynamics; nephrotoxicity; oxidative stress; renal aging
    DOI:  https://doi.org/10.3390/biom16081112
  15. Front Med (Lausanne). 2026 ;13 1905758
    Fragile mitophagy in long COVID: a proposed recovery-failure endotype for post-exertional malaise.
    Robert Groysman.
      Long COVID is frequently characterized by exertion intolerance, delayed symptom exacerbation, treatment sensitivity, and prolonged recovery. Post-exertional malaise (PEM) is often interpreted as a manifestation of low energy availability, autonomic dysfunction, immune activation, endothelial disturbance, or deconditioning. This paper proposes an additional recovery-failure mechanism for a PEM-dominant subgroup: fragile mitophagy, defined as a mismatch in which mitochondrial injury and mitophagy engagement occur but lysosomal completion of mitochondrial degradation is inadequate. Incomplete clearance could permit mitochondrial debris and danger signaling to persist and amplify oxidative, innate immune, endothelial, and neuroimmune responses after physiologic stress. The model predicts delayed crashes, progressive lowering of baseline with repeated exertion, and poor tolerance of interventions that increase mitochondrial turnover when lysosomal capacity is insufficient. Patient-derived Long COVID studies demonstrate mitochondrial, metabolic, and structural abnormalities but do not yet establish defective dynamic mitophagy flux or lysosomal completion. Hydroxychloroquine and chloroquine are used only as pharmacologic analogies showing that late autophagic flux can be impaired by disrupted lysosomal handling. Trehalose, genistein, curcumin, and the curcumin analog C1 are presented as experimental mechanistic probes because of reported effects on TFEB or autophagy-lysosome biology, not as established Long COVID treatments. The central prediction is that PEM severity will correlate more closely with impaired lysosomal completion, abnormal mitophagy flux, mitochondrial debris, and danger signaling than with baseline adenosine triphosphate (ATP) deficiency alone.
    Keywords:  endotype; fragile mitophagy; long COVID; lysosome; mitochondrial DNA; mitochondrial dysfunction; mitophagy; post-exertional malaise
    DOI:  https://doi.org/10.3389/fmed.2026.1905758
  16. Molecules. 2026 Aug 11. pii: 2801. [Epub ahead of print]31(16):
    Ginsenoside Rh1 Modulates GABAergic Inhibitory Homeostasis and Mitochondrial Quality Control During Lead (Pb)-Associated Neuronal Dysfunction.
    Xiang Li, Tingting Wang, Linfeng Mo, Huixin Cao, Zhongting Lv, Jia Yu, Shuang Liu, Yantong Sun, Tianli Chen.
      Disruption of neuronal excitation-inhibition balance and mitochondrial quality control may contribute importantly to lead (Pb)-induced neurotoxicity, but nutritional modulators targeting these processes remain poorly characterized. This study investigated the protective effects and underlying mechanisms of ginsenoside Rh1, a ginseng-derived bioactive compound, in Pb-exposed mice and Pb-treated HT22 hippocampal cells. Chronic Pb exposure caused spatial recognition deficits, reduced exploratory activity, anxiety-like behaviors, and marked neuronal injury, accompanied by Pb accumulation in blood and brain tissues, elevated IL-1β, TNF-α, and IL-6 levels, oxidative stress, reduced Gama-aminobutyric acid (GABA) content, and dysregulated NKCC1/KCC2 expression. In HT22 cells, Pb increased intracellular ROS generation and disrupted mitophagy-related signaling, as indicated by alterations in PINK1, Parkin, LC3, P62, and GABARAP. Rh1 treatment alleviated Pb-induced behavioral abnormalities and neuronal pathology, reduced Pb burden, suppressed neuroinflammatory responses, enhanced antioxidant defenses, improved Pb-associated alterations in GABAergic regulation, and modulated mitochondrial quality-control signaling in vivo and in vitro. These findings suggest that Rh1 may represent a promising nutritional intervention strategy for mitigating Pb-associated neurotoxicity.
    Keywords:  GABAergic homeostasis; Pb metal neurotoxicity; ginsenoside Rh1; mitophagy
    DOI:  https://doi.org/10.3390/molecules31162801
  17. Biochim Biophys Acta Mol Basis Dis. 2026 Aug 24. pii: S0925-4439(26)00298-X. [Epub ahead of print]1873(1): 168432
    Mfn2-related mitochondrial dysfunction regulates renal fibrosis through ferroptosis in chronic kidney disease.
    Mingyu Zhang, Jingyu Wang, Ying Yang, Yutong Ma, Jiayi Huang, Hao Geng, Xiao Bai, Weihao Shang, Li Sun.
      Chronic kidney disease (CKD) has become a global public health concern and renal fibrosis is the ultimate outcome of CKD progressing to end-stage renal disease. The effective treatment for renal fibrosis is limited. Ferroptosis is a type of programmed cell death characterized by iron deposition and lipid peroxidation. Mitochondria are essential organelles that play a critical role in maintaining cellular function. However, the effect of ferroptosis and mitochondrial dysfunction on renal fibrosis remains unclear. In this study, we confirmed that the expression of glutathione peroxidase 4 (GPX4) and Parkin was decreased in the renal tissues of CKD patients. Their levels were negatively correlated with serum creatinine (Scr) and C-reactive protein (CRP) and positively with estimated glomerular filtration rate (eGFR). Subsequently, we established unilateral ureteral obstruction (UUO) mice models and transforming growth factor-β1 (TGF-β1)-induced fibrosis-like changes in human renal tubular epithelial cells (HK-2 cells). The results showed that mitophagy-related proteins were decreased in renal fibrosis. Carbonylcyanide-3-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, alleviates renal fibrosis by inhibiting ferroptosis, whereas mitochondrial division inhibitor 1 (Mdivi-1) exerts the opposite effect. In addition, bioinformatics analysis showed mitofusin2 (Mfn2) was involved in mitophagy and ferroptosis. We then conducted function experiments and revealed that Mfn2 knockdown inhibited mitophagy, exacerbated ferroptosis and renal fibrosis, while overexpression of Mfn2 promoted mitophagy, alleviated ferroptosis and renal fibrosis. In conclusion, this study is the first to illustrate the role and relationship of mitochondrial dysfunction, especially mitophagy, and ferroptosis in renal fibrosis and their interaction with Mfn2, providing new insights and potential therapeutic targets for renal fibrosis.
    Keywords:  Chronic kidney disease; Ferroptosis; Mfn2; Mitochondrial dysfunction; Mitophagy; Renal fibrosis
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168432
  18. Biomolecules. 2026 Aug 11. pii: 1171. [Epub ahead of print]16(8):
    Exercise-Induced Regulation of Bone Remodeling via Mitophagy: A Review of Current Evidence.
    Sicheng Yan, Xinjia Li, Yu Yuan, Yongjie Yang, Xuewen Tian, Xi Chen, Lan Zhang, Shihua Zhang.
      Bone remodeling imbalance represents the fundamental pathological basis of osteoporosis. Exercise is broadly regarded as a valuable non-pharmacological strategy for preventing and managing osteoporosis; however, the precise molecular mechanisms through which exercise modulates bone metabolism remain incompletely understood. Mitophagy has recently been recognized as an important mediator linking exercise to the regulation of bone remodeling. This review centers on the "exercise-mitophagy-bone remodeling" axis, systematically outlining the biological processes and regulatory determinants of mitophagy within the bone microenvironment. Evidence suggests that mitophagy facilitates bone formation by preserving mitochondrial quality, attenuating oxidative stress, and optimizing cellular energy metabolism. Moreover, it exerts stage-specific inhibitory effects on bone resorption during osteoclast differentiation. Particular emphasis is placed on the mechanisms by which exercise activates mitophagy-related signaling pathways via metabolic, mechanical, and hypoxic stimuli. In addition, exercise may enhance the efficiency of this regulatory axis by maintaining vitamin D and calcium homeostasis and modulating estrogen signaling pathways. The differential effects of exercise modalities and durations on these processes are also critically evaluated. Finally, this review addresses current limitations in existing research and highlights future directions, including the optimization of exercise interventions targeting mitophagy and the integration of multi-omics approaches. These findings offer a theoretical basis for designing precise exercise regimens and combined therapeutic approaches in the management of osteoporosis.
    Keywords:  bone metabolism; bone remodeling; exercise; mitophagy; osteoporosis
    DOI:  https://doi.org/10.3390/biom16081171
  19. Antioxidants (Basel). 2026 Aug 21. pii: 1043. [Epub ahead of print]15(8):
    Mitochondrial Ca2+ Influx via MCU-1 Contributes to Oxidative Mitochondrial Defects in PDR-1/Parkin-Deficient Caenorhabditis elegans Body-Wall Muscle.
    Masahiro Kawasumi, Mika Teranishi.
      Parkinson's disease (PD) is widely regarded as a disorder of dopaminergic neurons that involves mitochondrial dysfunction, impaired mitophagy, and oxidative stress. However, the nature and significance of skeletal muscle pathology remain unclear. In this study, we used Caenorhabditis elegans, which lack muscle stem cells in adulthood, to examine the effects of PDR-1/Parkin deficiency on mitochondrial homeostasis and motor function under conditions where muscle regeneration does not occur. Silencing of pdr-1 attenuated age-related mitochondrial fragmentation in body-wall muscle cells but was associated with later impairments in locomotor activity and loss of nuclear GFP signals, suggesting progressive muscle cell damage. By day 2 of adulthood, mitochondrial reactive oxygen species (mtROS) levels were elevated in muscle cells subjected to pdr-1 RNAi, and in the pdr-1(gk448) mutant this mtROS elevation was accompanied by a reduction in mitochondrial membrane potential (ΔΨm). In vivo imaging further revealed elevated mitochondrial Ca2+ levels ([Ca2+]mito) in PDR-1-deficient muscle cells. Moreover, the mtROS increase associated with PDR-1 deficiency was suppressed in mcu-1 mutants. These findings support a model in which MCU-1-dependent elevation of [Ca2+]mito contributes to oxidative mitochondrial defects in PDR-1/Parkin-deficient muscle.
    Keywords:  Caenorhabditis elegans; Parkinson’s disease; body-wall muscle cells; mitochondrial calcium influx; mitochondrial membrane potential; mitochondrial quality control; mitochondrial reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox15081043
  20. Naunyn Schmiedebergs Arch Pharmacol. 2026 Aug 29.
    Propofol regulates SLC6A2 expression via NAT10-mediated ac4C modification to modulate excessive mitophagy and hippocampal neuron dysfunction in aged postoperative cognitive dysfunction.
    Ranran Xu, Deming Xu.
      Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, and propofol exposure has been implicated in its pathogenesis. This study investigated whether propofol exacerbates hippocampal neuron dysfunction via N4-acetylcytidine (ac4C) modification mediated by N-acetyltransferase 10 (NAT10). HT22 cells were treated with propofol to assess cytotoxicity, inflammation, oxidative stress, and mitophagy. The NAT10/SLC6A2 interaction was validated using ac4C RNA immunoprecipitation (RIP), RNA pull-down, and dual-luciferase reporter assays. A POCD model was established by tibial fracture surgery in C57BL/6 J mice. Cognitive function was evaluated using Morris water maze and Y-maze tests. Propofol treatment upregulated SLC6A2 and NAT10 expression in HT22 cells (P < 0.05). Knockdown of SLC6A2 attenuated propofol-induced cytotoxicity, apoptosis, inflammation, oxidative stress, mitochondrial depolarization, and excessive mitophagy (P < 0.05). Mechanistically, NAT10 directly bound to SLC6A2 mRNA and induced ac4C modification of SLC6A2 mRNA, enhancing its stability. Overexpression of SLC6A2 reversed the protective effects of NAT10 knockdown (P < 0.05). In addition, the NAT10/SLC6A2 axis mediated propofol-induced activation of the NF-κB pathway (P < 0.05). In aged POCD mice, knockdown of SLC6A2 improved cognitive performance and reduced neuroinflammation, oxidative stress, and excessive mitophagy (P < 0.05). Propofol promotes excessive mitophagy and hippocampal neuron dysfunction in aged POCD via the NAT10-mediated ac4C modification-dependent upregulation of SLC6A2. Targeting SLC6A2 may represent a potential therapeutic strategy for POCD.
