bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–04–05
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Cytosolic AcCoA: a metabolic signal bridging nutrient sensing and mitophagy.
  2. Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.
  3. STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
  4. Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
  5. ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
  6. HSP72 interacts with PRDX6 to deubiquitinate mitochondrial PINK1, activating mitophagy to treat MASLD.
  7. Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
  8. TUFM: a central regulator in mitochondrial quality control and beyond.
  9. Preoperative Beta-Hydroxy-Beta-Methyl-Butyrate Supplementation Reduces Mitochondrial Dynamics Proteins and Preserves Hepatic Mitochondrial Function After Partial Hepatectomy in Mice.
  10. Dysregulation of Drp1 and Mfn2 is associated with reduced PSD-95, synaptophysin, and BDNF expression in a rat model of Alzheimer's disease.
  11. Mitochondrial fission process 1 is required for bovine oocyte maturation through regulation of mitochondrial function and dynamics.
  12. The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.
  13. Decidual protein induced by progesterone enhances HIF-1α stability to promote mitophagy and glycolysis.
  14. Caveolin-1 deficiency exacerbates liver fibrosis by driving lipid metabolic reprogramming in hepatic stellate cells via DRP1-mediated mitochondrial fission.
  15. Oxidative Stress and Mitophagy in Rats With Nitroglycerin/Inflammatory Soup-Induced Migraine: A Comparative Study.
  16. Zn2+-Dependent Modulation of the Mitochondrial Ca2+ Uniporter Underlies Resveratrol-Mediated Protection against Myocardial Ischemia-Reperfusion Injury.
  17. Measurement of mitochondria amount and clearance using flow cytometry: effect of mitophagy inhibitors in leukemia cells.
  18. Electroacupuncture inhibited neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy after ischemic stroke.
  19. SOD2-Superoxide Metabolic Axis Regulates Mitophagy and Modulates TKIs Sensitivity in Head and Neck Squamous Cell Carcinoma.
  20. Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.
  21. Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression.
  22. Mitophagy at the intersection of ferroptosis and cuproptosis in osteosarcoma: Molecular interactions and therapeutic implications.
  23. Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models.
  24. Targeting the Gut-Liver Mitochondria Axis in MASLD: Mechanisms and Therapeutic Perspectives.
  25. Targeting REV-ERBα/BNIP3 axis attenuates pulmonary arterial hypertension by repressing mitophagy in mice.
  26. Hydrogen-Enriched Hyaluronic Acid Dressing Ameliorates Diabetic Foot Ulcer via Promoting Mitophagy.
  27. Danshensu ameliorates doxorubicin cardiotoxicity by attenuating oxidative stress and JNK-mediated mitochondrial dysfunction.
  28. Mitochondrial IRF3 drives pulmonary fibrosis by impairing mitophagy and triggering ferroptosis.
  29. NPC1L1, stabilized by PABPC1/IGF2BP1, accelerates atherosclerosis by enhancing CYP11A1-mediated mitophagy and ferroptosis.
  30. The chemically defined herbal mixture ADAPT-232 delays mitochondrial dysfunction and promotes healthspan through mitophagy-related pathways mediated by the DAF-16/NHR-49 axis.
  31. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  32. [Experimental study on the role of TRPM2 in regulating osteoblast differentiation through mitophagy in periodontitis].
  33. Mitophagy in Macrophages: A Metabolic Checkpoint in Inflammation-to-Repair Transition in Atherosclerosis