    Keywords:  Mitophagy; N-acetyltransferase 10; N4-acetylcytidine modification; Postoperative cognitive dysfunction; Propofol; Solute carrier family 6 member 2
    DOI:  https://doi.org/10.1007/s00210-026-05839-z
  21. Cell Signal. 2026 Aug 24. pii: S0898-6568(26)00504-8. [Epub ahead of print]148 112846
    Mitochondria-centered signalling in pulmonary hypertension: From metabolic reprogramming to vascular remodeling and right ventricular failure.
    Mengjie Zhang, Siqin Peng, Na Liang, Zijia Leng, Xiaohua Wang, Shaoxin Gong, Tianhong Peng, Aiping Wang.
      Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance, and right ventricular failure. Beyond its bioenergetic function, mitochondria act as signalling hubs that integrate metabolic flux, redox homeostasis, calcium handling, organelle contact sites, and cell-death programs. Accumulating evidence indicates that mitochondrial signalling abnormalities contribute to PH by promoting pulmonary artery smooth muscle cell proliferation, endothelial dysfunction, apoptosis resistance, inflammatory activation, and right ventricular metabolic remodeling. In this review, we summarize mitochondria-centered signalling pathways in pulmonary hypertension, with a primary focus on the well-established mechanisms in Group 1 PAH, including HIF-1α/PDK-mediated metabolic reprogramming, ROS-sensitive signalling, Drp1-dependent mitochondrial fission, PINK1/Parkin-mediated mitophagy, and MAM-regulated calcium transfer. Emerging evidence from other PH groups is also discussed where available.
    Keywords:  Metabolic reprogramming; Mitochondria; Mitochondrial dynamics; Mitophagy; Oxidative stress; Pulmonary artery smooth muscle cells; Pulmonary hypertension
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112846
  22. Biology (Basel). 2026 Aug 07. pii: 1334. [Epub ahead of print]15(16):
    Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.
    Maria Ciuro, Chantal Rovetto, Angela A Sirna, Salvatore Giunta, Giampiero Leanza, Rosario Gulino.
      Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1G93A mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS.
    Keywords:  Mdivi-1; SOD1G93A mouse model; TAR DNA-binding protein 43; amyotrophic lateral sclerosis; dynamin-related protein 1; mitochondrial dynamics; motor neurons; physiology; skeletal muscle atrophy; synaptic plasticity
    DOI:  https://doi.org/10.3390/biology15161334
  23. Biomolecules. 2026 Aug 11. pii: 1169. [Epub ahead of print]16(8):
    Electroacupuncture Prevents TBI-Induced Synaptic Loss by Inhibiting CaMKII/Drp1-Dependent Mitochondrial Fission.
    Sisi Zhao, Luxi Cao, Feidan Deng, Zhenge Liao, Xiaoxiang Li, Guanglei Li, Chunzhi Tang, Yimin Zhang, Shujun Lin.
      (1) Background: Traumatic brain injury (TBI) triggers synaptic loss, leading to long-term neurological deficits. Electroacupuncture (EA) benefits neurological conditions, but its mechanisms after TBI remain unclear. (2) Methods: We used a controlled cortical impact (CCI) mouse model. Behavioral outcomes were assessed using the modified neurological severity score (mNSS), rotarod, Y-maze, and novel object recognition test (NORT). Synaptic morphology was examined by transmission electron microscopy (TEM). Energy metabolism was assessed using biochemical assays, and mitochondrial function was assessed using flow cytometry. Quantitative real-time PCR (qPCR) and Western blotting (WB) were used to examine the underlying molecular mechanisms. (3) Results: We found that EA ameliorates TBI-induced motor and cognitive impairments by preserving synaptic and mitochondrial integrity. EA-treated mice showed improvements in mNSS, rotarod, NORT, and Y-maze performance, along with preserved synaptic ultrastructure and mitochondrial function. CaMKII overexpression abolished EA-induced neuroprotection, identifying the CaMKII/Drp1 axis as a key mediator. (4) Conclusions: Thus, EA limits TBI deficits by restraining CaMKII/Drp1-driven mitochondrial fission and subsequent synaptic loss.
    Keywords:  CaMKII/Drp1; electroacupuncture; mitochondrial fission; synaptic loss; traumatic brain injury
    DOI:  https://doi.org/10.3390/biom16081169
  24. J Ethnopharmacol. 2026 Aug 25. pii: S0378-8741(26)01195-5. [Epub ahead of print] 122340
    Gastrodia elata Blume-Acorus tatarinowii Schott herb pair alleviates seizures and hippocampal injury in TLE rats with alterations in mitophagy and NLRP3 inflammasome pathways.
    Jiaqing Hu, Xufei Chen, Ruoshi Tian, Qiulian Zeng, Yan Yang, Xirui He.
       ETHNOPHARMACOLOGICAL RELEVANCE: Temporal lobe epilepsy (TLE) is the most common drug-resistant focal epilepsy, with its progression tightly linked to mitochondrial dysfunction, neuroinflammation and neuronal injury. The herbal pair Gastrodia elata Blume and Acorus tatarinowii Schott (GEAT) is traditionally used for convulsive disorders, but its anti-epileptic mechanisms remain unclear.
    AIM OF THE STUDY: To investigate the therapeutic potential of GEAT in TLE and explore the potential mechanisms associated with its neuroprotective effects.
    MATERIALS AND METHODS: The components of GEAT were characterized by LC-MS/MS. A pilocarpine-induced TLE rat model was used. Seizure severity was scored using the Racine scale. Anxiety-like and memory behaviors were assessed using open-field and fear-conditioning tests. The therapeutic effects and mechanisms of GEAT were evaluated using histology, immunofluorescence, transmission electron microscopy, the JC-1 assay, and Western blotting.
    RESULTS: GEAT reduced seizures and improved anxiety-like behavior and contextual memory impairment in TLE rats. GEAT also attenuated hippocampal neuronal injury, reduced glial reactivity and altered microglial phenotype-related markers, and improved mitochondrial ultrastructural abnormalities and membrane potential. Additionally, GEAT treatment was associated with increased expression of PINK1/Parkin-related proteins and lysosome-associated proteins, as well as changes in HMGB1/TLR4/NF-κB/NLRP3 inflammasome-related markers and apoptosis-/pyroptosis-related proteins.
    CONCLUSIONS: Our findings show that GEAT alleviates seizures and hippocampal injury in TLE rats, accompanied by changes in mitophagy and lysosome-related proteins and HMGB1/TLR4/NF-κB/NLRP3 inflammasome markers, suggesting potential involvement of these pathways in its protective effects. This study provides evidence for the application of GEAT in TLE and a basis for further exploring the link between mitochondrial quality control and neuroinflammation in TLE.
    Keywords:  Gastrodia elata Blume-Acorus tatarinowii Schott herb pair; Lysosome; Mitophagy; NLRP3 inflammasome; Temporal lobe epilepsy
    DOI:  https://doi.org/10.1016/j.jep.2026.122340
  25. Cell Biochem Biophys. 2026 Aug 26.
    Berberine Modulates Mitophagy-Related Gene Expression and Suppresses Breast Cancer Cells: A Multi-Omics and Experimental Study.
    Hong Wang, Yingjin Luo, Kaihua Zheng, Xiaoqing Wu, Jiale Lv, Yongliang Mei, Wei Ren.
      Breast cancer became the most commonly diagnosed cancer worldwide in 2020. Mitophagy, as a key mechanism for selectively clearing damaged mitochondria, plays an important role in breast cancer-related processes. Berberine has shown its anti-tumor ability in multiple types of tumors, but whether berberine exerts its anti-breast cancer effects through modulating mitophagy-related genes remains to be elucidated. This study integrated the Gene Expression Omnibus (GEO) database and single-cell sequencing, explored the key genes that interfere with breast cancer, evaluated and verified the efficacy of berberine against breast cancer by molecular docking and in vitro experiments, and provided a novel direction to breast cancer prevention and therapy and drug development. Screening autophagy-related targets through the GEO database combined with the autophagy gene library and revealing the relationship within cancerous cells with immunological cells through single-cell sequencing. Using molecular docking and in vitro tests to evaluate and confirm the efficacy of berberine against breast cancer. In this study, 20 pivotal genes were screened and identified. These genes are mainly involved in autophagy-related pathways that are significantly activated in breast cancer. Enrichment analysis showed that autophagy and mitophagy pathways were obvious in breast cancer. The immune microenvironment of single-cell shows that pathological changes of fibroblasts and NK cells mediated by macrophage invasion in tumor tissue may be an important molecular mechanism of breast cancer. Molecular docking and in vitro experiments suggest that berberine can effectively inhibit breast cancer by targeting BECN1, BCL2, HIF1A, MYC, PINK1, and FOXO3 to regulate autophagy initiation and mitochondrial quality control, while CASP3 was assessed only at the mRNA level due to the intrinsic CASP3 deficiency in MCF-7 cells. Through GEO data combined with single-cell sequencing and in vitro experimental verification, this study revealed the pivotal gene of mitophagy in breast cancer and provides evidence that berberine modulates mitophagy-related genes and induces mitochondrial damage. These findings offer a theoretical basis for further investigation into berberine in breast cancer therapy.
    Keywords:  Berberine; Breast Cancer; Mitophagy; Single-Cell Technology; Transcriptome
    DOI:  https://doi.org/10.1007/s12013-026-02156-3
  26. Antioxidants (Basel). 2026 Jul 29. pii: 944. [Epub ahead of print]15(8):
    A Purified Lycii Fructus Polysaccharide Fraction Extends Healthspan in Caenorhabditis elegans with an ATFS-1/UBL-5-Associated Mitochondrial Unfolded Protein Response.
    Yanting Hu, Xuhan Zhang, Yihang Xu, Wenhao Fan, Zhouyuan Xue, Yutong Wang, Zhongyuan Wang, Fang Zhang, Jialiang Hu, Zheng Qiu.
      Mitochondrial unfolded protein response (UPRmt) is crucial in preserving mitochondrial health and, consequently, in prolonging healthspan. Natural bioactive polysaccharides have emerged as a central focus for delaying senescence, although their links to mitochondrial stress responses remain incompletely understood. In this study, a purified fraction of Lycii Fructus polysaccharide (FSP) significantly extended lifespan, improved healthspan-related phenotypes, and enhanced resistance to heat, oxidative, and ultraviolet stress in C. elegans. FSP also preserved mitochondrial abundance and morphology, increased adenosine triphosphate (ATP) levels and mitochondrial membrane potential, and reduced reactive oxygen species. Transcriptomic and qPCR analyses, together with hsp-60 and hsp-6 reporter assays, showed an enhanced UPRmt-associated response after FSP treatment. FSP-mediated lifespan extension was not observed in the atfs-1 and ubl-5 mutant strains, supporting pathway involvement of ATFS-1/UBL-5-dependent UPRmt signaling. FSP reduced senescence-associated β-galactosidase positivity and improved mitochondrial function in human dermal fibroblasts. Our findings provide a vision of regulating UPRmt for anti-aging interventions with plant polysaccharides and highlight the anti-aging potential of FSP by improving mitochondrial health.
    Keywords:  ATFS-1; Caenorhabditis elegans; Lycii Fructus polysaccharide; healthspan; human dermal fibroblasts; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.3390/antiox15080944
  27. Adv Sci (Weinh). 2026 Aug 27. e77368
    KLF5 Downregulation Links Impaired BNIP3-Mediated Mitophagy to Inflammatory Valve Remodeling in Calcific Aortic Valve Disease.
    Jin-Hui Bian, Jia-Xi Gu, Zhang Yue, Chun-Ze Yuan, Hai-Bin Ji, Ao Li, Yu Zhong, Xiu-Fan Xu, Yu-Qiu He, Ye-Fan Jiang, Hong-Shan Chen, Xiang Chen, Meng-Lin Chao, Yong-Feng Shao.
      Calcific aortic valve disease (CAVD) lacks effective drug therapy. This study integrated human valve transcriptomic datasets and tissue specimens, public single-cell and spatial transcriptomics, primary human valvular interstitial cell (VIC) models, and ApoE-/- mice fed a high-fat diet to define the role of KLF5 in VIC remodeling. KLF5 expression was reduced in calcified human valves and associated with hemodynamic severity; tissue and single-cell analyses localized this reduction to VIC-rich lesions and disease-associated VIC states. In primary VICs, KLF5 overexpression suppressed, whereas KLF5 knockdown enhanced, osteogenic medium-induced inflammatory signaling and mineralization. Systemic AAV-mediated KLF5 overexpression attenuated valve dysfunction, leaflet thickening, mineral deposition, and BMP2 expression in ApoE-/- mice. Mechanistically, KLF5 loss increased cytosolic mtDNA accumulation and activated cGAS-STING and NLRP3-associated signaling, whereas cGAS knockdown reduced downstream signaling and interferon-stimulated gene induction. KLF5 directly activated the BNIP3 promoter and supported BNIP3-mediated mitophagy. BNIP3 knockdown markedly reduced the ability of KLF5 overexpression to preserve mitophagic flux and restrain inflammatory signaling and mineralization, whereas BNIP3 re-expression mitigated the corresponding phenotypes in KLF5-deficient VICs. These findings identify a VIC-centered KLF5-BNIP3 regulatory pathway that supports mitochondrial quality control and limits mtDNA-sensitive sterile inflammation, providing a mechanistic rationale for future therapeutic investigation in CAVD.
    Keywords:  BNIP3; Krüppel‐like factor 5; calcific aortic valve disease; mitochondrial DNA
    DOI:  https://doi.org/10.1002/advs.77368
  28. Am J Physiol Cell Physiol. 2026 Aug 26.
    NAD⁺ or β-Hydroxybutyrate Each Protects Against Tachypacing-induced Metabolic Remodeling Through Regulation of Mitophagy in HL-1 Cardiomyocytes.
    Xi Qi, Liangyu Hu, Alexia van Rinsum, Werner Jh Koopman, Jaap Keijer, Deli Zhang.
      Atrial fibrillation is associated with metabolic remodeling and mitochondrial dysfunction, leading to impaired energy production, oxidative stress, and structural changes. Targeting metabolic pathways may therefore provide therapeutic benefit. We previously showed that nicotinamide adenine dinucleotide and beta-hydroxybutyrate protect against pacing-induced contractile dysfunction, but their effects on mitochondrial and metabolic remodeling remain unclear. In this study, atrial cardiomyocytes were subjected to rapid electrical stimulation to mimic atrial fibrillation-related stress. Cells were treated with nicotinamide adenine dinucleotide, beta- hydroxybutyrate, or control. Metabolic changes were evaluated by transcriptomic analysis, protein expression, and imaging of pathways related to fatty acid oxidation, glycolysis, and lipid accumulation. Glycolytic activity was assessed by measuring glucose consumption and lactate production, and mitochondrial function was determined by high-resolution respirometry. Markers of mitophagy and NLRP3 inflammasome activation were also examined. Tachypacing-induced metabolic remodeling is characterized by reduced fatty acid oxidation and fatty acid oxidation-linked mitochondrial respiration, increased glycolysis, oxidative stress, and lipid droplet accumulation, impaired mitophagy, and activation of NLRP3-related inflammatory signaling. Treatment with nicotinamide adenine dinucleotide or beta-hydroxybutyrate attenuated many of these changes and partially restored mitochondrial respiratory capacity and metabolic balance. Notably, knockdown of mitophagy-related proteins (mitofusin 2, PTEN-induced kinase 1, and Parkin) caused contractile dysfunction and diminished the protective effects of both treatments on cardiomyocyte contractile function, suggesting that mitophagy may mediate the functional benefits of these compounds. These findings indicate that mitochondrial and metabolic remodeling are closely associated with tachypacing-induced cellular dysfunction and mitophagy and suggest that metabolic interventions may help preserve cardiomyocyte function partially by preserving mitophagy.
    Keywords:  Atrial fibrillation; NAD⁺; metabolic remodeling; βOHB
    DOI:  https://doi.org/10.1152/ajpcell.00253.2026
  29. Drug Des Devel Ther. 2026 ;20 613828
    Remimazolam Attenuates Neurological Injury After TBI: A Potential Role of α7nAChR-Associated Mitophagy Enhancement and Pyroptosis Suppression in BV2 Cells.
    Longfei Li, Rugan Bao, Yao Meng, Xiaoyan Li, Hangbing Li, Pengyu Duan, Yonghong Bi, Jiali Chen, Yuling Xing, Lan Luo, Yang Yu, Miao Yu, Muyan Cui, Bing Zhang.
       Purpose: Traumatic brain injury (TBI) remains a major cause of disability and mortality worldwide. This study investigated whether remimazolam improves neurological outcomes after experimental TBI and whether these effects are associated with α7 nicotinic acetylcholine receptor (α7nAChR) related regulation of mitophagy and pyroptosis.
    Material and Methods: Computational analyses, LPS/ATP-stimulated BV2 cells, and a mouse model of TBI were used. Molecular docking, molecular dynamics simulations, cellular thermal shift assays, and calcium influx assays were performed to evaluate the potential interaction between remimazolam and α7nAChR. Mitochondrial function, mitophagy-related markers, NLRP3, ASC, caspase-1, and GSDMD-N were assessed in BV2 cells. Neurological and behavioral outcomes were evaluated using the modified neurological severity score, rotarod test, open-field test, and novel object recognition test, together with histopathological, inflammatory, and molecular analyses of peri-lesional brain tissue. Methyllycaconitine (MLA) and flumazenil were used to assess the involvement of α7nAChR related signaling and the classical benzodiazepine sensitive GABA_A receptor pathway.
    Results: Remimazolam showed a predicted interaction with α7nAChR. In vitro, it enhanced mitophagy, improved mitochondrial function, and reduced the expression of NLRP3, Caspase-1, ASC, and GSDMD-N. In vivo, remimazolam improved neurological and behavioral outcomes, attenuated histopathological brain injury and neuroinflammation, promoted mitophagy and suppressed pyroptosis. MLA and flumazenil partially attenuated these protective effects.
    Conclusion: Remimazolam attenuates neurological injury in experimental TBI and LPS/ATP-stimulated BV2 cells, partly through α7nAChR associated mitophagy enhancement and pyroptosis inhibition, while GABA_A receptor signaling may also be involved in these effects. These findings support its potential neuroprotective value in anesthesia and perioperative management.
    Keywords:  microglia; mitophagy; pyroptosis; remimazolam; traumatic brain injury; α7nAChR
    DOI:  https://doi.org/10.2147/DDDT.S613828
  30. Toxicology. 2026 Aug 27. pii: S0300-483X(26)00179-4. [Epub ahead of print] 154572
    The role of Mfn2/PERK mediated ER-mitochondrial communication in autophagy induced by silica nanoparticles in HT22 cells.
    Tiantian Tian, Yuanyuan Zhang, Xinyue Li, Jia Zhang, Ying Hao, Huiyuan Hu, Kai Ma, Mingqian Wang, Wei Quan, Haiying Du, Minghua Jin.
      Widespread application of silica nanoparticles (SiNPs) has raised concerns regarding potential neurotoxic risks, yet the complex mechanisms underlying cellular damage remain incompletely understood. Mitochondria associated endoplasmic reticulum membranes (MAMs), which are regulated by the key tethering protein Mitofusin 2 (Mfn2), serve as crucial platforms for interorgan crosstalk. However, whether ER-mitochondria communication mediated by Mfn2/PERK participate in SiNPs triggered neurotoxicity has not been elucidated. therefore, this study established an in vitro model of HT22 cells exposed to SiNPs to explore the mechanisms of the mitochondrial dynamic imbalance, ERS and autophagy. We detected cell viability, morphology and ultrastructure, antioxidant function, mtROS, Mfn2/PERK, mitochondrial dynamic, ERS, and autophagy-related proteins to investigate the role of mtROS/Mfn2/PERK in SiNPs-induced damage to HT22 cells. The results showed that the viability of HT22 cells was gradually decreased after exposure to 0-100μg/mL SiNPs for 24hours. Meanwhile, a series of cellular changes were observed, including oxidative damage, calcium overload, increased intracellular and mitochondrial ROS, decreased ATP content, broken mitochondrial cristae, swollen ER, expression of Mfn2 and PERK. Additionally, the structural and functional integrity of the Mfn2/PERK was impaired, and the expression of mitochondrial dynamics-related proteins was abnormal, thereby inducing ERS and promoting autophagy-related changes. Inhibition of mtROS or ERS and activation of Mfn2 alleviated mitochondrial dynamics imbalance and ERS, and were accompanied by attenuation of SiNPs-induced alterations in Mfn2/PERK signaling and autophagy-related proteins. This further confirms that there is a certain connection between mitochondrial function and ERS after SiNPs exposure, and that autophagy is induced through the mtROS/Mfn2/UPR signaling pathway.
    Keywords:  Autophagy; Endoplasmic reticulum stress (ERS); Mitochondrial dynamics; Mitochondrial reactive oxygen species; Silica nanoparticles (SiNPs)
    DOI:  https://doi.org/10.1016/j.tox.2026.154572
  31. Aging Cell. 2026 Sep;25(9): e70684
    Aging-Related Myocardial Susceptibility Lowers Cardiac Tolerance to Chronic Intermittent Hypoxia Through Dynamin-Related Protein 1-Associated Mitochondrial Vulnerability.
    Yinghui Su, Yuyang Miao, Jin Tan, Feng Wang, Qiang Zhang.
      Chronic intermittent hypoxia (CIH), a cardinal pathophysiological feature of obstructive sleep apnea (OSA), repeatedly exposes the heart to hypoxia-reoxygenation stress. The cardiac outcome of CIH, however, may depend on the biological state of the target myocardium. Here, we investigated whether a pre-existing aging-related myocardial susceptibility lowers the tolerance threshold for CIH-induced injury and whether Dynamin-related protein 1 (Drp1) contributes to the enhanced vulnerability of senescence-like cardiomyocytes under CIH. Using G3 Tert-deficient (Tert-/-) mice and D-galactose (D-gal)-induced senescence-like primary cardiomyocytes, we show that aging-related susceptibility consistently amplifies CIH-induced cardiac injury. In young wild-type mice, 8 weeks CIH induced early cardiac remodeling and senescence-associated myocardial stress without overt systolic decompensation. In Tert-/- mice, the same CIH exposure shifted the cardiac response further toward maladaptive remodeling. Compared with CIH alone, EF and FS were reduced by an additional 24.6% and 15.8%, respectively. In senescence-like cardiomyocytes, CIH amplified mitochondrial vulnerability, with impaired energy production, elevated mitochondrial oxidative stress, and a fission-biased mitochondrial dynamics marker profile. Drp1 knockdown did not fully reverse this mitochondrial state but restored 55.1% of the CIH + D-gal induced ATP decline and reversed 47.4% of the mitochondrial ROS excess, while attenuating DNA damage response activation and senescence-associated signaling. These findings indicate that aging-related myocardial susceptibility is not a passive contextual factor in CIH-induced injury but a biological state that actively shapes the cardiac response to repeated hypoxia-reoxygenation stress. Drp1-associated mitochondrial dynamics imbalance may represent a functional link between diminished mitochondrial stress tolerance and amplified cardiomyocyte vulnerability.
    Keywords:  cardiomyocyte; chronic intermittent hypoxia (CIH); dynamin‐related protein 1 (Drp1); mitochondria; myocardium; senescence
    DOI:  https://doi.org/10.1111/acel.70684
  32. Circ Res. 2026 Aug 26.
    Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.
    David R Rawnsley, Moydul Islam, Chen Zhao, Xumin Guan, Yasaman Kargar Gaz Kooh, Adelita Mendoza, Honora Navid, Minu Kumari, Phalgun Pandi, John T Murphy, Jess Nigro, Attila Kovacs, Lina Greenberg, Kartik Mani, Michael Greenberg, Nathaniel Huebsch, Xiucui Ma, Abhinav Diwan.
       BACKGROUND: Protein quality control is critical for maintaining sarcomere structure and function in cardiomyocytes. Mutations in protein quality control pathway proteins, namely, CRYAB-R120G (arginine to glycine at position 120) and BAG3-P209L (proline to lysine at position 209), induce protein aggregates and cardiomyopathy in humans. Novel observations in yeast demonstrate mitochondrial uptake of cytosolic protein aggregates. We hypothesized that mitochondrial uptake of cytosolic protein aggregates, and their removal by mitophagy, a lysosomal degradative pathway, facilitates cytosolic protein quality control in cardiomyocytes.
    METHODS: Mice with inducible cardiac myocyte-specific ablation of TRAF2 (TNF receptor-associated factor 2; TRAF2-icKO), which impairs mitophagy, were assessed for protein aggregates with biochemical fractionation and super-resolution imaging. Human-induced pluripotent stem cell-derived cardiomyocytes with TRAF2 ablation or R120G knock-in to the CRYAB locus were assessed for protein aggregates and effects of mitophagy stimulation. Transgenic mice expressing R120G-CRYAB protein (R120G-transgenic mice) were subjected to adeno-associated virus 9-cTnT (cardiac troponin T) promoter-driven TRAF2 or PARKIN gain-of-function and TRAF2 loss of function in cardiomyocytes to determine the effect of mitophagy modulation on cardiac structure, function, and protein aggregate pathology.
    RESULTS: TRAF2-icKO mice demonstrate accumulation of mitochondrial and cytosolic protein aggregates and DESMIN mislocalization to protein aggregates. TRAF2 null human-induced pluripotent stem cell-derived cardiomyocytes demonstrate impaired mitophagy with accumulation of polyubiquitinated proteins and disrupted sarcomeres, which are rescued by both TRAF2 and PARKIN transduction. Isolated mitochondria take up cardiomyopathy-associated aggregate-prone cytosolic proteins, namely, R120G-CRYAB and P209L-BAG3. R120G-CRYAB mutant protein increasingly localizes to mitochondria in human and mouse cardiomyocytes. R120G-transgenic mice demonstrate upregulation of myocardial TRAF2 with increased mitophagy. Adult-onset inducible haplo-insufficiency of TRAF2 resulted in accelerated mortality, left ventricular systolic dysfunction, and increased protein aggregates in R120G-transgenic mice. Conversely, adeno-associated virus 9-TRAF2 transduction in R120G-transgenic mice stimulated mitophagy, reduced mortality, attenuated LV systolic dysfunction, reduced cytosolic protein aggregates, and restored DESMIN localization.
    CONCLUSIONS: Stimulation of mitophagy in cardiomyocytes facilitates removal of cytosolic protein aggregates as a mechanism to ameliorate proteotoxic cardiomyopathy.
    Keywords:  autophagosomes; heart failure; longevity; myocytes, cardiac; protein aggregates
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.328328
  33. Front Mol Neurosci. 2026 ;19 1940362
    Correction: Silencing ATF3 mediates mitochondrial homeostasis and improves ischemic stroke through regulating the MAPK signaling pathway.
    Haifengqing Li, Fan Zhang, Cong Zhang, Min Zhou, Qing Liu, Guoyong Zeng.
      [This corrects the article DOI: 10.3389/fnmol.2025.1554802.].
    Keywords:  activating transcription factor 3; ischemic stroke; mitochondrial homeostasis; mitogen activated protein kinase; signaling pathway
    DOI:  https://doi.org/10.3389/fnmol.2026.1940362
  34. Nat Commun. 2026 Jul 24. pii: 9041. [Epub ahead of print]17(1):
    Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.
    Xiao-Chen Xie, Yang Guo, Ran Guo, Yong-Ze Li, Shan-Shan Wang, Xiao-You Jiang, Shuang Hao, Ye Zhang, Yu-Han Li, Xi-Yan Liu, Xiao-Xu Wu, Xin-Yue Zhang, Wen-Dong Guo, Yan-Ling Feng, Jia-Bin Li, Chen Liu, Liang Wang, Zhen-Hua Li, Wei-Ping Teng, Zhong-Yan Shan, Liu Cao, Qi-Qiang Guo.
      Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-76047-9
  35. Pak J Pharm Sci. 2026 Nov 01. 39(11): 3311-3322
    Prunasin alleviates OGD/R-induced injury in H9c2 cardiomyocytes via SRC/EGFR-AKT-FoxO-mediated mitochondrial quality control.
    Jiang Li, Yaoshu Li, Chengyang Xu, Yingying Chen.
       BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is still difficult to manage clinically, mainly due to limited effective strategies that can simultaneously address oxidative stress, mitochondrial dysfunction and myocardial cell loss. Prunasin is a cyanide glycoside derived from plants of the genus Prunus. Its biological activity has been reported, but its role in ischemia-reperfusion related cardiac injury is not yet clear.
    OBJECTIVES: To evaluate the protective effect of prunasin in an oxygen glucose deprivation/reoxygenation (OGD/R) myocardial cell model and explore its potential mechanism.
    METHODS: Firstly, potential targets and pathways were explored through network pharmacology and molecular docking. Then, functional validation was performed using H9c2 cells subjected to OGD/R. Evaluated cell viability, LDH release, apoptosis, ROS levels, ATP content, mitochondrial membrane potential and key signaling proteins.
    RESULTS: Network pharmacology highlighted SRC, EGFR and AKT1 as core targets and molecular docking results showed stable binding between prunasin and SRC, supporting this discovery. In experiments, prunasin increased cell viability in a dose-dependent manner and reduced LDH leakage, cell apoptosis and ROS accumulation. Mitochondrial function is also protected, manifested by the recovery of ATP levels and membrane potential. Mechanistically, prunasin activates the SRC/EGFR-AKT-FxO axis, accompanied by enhanced mitochondrial biogenesis, rebalancing of fission/fusion kinetics and increased mitochondrial autophagy, collectively promoting improved mitochondrial quality control under OGD/R stress conditions.
    CONCLUSIONS: Prunasin regulates mitochondrial quality control through the SRC/EGFR-AKT-FxO signaling pathway, thereby reducing OGD/R-induced myocardial cell injury, indicating its potential as a candidate drug for myocardial ischemia-reperfusion intervention.
    Keywords:  Cardioprotection; Mitochondrial quality control; OGD/R-induced cardiomyocyte injury; Prunasin; SRC/EGFR-AKT-FoxO signaling
    DOI:  https://doi.org/10.36721/PJPS.2026.39.11.307.1
  36. Antioxidants (Basel). 2026 Jul 24. pii: 922. [Epub ahead of print]15(8):
    Curcumin-Loaded Milk-Derived Exosomes Improve the Developmental Competence of Yak Oocytes by Regulating Mitophagy.
    Tingting Lu, Xin Ma, Meng Wang, Yangyang Pan, Xiaoqing Yang, Shantong Qiu, Xueru Yang, Sijiu Yu.
      Yaks are a distinctive livestock species native to the Qinghai-Tibet Plateau. However, the low in vitro maturation rate of their oocytes significantly limits the efficiency of assisted reproductive technologies. Curcumin (CUR), known for its bioactive functions, including antioxidant and anti-inflammatory properties, suffers from low water solubility and bioavailability, which restricts its practical applications. This study aimed to develop a curcumin-loaded bovine milk-derived exosome nanodelivery system (CUR-mEXOs) and investigate its effects on the in vitro maturation of yak oocytes and the embryonic development of parthenogenetic embryos, leveraging its natural biocompatibility and targeted delivery properties. The results indicated that the isolated mEXOs exhibited typical exosome morphology and nanoscale particle size characteristics and were effectively internalized by the oocytes. During in vitro maturation, treatment with 10 μM CUR produced optimal outcomes. Compared to free CUR, CUR-mEXOs significantly enhanced the cumulus expansion index and the rate of first polar body expulsion, reduced intracellular ROS accumulation and mitochondrial superoxide levels, and improved mitochondrial function and spindle morphology, while simultaneously upregulating the expression of factors related to mitochondrial autophagy and oocyte maturation. Following intervention with the mitochondrial autophagy inhibitor CsA, the promotive effect of CUR-mEXOs was significantly diminished, leading to increased blastocyst apoptosis and a decrease in the total cell count. In summary, CUR-mEXOs can enhance the quality of in vitro maturation of yak oocytes and their embryonic developmental capacity following parthenogenesis by regulating mitochondrial autophagy. This study established an experimental foundation for optimizing the in vitro maturation system of yak oocytes and developing strategies for the delivery of natural bioactive substances. Additionally, this study provides a theoretical basis for enhancing the efficiency of assisted reproductive technologies in yaks.
    Keywords:  curcumin; drug delivery; in vitro oocyte maturation; milk-derived exosomes; mitophagy; yak
    DOI:  https://doi.org/10.3390/antiox15080922
  37. Acta Physiol (Oxf). 2026 Oct;242(10): e70299
    ITCH-Mediated Ubiquitination and Degradation of THBS1: A Key Mechanism for Enhancing Mitochondrial Biogenesis and Alleviating Mouse Skeletal Muscle Atrophy.
    Wan Yu, Yanteng Wang, Na Li, Difei Wang.
       AIM: Skeletal muscle atrophy is tightly associated with maladaptive alterations in mitochondrial function and morphology. Itchy E3 ubiquitin-protein ligase (ITCH) modulates mitochondria, and thrombospondin 1 (THBS1) positively regulates muscle atrophy, but their roles in muscle atrophy are unclear.
    METHODS: A muscle atrophy model was established in C57BL/6 mice via daily intraperitoneal injection of dexamethasone (Dex, 20 mg/kg). ITCH overexpression in skeletal muscle was achieved by adeno-associated virus serotype 9 injection. C2C12 cells were treated with 50 μM Dex to mimic in vitro muscle atrophy. Skeletal muscle atrophy in mice was evaluated using hematoxylin-eosin staining and immunofluorescence staining. Mitochondrial damage was assessed via transmission electron microscopy, succinate dehydrogenase staining, and JC-1 staining. Immunoprecipitation-liquid chromatography/mass spectrometry, molecular docking, and co-immunoprecipitation were used to investigate the interaction between ITCH and THBS1. Phosphoproteomics analysis was performed to detect the THBS1 downstream proteins.
    RESULTS: Dex treatment downregulated ITCH expression in skeletal muscle. ITCH overexpression increased body weight, muscle mass, and muscle strength, downregulated the expression of atrophy-related genes (Atrogin-1, Mstn, MuRF-1), and promoted mitochondrial biogenesis. The results of the C2C12 cells were consistent with those obtained in vivo. Proteomic profiling and Co-IP confirmed ITCH-THBS1 interaction and subsequent THBS1 ubiquitination. THBS1 knockdown reduced the expression of Atrogin-1 and MuRF-1 and inhibited the phosphorylation of JUN and Map3k7, whereas THBS1 overexpression reversed the ITCH-mediated improvement in mitochondrial biogenesis.
    CONCLUSION: ITCH enhances mitochondrial biogenesis and mitigates Dex-induced muscle atrophy by promoting the ubiquitin-dependent degradation of THBS1 and subsequent inhibition of downstream JUN/Map3k7 phosphorylation.
    Keywords:  itchy E3 ubiquitin‐protein ligase; mitochondrial biosynthesis; skeletal muscle atrophy; thrombospondin 1; ubiquitination
    DOI:  https://doi.org/10.1111/apha.70299
  38. Front Cell Dev Biol. 2026 ;14 1866640
    Mitochondrial regulation of cellular senescence heterogeneity.
    Minseo Ahn, Sung-Jin Yoon, Jae Ho Seo.
      Cellular senescence is a stable cell-cycle arrest program accompanied by extensive metabolic remodeling and acquisition of a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that senescence is not a uniform endpoint but a heterogeneous spectrum of cell states shaped by the nature of the initiating stimulus. Mitochondria have recently emerged as central regulators of this heterogeneity by integrating metabolic, redox, and inflammatory signaling. Senescent cells share common mitochondrial features-including increased mitochondrial mass, elevated reactive oxygen species (ROS), impaired mitophagy, and altered metabolic programs-yet distinct senescence subtypes exhibit unique mitochondrial adaptations. Replicative senescence is governed by a telomere-mitochondria feedback loop, whereas stress- and oncogene-induced senescence involve rapid mitochondrial stress responses and stimulus-specific metabolic rewiring. Therapy-induced senescence further introduces context-dependent mitochondrial dependencies that influence therapeutic resistance and senolytic vulnerability. In this review, we synthesize current understanding of mitochondrial regulation across senescence subtypes and highlight how mitochondrial dysfunction actively drives senescence heterogeneity. We further discuss emerging therapeutic strategies that exploit mitochondrial vulnerabilities to selectively modulate or eliminate senescent cells. Understanding mitochondrial control of senescence heterogeneity provides a conceptual framework for developing precision interventions in aging and cancer.
    Keywords:  cellular senescence; metabolic reprogramming; mitochondrial dysfunction; mitophagy; reactive oxygen species (ROS); senescence heterogeneity; senescence-associated secretory phenotype (SASP); senolytics
    DOI:  https://doi.org/10.3389/fcell.2026.1866640
  39. J Nutr. 2026 Aug 24. pii: S0022-3166(26)00450-5. [Epub ahead of print] 101801
    Mitochondrial Fusion Protein Mitofusin-2 Mediates the Protection of Fish Oil Against Porcine Intestinal Injury Induced by Deoxynivalenol.
    Kan Xiao, Minfang Zhang, Qingqing Lv, Qilong Xu, Hanqiu Gong, Xiaoye Xu, Junjie Guo, Shaokui Chen, Jiangchao Zhao, Yulan Liu.
       BACKGROUND: Fish oil, rich in EPA and DHA, exerts beneficial effects on gastrointestinal diseases in humans and animals.
    OBJECTIVE: This study aimed to investigate whether fish oil attenuated DON-induced intestinal dysfunction and abnormal expression of mitochondrial fission/fusion-related proteins in weaned piglets.
    METHODS: Twenty-four weaned pigs were used in a 2 × 2 factorial design (6 pigs /group) and the factors included dietary treatments (5% corn oil or fish oil) and DON exposure (4 mg/kg DON or not). After 21 d feeding, intestinal samples were collected. IPEC-1 cells were treated with 41 μM EPA or 38 μM DHA, with or without 0.5 μg/mL DON. siRNA targeting mitochondrial fission/fusion-related proteins (dynamin-related protein 1 (Drp1), mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2)) were used to explore the molecular mechanism.
    RESULTS: Fish oil improved growth performance (P < 0.05) and increased expression of mitochondrial fission/fusion-related proteins including Drp1, Mfn1, and Mfn2 (P < 0.05), accompanied by restoring jejunal morphology, digestion, and barrier function, and mitochondrial function (P < 0.05) of piglets after DON exposure. EPA or DHA attenuated cell damage, mitochondria dysfunction, cell apoptosis (P < 0.001), and increased Drp1, Mfn1 and Mfn2 protein expression (P < 0.05) after DON exposure in IPEC-1 cells. EPA/DHA alleviated cell injury, mitochondria dysfunction and cell apoptosis (P < 0.001) in the presence of siDrp1 and siMfn1, however EPA or DHA could not alleviate these indexes (P > 0.05) in the presence of siMfn2.
    CONCLUSIONS: The protective effects of EPA/DHA against DON-induced intestinal injury were strongly associated with Mfn2 signaling.
    Keywords:  DON; fish oil; intestinal injury; mitochondrial fission/fusion; piglets
    DOI:  https://doi.org/10.1016/j.tjnut.2026.101801
  40. Free Radic Biol Med. 2026 Aug 24. pii: S0891-5849(26)01048-8. [Epub ahead of print]256 257-270
    Circulating cell-free mitochondrial DNA as a redox-associated marker of mitochondrial homeostasis disruption during gastric carcinogenesis.
    Tie Zhao, Justice Afrifa, Yingwei Xue, Jing Chen, Yunlong Li, Dong Wang, Ting Yang, Xiao Liang, He Zhang, Shuaihang Pang, Mengdi Cai, Wayne A Schroder, Songbin Fu, Jingcui Yu.
      Circulating cell-free mitochondrial DNA (ccf-mtDNA) is an emerging non-invasive marker across cancers. Yet, in gastric cancer (GC), its relationship to tissue mtDNA content, oxidative remodeling and somatic mtDNA variants, and thus its basis in mitochondrial homeostasis, remains poorly defined. We analyzed 169 individuals: 70 GC patients, 29 with precancerous gastric lesions and 70 healthy controls. MtDNA copy number was measured by quantitative PCR, and plasma biomarkers of oxidative damage (8-hydroxy-2'-deoxyguanosine, 8OH-dG; 4-hydroxynonenal, 4HNE) and of antioxidant capacity (glutathione peroxidase-1, GPX-1) were measured by ELISA. MtDNA variants were identified by next-generation sequencing. In MKN-28 GC cells, mitochondrial transcription factor A (TFAM) was manipulated with lentiviral vectors to alter mtDNA content. The results showed that GC progression was accompanied by higher ccf-mtDNA, shifts in plasma oxidative damage and antioxidant markers, and accumulation of mtDNA variants, alongside lower mtDNA content in cancers than in adjacent tissues. In GC cells, lowering mtDNA content by TFAM silencing promoted the malignant phenotype and increased intracellular superoxide-related fluorescence. By multiplex immunohistochemistry, tissue markers of mitochondrial maintenance and mtDNA release declined without a rise in caspase-3. D-loop variants already present at the precancerous stage suggest early mitochondrial changes, whereas predicted deleterious coding variants affecting respiratory chain components were observed in GC tissues. These findings support a redox-associated model of mitochondrial homeostasis that links impaired mitochondrial maintenance, mtDNA instability, and ccf-mtDNA accumulation, and provide a tissue-anchored mechanistic basis for the circulating mtDNA changes detected by plasma-based approaches in GC.
    Keywords:  Cell-free mitochondrial DNA; D-loop variant; Gastric cancer; Mitochondrial DNA copy number; Oxidative stress; TFAM
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.046
  41. Genetics. 2026 Aug 26. pii: iyag203. [Epub ahead of print]
    Traffic jam at the powerhouse: restoring protein homeostasis at the mitochondria via MFB1 and HSP31 collaboration with clinical implications. An Educational Primer for use with "Cellular proteostasis during mitochondrial protein import clogging requires the mitochondrial F-box protein 1 and DJ-1 homolog HSP31 in Saccharomyces cerevisiae".
    Mahima Ghosh, Patricia Melloy.
      
    Keywords:   AAC2 ; HSP31 ; MFB1 ; budding yeast; cytotoxicity; mitochondrial protein import; proteostasis
    DOI:  https://doi.org/10.1093/genetics/iyag203
  42. Metabol Open. 2026 Sep;31 100492
    Transcriptomic and genetic evidence highlights EHHADH in a FUNDC1-associated mitochondrial network in diabetic nephropathy.
    Yuzhi Chen, Demei Ying, Xuli Guo, Shaozhe Wang, Wenjing Liu, Siwen Wang, Na Kuang, Jiahan Li, Nan Chen.
       Background: Diabetic nephropathy (DN) is a major microvascular complication of diabetes and the leading cause of end-stage renal disease. Glomerular and tubular injury, mitochondrial dysfunction, and impaired mitophagy are core factors driving the progression of DN. Recent studies have identified FUNDC1 as a crucial mitophagy receptor; however, its regulatory mechanism in DN remains poorly elucidated.
    Methods: This study integrated compartmental transcriptomics, gene interaction network analysis, and summary-data-based Mendelian randomization (SMR) for systematic research. Differentially expressed genes (DEGs) were extracted from the glomerular dataset GSE96804 and the tubular dataset GSE294519. The intersecting genes of these DEGs with FUNDC1-interacting genes and mitochondrial dysfunction-related genes were obtained to screen core hub genes. Combined with renal expression quantitative trait locus (eQTL) data and DN genome-wide association study (GWAS) data, SMR analysis was performed. Functional enrichment analysis, gene set enrichment analysis (GSEA), and upstream transcription factor prediction were further conducted.
    Results: A total of 5560 DEGs were screened based on adjusted P values (Padj), including 2625 glomerular DEGs, 3199 tubular DEGs, and 264 common DEGs. Twenty FUNDC1-related core hub genes were finally identified, which were mainly enriched in mitophagy and mitochondrial energy metabolism pathways. After correction and screening via the HEIDI test, Transcriptomic and genetic evidence highlights EHHADH in a FUNDC1-associated mitochondrial network in diabetic nephropathy, and its expression was downregulated in DN lesional tissues. FUNDC1 and EHHADH were both associated with mitochondrial metabolic pathways, and E2F4 was predicted to be their common upstream regulatory factor.
    Conclusions: Multi-dimensional results suggest that EHHADH may represent a candidate gene within a FUNDC1-associated mitochondrial regulatory network in DN. The coordinated expression patterns of FUNDC1 and EHHADH suggest their potential involvement in mitochondrial homeostasis-related processes during DN progression.
    Keywords:  Diabetic nephropathy; EHHADH; FUNDC1; Mendelian randomization; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.metop.2026.100492
  43. MedComm (2020). 2026 Sep;7(9): e70911
    Mitochondria as the Hub of Apoptosis: A Comprehensive Insight From Mitochondria to Interactions With Other Organelles.
    Rubin Tan, Jinming Zhao, Rong Wang, Yue Shi, Zaozao Chen, Yixuan Ma, Na Li, Wenqing Duan, Duo Lin, Chunxiang Zhang.
      Apoptosis is a core program regulating organismal homeostasis and plays a pivotal role in the onset and progression of most diseases. Increasing evidence in recent years indicates that mitochondria are not only central to cellular metabolism but also play a pivotal role in regulating apoptosis. However, no systematic review elucidating how mitochondria finely regulate apoptotic processes through multidimensional mechanisms, including apoptosis-resistant diseases such as cancer. This paper systematically summarizes the molecular mechanisms by which mitochondria mediate apoptosis. We focus on the regulation of cytochrome c (Cyt c) release by the Bcl-2 protein family and the activation of downstream caspase cascades. Furthermore, we provide an in-depth analysis of intrinsic factors, including mitochondrial structural remodeling (membrane rupture, cristae remodeling, and membrane lipid redistribution), dynamics imbalance (fusion, fission, and mitophagy), and mitochondrial DNA abnormalities, as well as extrinsic factors involving interorganelle interactions with the endoplasmic reticulum, lysosomes, and other organelles. Additionally, we review clinical and preclinical advances in drugs targeting these pathways. This review aims to provide a comprehensive perspective on the complex network of mitochondrial regulation of apoptosis and offer valuable insights for developing novel clinical therapeutic strategies for cancer and other diseases.
    Keywords:  MAM; MOMP; apoptosis; mitochondria; mitochondrial autophagy; mitochondrial transplantation; mtDNA
    DOI:  https://doi.org/10.1002/mco2.70911
  44. J Gastroenterol Hepatol. 2026 Aug 24.
    Oral Colon- and Mitochondria-Targeted Nanoparticles Alleviate Ulcerative Colitis by Reeducating Macrophage Polarization via SIRT3/FOXO3a-Mediated Mitochondrial Restoration.
    Ruya Mei, Rong Zhang, Zhengyang Li, Jie Luo, Xinyue Zhang, Tong Zhang, Guanglei Lv, Juhua Zhang, Bingqing Liang, Yuzhong Yan.
       BACKGROUND AND AIM: Mitochondrial dysfunction in macrophages drives pro-inflammatory M1 polarization in ulcerative colitis (UC). We developed a colon-targeted, mitochondria-directed nanoplatform (KSF@SS31@S100Ns) to restore mitochondrial fitness and alleviate UC.
    METHODS: Kaempferol-loaded silk fibroin (SF) nanoparticles were conjugated with SS-31 peptide and coated with pH-sensitive Eudragit S100. Physicochemical properties, release profile, and uptake were characterized. Mitochondrial function, macrophage polarization, and SIRT3/FOXO3a signaling were assessed in LPS-stimulated RAW264.7 cells. Efficacy and mechanisms were evaluated in a DSS-induced colitis mouse model.
    RESULTS: Nanoparticles showed uniform size (~307 nm), high stability, and pH-dependent release. SS-31 enhanced macrophage uptake and mitochondrial localization. In vitro, KSF@SS31Ns restored mitochondrial membrane potential and ATP, reduced ROS, promoted mitophagy, and shifted macrophages toward the M2 phenotype via SIRT3/FOXO3a activation. In vivo, oral KSF@SS31@S100Ns accumulated in inflamed colons, reduced disease severity, suppressed pro-inflammatory cytokines, elevated IL-10, restored tight-junction proteins, and increased M2 macrophages.
    CONCLUSIONS: KSF@SS31@S100Ns effectively treats experimental colitis by restoring mitochondrial homeostasis, reprogramming macrophage polarization, and repairing the intestinal barrier, offering a translational nanotherapeutic strategy for UC.
    DOI:  https://doi.org/10.1111/jgh.70668
  45. Front Clin Diabetes Healthc. 2026 ;7 1860424
    Bone morphogenetic protein 4-associated mitochondrial dysfunction in diabetic nephropathy involves Parkin downregulation.
    Masanori Tamaki, Tatsuya Tominaga, Kazuhiro Hasegawa, Takahiro Kida, Shinji Miyakami, Ikuko Shimizu, Sumiyo Yamaguchi, Masanori Minato, Kojiro Nagai, Shu Wakino.
       Background: Diabetic nephropathy (DN) is characterized by mesangial expansion and mitochondrial dysfunction. Although bone morphogenetic protein 4 (BMP4) is a pro-fibrotic factor in DN, its role in mesangial mitochondrial homeostasis remains unclear. This study investigated whether a decrease in Parkin is involved in mitochondria-related abnormalities following BMP4 stimulation.
    Methods: Renal tissues from streptozotocin (STZ)-induced diabetic mice were subjected to biochemical, histological, and molecular analyses. In vitro, cultured mouse mesangial cells were exposed to recombinant BMP4 in the presence or absence of the activin receptor-like kinase (ALK) inhibitor LDN-193189. A mesangial cell line overexpressing Parkin was used to assess the role of Parkin under BMP4 stimulation. Mitochondrial function and the expression of Parkin and related genes were analyzed.
    Results: In STZ-induced diabetic mice, mesangial expansion was accompanied by mitochondrial abnormalities, increased BMP4 expression, diminished mtDNA copy number, and decreased expression of Parkin and related genes. In cultured mesangial cells, BMP4 stimulation was accompanied by a decrease in Parkin expression and reduced mitochondria-related indices, including decreased expression of mitochondrial function-related genes, reduced ATP production, and loss of membrane potential. The BMP4-induced changes in gene expression and mitochondrial functional indices were ameliorated by ALK inhibition. Furthermore, Parkin overexpression ameliorated BMP4-induced decreases in gene expression and mitochondrial functional indices.
    Conclusion: These findings suggest that decreased Parkin expression associated with BMP4 stimulation may be one of the molecular alterations contributing to mitochondria-related abnormalities in mesangial cells. Disrupted mitochondrial homeostasis accompanied by decreased Parkin expression may represent a candidate therapeutic pathway in DN.
    Keywords:  BMP4; diabetic nephropathy; mesangial cell; mitochondrial dysfunction; parkin
    DOI:  https://doi.org/10.3389/fcdhc.2026.1860424
  46. Int J Mol Sci. 2026 Aug 17. pii: 7338. [Epub ahead of print]27(16):
    Altered TAGLN Expression During HBV Replication Correlates with OPA1 Levels.
    Juan Wen, Guoli Chen, Zhengyun Liu, Tianshun Wang, Jiarong Xie, Mingxia Xiong, Guo Luo, Huan Wang.
      Hepatitis B virus (HBV) exploits host proteins to reshape cellular physiology and metabolism, thereby supporting its replication. Transgelin (TAGLN), an actin-binding protein highly expressed in HBV-associated hepatocellular carcinoma, has a poorly defined role in HBV infection. HBV infection upregulated TAGLN expression both in vitro and in vivo. Silencing TAGLN suppressed HBV replication, increased mitochondrial fission, and elevated intracellular ATP levels. Mitochondrial proteomic analysis identified optic atrophy 1 (OPA1), a mitochondrial dynamin protein, as differentially expressed, with higher levels in HBV-positive HepG2.2.15 cells than in parental HepG2 cells. TAGLN deficiency was associated with reduced OPA1 expression. Similarly, modulation of OPA1 expression was associated with corresponding changes in TAGLN levels and HBV replication. Collectively, these findings indicate an association between TAGLN and OPA1 in the context of HBV replication. However, the precise regulatory hierarchy and molecular basis of this association remain to be determined.
    Keywords:  Hepatitis B virus (HBV); mitochondria; optic atrophy 1 (OPA1); transgelin (TAGLN)
    DOI:  https://doi.org/10.3390/ijms27167338
  47. Oncol Res. 2026 ;34(9): 14
    Mitochondrial Dysfunction in Renal Cell Carcinoma: A Comprehensive Review of Pathogenic Mechanisms and Emerging Therapeutic Opportunities.
    Yanhong Wang, Junbo Liu, Qiaoping Xu, Zhao Ma.
      In renal cell carcinoma (RCC), alterations in cellular metabolism are a defining feature, among which impaired mitochondrial function stands out as a key factor influencing both tumor aggressiveness and patient responses to therapy. The aim of this review is to systematically synthesize current knowledge on the role of mitochondrial dysfunction in RCC pathogenesis and to explore emerging therapeutic strategies targeting mitochondrial vulnerabilities. This comprehensive analysis examines the integrated dysregulation of core mitochondrial processes-bioenergetic metabolism, organelle dynamics, programmed cell death pathways, redox homeostasis, and selective autophagy-in driving RCC pathogenesis. Our synthesis reveals how genetic drivers, molecular regulators, and microenvironmental cues converge to remodel mitochondrial function, creating both adaptive advantages and therapeutic vulnerabilities. A paradoxical duality emerges in mitochondrial biology: processes such as fission, mitophagy, and reactive oxygen species (ROS) generation can simultaneously support tumor adaptation while rendering cells susceptible to targeted interventions. We evaluate emerging therapeutic approaches directed at mitochondrial vulnerabilities, including metabolic inhibitors, nanoscale delivery systems, and phytochemical agents, while addressing current limitations in specificity and resistance mechanisms. Based on current preclinical evidence, this integrated perspective establishes mitochondrial dysfunction as a central determinant of RCC malignancy and suggests potential combinatorial strategies for precision oncology approaches that warrant further investigation.
    Keywords:  Kidney cancer; apoptosis evasion; drug resistance; mitochondrial metabolism; mitochondrial quality control; oxidative phosphorylation; targeted therapy
    DOI:  https://doi.org/10.32604/or.2026.082432
  48. J Am Heart Assoc. 2026 Aug 27. e047618
    Neonatal Reversible Aortic Constriction Mice Model Unlocks Distinctive Footprints of Young Heart Recovery.
    Longming Huang, Kai Luo, Xinjie Zhang, Guowei Zeng, Bo Chen, Cong Li, Xiaoyang Zhang, Haoyu Li, Mengyi Zhang, Wenjun Zhou, Jinwen Pang, Jinghao Zheng, Bozhong Shi, Xiaomin He.
       BACKGROUND: Left ventricular (LV) reverse remodeling has been linked to long-term prognosis and life quality of pediatric patients with LV outflow tract obstruction. However, a lack of suitable animal model limits further study of LV reverse remodeling in young hearts. This study reports on the development and mechanism exploration of an animal model mimicking pediatric LV reverse remodeling.
    METHODS: A reversible neonatal ascending aorta constriction mice model using absorbable suture was established to simulate pediatric LV reverse remodeling. Cardiac hypertrophy, myocardial fibrosis, angiogenesis, exercise tolerance, and myocardial reserve throughout the reverse remodeling process were evaluated. Multiple-time points RNA sequencing identified key genes and pathways involved. Cardiomyocyte-specific stimulator of interferon genes (STING) knockout mice were generated for mechanism study.
    RESULTS: In the reversible neonatal ascending aorta constriction model, hydrolysis of the absorbable suture reduced cardiac afterload after ventricular remodeling, initiating reverse remodeling at 4 weeks postsurgery. Reverse remodeling young hearts displayed improved function, resolution of fibrosis, but persistent hypertrophy, reduced exercise capacity, and myocardial reserve. Multiple-time points RNA sequencing and in vivo experiments revealed a gradual upregulation of mitophagy during reverse remodeling, along with suppression of the mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS) in which the STING gene is flanked by loxP sites-STING pathway. Cardiomyocyte-specific STING knockout enhanced early reverse remodeling. The early application of urolithin A promoted mitophagy and suppressed the mtDNA-cGAS-STING pathway, accelerating reverse remodeling.
    CONCLUSIONS: This study introduces a novel model of pediatric LV reverse remodeling in male mice, delineating the trajectory and transcriptional footprints during the reverse remodeling process. The Mitophagy-mtDNA-cGAS-STING axis plays a vital role and holds therapeutic potential to promote young heart recovery.
    Keywords:  STING; mitophagy; neonatal mice; reverse remodeling; young heart
    DOI:  https://doi.org/10.1161/JAHA.125.047618
  49. Cells. 2026 Aug 18. pii: 1482. [Epub ahead of print]15(16):
    Inflammation-Associated Changes in Piezo1 Expression, Mitophagy-Related Markers, and Matrix Dysregulation in an LPS-Stimulated Co-Culture Organoid System.
    Kavitha Raja, Dineshwary Grace Suresh, Jamila Khalid Albeshri, Surendra Singh Rawat, Ivan James Prithishkumar, Thomas Nau, Nerissa Naidoo.
      Osteoarthritis (OA) is a progressive joint disease characterized by cartilage degeneration, chronic low-grade inflammation, and disruption of tissue homeostasis. Although the mechanosensitive ion channel Piezo1 has been implicated in OA pathogenesis, its expression may also be modulated by inflammatory stimuli independently of applied mechanical loading. This study established a scaffold-free three-dimensional co-culture organoid model comprising human bone marrow-derived mesenchymal stem cell-derived chondrocyte-like cells and M-CSF/RANKL-differentiated RAW264.7-derived osteoclast-like cells to investigate Piezo1-associated molecular responses, inflammatory signaling, and mitophagy-related markers under lipopolysaccharide (LPS)-induced inflammatory conditions. Osteoclast-like differentiation was validated in parallel monolayer cultures by tartrate-resistant acid phosphatase staining and the presence of multinucleated cells before the corresponding differentiated cultures were used for organoid generation. Histological staining, immunofluorescence, CellTiter-Glo 3D viability assay, lactate dehydrogenase cytotoxicity assay, RT-qPCR, and Western blotting were used to evaluate extracellular matrix formation and inflammatory, catabolic, and mitochondrial quality-control-associated markers. LPS stimulation increased the expression of Piezo1, HIF-1α, phosphorylated CaMKII, NLRP3, cleaved Caspase-1, and MMP13, together with alterations in mitophagy- and autophagy-associated markers. Among the evaluated compounds, curcumin produced the greatest improvement in viability relative to the LPS-treated group and was selected for subsequent molecular analyses. Curcumin treatment was associated with reduced inflammatory and catabolic marker expression and partial preservation of cartilage-associated matrix markers. These findings demonstrate inflammation-associated changes in Piezo1 expression and related molecular markers but do not establish mechanically activated Piezo1 signaling or Piezo1-dependent causality. The organoid system therefore represents an exploratory LPS-induced inflammatory model exhibiting selected OA-relevant molecular and matrix-associated features.
    Keywords:  Piezo1; autophagy; curcumin; mitophagy; organoid; osteoarthritis
    DOI:  https://doi.org/10.3390/cells15161482
  50. Viruses. 2026 Aug 19. pii: 910. [Epub ahead of print]18(8):
    AMPK-Orchestrated Metabolic Reprogramming in Some Flavivirus Infections: Mechanisms and Therapeutic Opportunities.
    Kaci Craft, Imaan Muhammad, Shaokai Pei, Qiyi Tang.
      5'-Adenosine monophosphate-activated protein kinase (AMPK) is the principal cellular energy sensor that coordinates metabolic adaptation by balancing anabolic and catabolic pathways in response to energic stress. Beyond its canonical role in maintaining energy homeostasis, AMPK has emerged as a central regulator of host-pathogen interactions by integrating lipid metabolism, autophagy, mitochondrial dynamics, oxidative stress, and innate immune signaling. Flaviviruses, including dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus, extensively remodel host metabolism to establish productive infection. As a master regulator of cellular metabolism, AMPK can either restrict or facilitate flavivirus replication in a context-dependent manner by regulating lipid droplet biogenesis, fatty acid synthesis and beta-oxidation, autophagy, mitochondrial homeostasis, and interferon-mediated antiviral responses. Conversely, flaviviruses actively manipulate AMPK signaling and its downstream metabolic networks to promote endoplasmic reticulum remodeling, replication organelle biogenesis, energy production, and immune evasion. In this review, we summarize recent advances in understanding the multifaceted roles of AMPK during flavivirus infection, with an emphasis on its regulation of metabolic reprogramming, organelle remodeling, and antiviral immunity. We further discuss the therapeutic potential of pharmacologically targeting AMPK and its downstream pathways as a host-directed strategy for broad-spectrum antiviral intervention against flaviviruses.
    Keywords:  AMPK; Zika virus; autophagy; dengue virus; flavivirus; host-targeted antiviral therapy; innate immunity; lipid droplets; lipid metabolism; metabolic reprogramming; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/v18080910
  51. Front Psychiatry. 2026 ;17 1828806
    Integrative multi-omics and machine learning analysis identifies candidate biomarkers associated with mitochondrial quality control in major depressive disorder.
    Jingchun Li, Min Wang, Haoqi Liu, Kaiqiang Dong, Rongjuan Guo.
       Background: Major depressive disorder (MDD) possesses a complex pathogenesis, with abnormal mitochondrial quality control (MQC) proposed as a potential mechanism involved in the pathological process.
    Methods: This study integrated two microarray expression profiling datasets with a single-nucleus RNA sequencing (snRNA-seq) dataset from the human prefrontal cortex (PFC). Candidate genes were identified by intersecting differentially expressed genes (DEGs) from the training set with MQC-associated module genes identified through WGCNA. Ten machine learning algorithms ranked MQC-associated candidate biomarkers, followed by preliminary mRNA-level verification using PFC tissues from chronic restraint stress (CRS) rats. Additionally, MQC-related gene set activity was computationally inferred at the single-cell level to examine cell-type-specific transcriptional alterations associated with MDD.
    Results: The application of ten machine learning algorithms highlighted DCHS1 and HS3ST2 as candidate biomarkers linked to MQC-related transcriptional alterations. Gene set enrichment analysis (GSEA) indicated associations of these genes with oxidative phosphorylation and cytokine-cytokine receptor interaction pathways. In CRS rats, DCHS1 mRNA expression decreased, while HS3ST2 mRNA expression increased, aligning with bioinformatic findings. Among the 18 annotated cell types in the snRNA-seq dataset, computationally inferred MQRG activity significantly decreased in eight cell types, including several excitatory and inhibitory neuronal subtypes. Inhib_GRIK1 neurons exhibited cell-type-specific expression differences in DCHS1 and HS3ST2.
    Conclusion: DCHS1 and HS3ST2 may serve as candidate biomarkers associated with MQC-related transcriptional alterations in the PFC of patients with MDD. MQRG activity demonstrated marked cell-type heterogeneity and reduction across multiple PFC cell populations. These findings provide preliminary, hypothesis-generating evidence for the link between MQC-related transcriptional dysregulation and MDD; however, further functional experiments are necessary to ascertain whether DCHS1 and HS3ST2 directly regulate mitochondrial quality control.
    Keywords:  DCHS1; HS3ST2; machine learning; major depressive disorder; mitochondrial quality control; multi-omics
    DOI:  https://doi.org/10.3389/fpsyt.2026.1828806
  52. Int J Mol Sci. 2026 Aug 17. pii: 7332. [Epub ahead of print]27(16):
    IRF1 in Adipocytes Is Associated with Insulin Signaling and Mitochondrial Homeostasis in Diet-Induced Obesity.
    Airan Zhu, Ying Zhou, Kaili Ren, ChongXiu Sun.
      Obesity-associated metabolic disorders are characterized by impaired glucose and lipid metabolism, insulin resistance, and adipose tissue dysfunction. Interferon regulatory factor 1 (IRF1) is a transcription factor primarily involved in immune regulation; however, its role in adipocyte metabolic regulation remains incompletely understood. In this study, adipocyte-specific Irf1 knockout (Irf1 AKO) mice were generated using the Cre/loxP system and subjected to either a regular chow diet or a high-fat diet (HFD). Metabolic phenotyping, insulin signaling analysis, mitochondrial homeostasis-related assessment, and in vitro adipocyte experiments were performed. Adipocyte-specific IRF1 deficiency improved insulin-stimulated AKT phosphorylation in white adipose tissues and enhanced glucose tolerance and insulin sensitivity under HFD conditions. These metabolic improvements were accompanied by reduced oxygen consumption, energy expenditure, heat production, β3-adrenergic-induced lipolytic response, and cold tolerance. At the molecular level, IRF1 deficiency was associated with reduced TOMM20 expression, decreased mtDNA content, downregulation of oxidative phosphorylation-related genes, and reduced ATP levels in adipose tissues, suggesting altered mitochondrial homeostasis. In 3T3-L1 adipocytes, IRF1 knockdown increased insulin-stimulated AKT activation, glucose uptake, and lipid accumulation, whereas IRF1 overexpression showed opposite trends. Collectively, these findings suggest that adipocyte IRF1 is associated with insulin signaling, lipid metabolic remodeling, and mitochondrial homeostasis, and highlight a potential dissociation between improved insulin responsiveness and reduced energy expenditure in diet-induced obesity.
    Keywords:  IRF1; adipocyte; energy expenditure; glucose metabolism; insulin signaling; lipid metabolism; mitochondrial homeostasis; obesity
    DOI:  https://doi.org/10.3390/ijms27167332
  53. Int J Mol Sci. 2026 Aug 18. pii: 7376. [Epub ahead of print]27(16):
    Neuromuscular Dysfunction and Charcot-Marie-Tooth Disease Reversal in Mfn2 T105M Knock-In Rats.
    Jochen Weigele, Antonietta Franco, Gerald W Dorn.
      Charcot-Marie-Tooth (CMT) disease type 2A is a rare heritable disorder caused by pathogenic variants of mitofusin (MFN) 2 that suppress mitochondrial fusion and motility in peripheral nerves, culminating in denervation myoatrophy. The rarity of this condition and the limited choice of animal models preclude pre-clinical evaluation of many tests that could be translated to human trials. Here, we introduced the CMT2A pathogenic variant MFN2 T105M into the rat genome for phenotype characterization and evaluation of disease response to a third-generation mitofusin activator, 8015-P2. CMT2A rats exhibited peripheral motor and sensory neuron dysfunction. Functional, histological, neuroelectrophysiological and magnetic resonance imaging testing readily distinguished between wild-type (WT) and mutant rats via axonopathy and myoatrophy. Compound 8015-P2 reversed CMT2A-linked neuromuscular degeneration in a dose- and time-dependent manner; at 10 mg/kg/d, normalization occurred at 4 weeks. The minimal effective 8015-P2 dose was 2 mg/kg/day. Rapidity of phenotype reversal and primary muscle abnormalities are consistent with extra-neuronal effects of the causal MFN2 DNA variant. These data demonstrate unprecedented utility of the Mfn2 T105M rat as a model of CMT2A, expand the menu of clinically applicable tests that may have use in future human trials, and establish a strong foundation for exploration of extra-neuronal consequences of pathogenic mitofusin variants in non-mouse models.
    Keywords:  electromyography; magnetic resonance imaging; mitochondria; mitofusin activator; myopathy; neuropathy
    DOI:  https://doi.org/10.3390/ijms27167376
  54. J Cardiovasc Aging. 2026 ;pii: 12. [Epub ahead of print]6(2):
    Understanding cardiovascular aging as a disorder of mitochondrial network.
    Taslima Akter Shila, Dhrubo Ahmad, Jianli Zhao, Huilan Tan, Bo Wang, John Zhang, Yajing Wang.
      Cardiovascular aging is increasingly recognized as a mitochondrial-initiated systemic network dysfunction, a progressive, integrative failure driven by deteriorating mitochondrial quality and signaling. This review synthesizes emerging evidence linking comprehensive mitochondrial pathology to the erosion of cardiovascular resilience as a network-level dysfunction. Age-dependent remodeling of mitochondrial ultrastructure and component composition disrupts respiratory efficiency, positioning bioenergetic insufficiency as a central determinant of reduced stress tolerance across the cardiovascular system. Concurrently, defects in mitochondrial fission-fusion dynamics and impaired mitophagy propagate dysfunction within the mitochondrial network, amplifying the decline in energetic capacity. Beyond energy failure, the release of mitochondrial DNA, vesicles, and peptides activates innate immune sensors such as the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway, initiating chronic sterile inflammation that propagates maladaptive remodeling cascades throughout cardiovascular tissues and distal organs. We challenge the traditional view of mitochondria solely as energy producers, revealing that uncoupled perfusion and energy metabolism, together with nitric oxide imbalance, can serve as early indicators of diastolic dysfunction and ischemic susceptibility. Additionally, we introduce the concept of "mitochondrial age", a composite measure that integrates respiratory function, imaging-based structural indices, and circulating mitochondrial biomarkers to quantify mitochondrial health. This metric may serve as a translational tool for assessing cardiovascular aging through mitochondrial network communication. Finally, we highlight rejuvenation strategies aimed at restoring mitochondrial youthfulness, ranging from behavioral interventions (exercise, time-restricted feeding) to metabolic and molecular therapies targeting nicotinamide adenine dinucleotide (NAD+) metabolism, mitophagy, and endothelial mitochondrial protection. Collectively, this review defines cardiovascular aging as a network-level mitochondrial disorder, offering new conceptual and therapeutic directions for preserving cardiac and vascular function.
    Keywords:  Cardiovascular aging; endothelial dysfunction; epidemiology; heart failure with preserved ejection fraction; hypertension; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.20517/jca.2026.07
  55. J Ethnopharmacol. 2026 Aug 28. pii: S0378-8741(26)01201-8. [Epub ahead of print] 122346
    Forsythoside A Alleviates Hypertensive Nephropathy by Promoting Mitophagy and Inhibiting Ferroptosis via ASCL1-CCNB1/mTOR Pathway.
    Xiaoli Cui, Di Yang, Zhihong Zhang, Chunmei Wang, He Li, Jinghui Sun, Tianyu Zhang, Mengyang Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Forsythiae Fructus, a classic heat-clearing and detoxifying herb in traditional Chinese medicine (TCM), is widely used for inflammatory conditions. Its primary bioactive component, Forsythoside A (FTA), exhibits potent anti-inflammatory and antioxidant activities. Given that hypertensive nephropathy is characterized by chronic inflammation, oxidative stress, and fibrosis-hallmarks that correspond to "heat" and "toxin" pathologies in TCM theory-Forsythiae Fructus represents a rational candidate for HN therapy. However, the precise mechanisms by which FTA inhibits HN progression remain incompletely elucidated.
    AIM OF THE STUDY: This study aims to investigate the protective effects of FTA against Ang II-induced HN and to elucidate the underlying signaling mechanisms.
    MATERIALS AND METHODS: We established HN models in C57BL/6 mice and NRK-52E cells using Ang II. The effects of FTA on renal injury were investigated through renal dysfunction indicators and tissue staining. RNA sequencing, molecular docking, CETSA and SPR technologies were employed to explore potential target sites and mechanisms of FTA in renal injury.
    RESULTS: FTA mitigated Ang II-induced renal injury by reducing renal dysfunction markers (Cr, BUN and Alb/Cr), restoring renal tissue architecture, and decreasing inflammatory markers (Ilb, Il6, Tnf), without exerting antihypertensive effects. RNA sequencing revealed associations with mTOR and ASCL1.Taken together, our in vivo and in vitro data reveal that FTA binds to ASCL1 and inhibits its activity, subsequently blocking the downstream CCNB1/mTOR pathway to confer renal protection. This inhibition promotes mitophagy and inhibits ferroptosis, ultimately alleviating renal injury.
    CONCLUSIONS: This study confirmed that FTA can bind to ASCL1, targeting the ASCL1-CCNB1/mTOR pathway to protect the kidney from Ang II-induced injury, offering broad therapeutic prospects for the treatment of HN.
    Keywords:  ASCL1; Angiotensin II; Forsythoside A; Hypertensive Nephropathy; mTOR
    DOI:  https://doi.org/10.1016/j.jep.2026.122346
  56. J Cardiovasc Dev Dis. 2026 Aug 13. pii: 387. [Epub ahead of print]13(8):
    Autophagy-Targeted Vascular Remodeling in Pulmonary Arterial Hypertension: Molecular Mechanisms and Therapeutic Perspectives.
    Miao Li, Limei Piao.
      Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by progressively increased pulmonary vascular resistance and right heart failure. Its pathogenesis involves multiple factors, including genetic predisposition, inflammation, oxidative stress, and imbalances between cell proliferation and apoptosis. Recent studies indicate that autophagy has a context-dependent dual role in PAH. Flux-competent autophagy may be protective by clearing damaged mitochondria, limiting excessive inflammation, and maintaining metabolic homeostasis, whereas excessive autophagy initiation or impaired autophagosome-lysosome degradation may promote metabolic dysfunction, inflammatory signaling, abnormal vascular cell phenotypes, and pulmonary vascular remodeling. This focused narrative review summarizes the molecular mechanisms and key signaling pathways linking autophagy to PAH, with emphasis on PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy and the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) energy-sensing axis. It also evaluates potential therapeutic strategies targeting key nodes of autophagy, such as AMPK activators and mTOR inhibitors, along with their clinical research progress. Finally, this review provides an outlook on future research directions, emphasizing the need to further elucidate the dynamic regulatory mechanisms and cell-type specificity of autophagy in order to advance the clinical translation of autophagy-targeted precision therapies for PAH.
    Keywords:  AMPK/mTOR; PAH; autophagy; mitophagy; pulmonary arterial hypertension; therapeutic targets; vascular remodeling
    DOI:  https://doi.org/10.3390/jcdd13080387
  57. Protein Cell. 2026 Aug 25. pii: pwag058. [Epub ahead of print]
    Adaptor proteins recruit DRP1 into helical assemblies on mitochondria: Insights from super-resolution imaging.
    Xian'ao Zhao, Shihang Luo, Yuanyuan Zhou, Tianying Pan, Shuanglei Li, Shuai Zhou, Ke Xiao, Tianjie Yang, Ran Gong, Mingcong Zhang, Jingjing Zhang, Weixing Li, Lusheng Gu, Tao Xu, Wei Ji.
      
    DOI:  https://doi.org/10.1093/procel/pwag058
  58. Food Sci Biotechnol. 2026 Aug;35(10): 2727-2742
    Urolithins: microbial biosynthesis, metabolic pathways and health benefits for functional food and cosmeceutical applications.
    Jaichandru Srinivasan, Ravikant Vinayakrao Vinchurkar, Soumya Sangam, Olalekan Shadrach Fadare, Raghu Hirikyathanahalli Vishweswaraiah, Diwas Pradhan.
      The gut microbiota profoundly influences host health by producing bioactive metabolites from dietary substrates. Among these, urolithins derived from ellagitannins in pomegranates, nuts and berries have attracted major scientific interest. Urolithin A (UroA), in particular, is noted for enhancing mitochondrial function through mitophagy, alongside its anti-inflammatory, antioxidant and anticancer activities. Structurally, urolithins share a tricyclic lactone backbone, with variations in hydroxylation accounting for their diversity. Their bioavailability and physiological effects, however, depend on factors such as gastrointestinal pH, solubility and the individual's gut microbiota composition. This review explores the origins, microbial metabolic pathways, chemical structures and biological activities of urolithins, emphasizing their therapeutic potential in metabolic, neurodegenerative and dermatological health. Furthermore, it highlights the roles of microbial enzymes and biosynthetic routes, offering perspectives on strategies to optimize urolithin production and application in functional foods, pharmaceuticals and cosmeceuticals.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-026-02136-6.
    Keywords:  Anti-inflammatory; Cosmeceuticals; Ellagitannins; Functional foods; Gut metabolites; Lactic acid bacteria; Mitophagy; Urolithins
    DOI:  https://doi.org/10.1007/s10068-026-02136-6
  59. Mitochondrion. 2026 Aug 22. pii: S1567-7249(26)00095-4. [Epub ahead of print]91 102205
    Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
    Yang Yang, Nirajan Neupane, Jouni Kvist, Jonna Saarimäki-Vire, Matthias Schewe, Kalle Luopajärvi, Pooja Manjunath, Svetlana Konovalova, Rubén Torregrosa-Muñumer, Veijo Kinnunen, Pekka Katajisto, Timo Otonkoski, Eija Pirinen, Jayasimman Rajendran, Henna Tyynismaa.
      Mitochondrial protein homeostasis intersects with metabolic control, but the in vivo roles of specific mitochondrial co-chaperones remain unclear. The chaperone mtHSP70 plays a key role in import and folding of nuclear-encoded proteins targeted to mitochondrial matrix. Its protein folding cycle is regulated by the GrpE-like nucleotide exchange factor GRPEL1. Vertebrates also have a GRPEL2 paralog, postulated as the stress-sensitive counterpart, but its physiological relevance is not known. We show here that GRPEL2 is not essential for viability in mice, and its absence does not induce proteotoxic stress responses in stark contrast to GRPEL1. However, we find that GRPEL2 has a role in regulating body weight homeostasis. GRPEL2 knockout mice are protected from age- and diet-induced weight gain and maintain a better metabolic health and insulin sensitivity. Transcriptional profiling revealed minimal changes in liver and skeletal muscle, whereas white adipose tissue from Grpel2-deficient mice lacked the obesity-associated remodeling seen in controls. We propose that GRPEL2 fine-tunes metabolic setpoints without broadly perturbing mitochondrial protein import, thereby maintaining adipose tissue health during nutritional excess. These findings show that subtle alterations in mitochondrial chaperone systems reshape systemic metabolism and could suggest strategies to mitigate obesity and insulin resistance through targeted modulation of mitochondrial proteostasis.
    Keywords:  Adipose tissue; Body weight homeostasis; Grpel2; Mitochondrial protein import; Nucleotide exchange factor; mtHSP70
    DOI:  https://doi.org/10.1016/j.mito.2026.102205
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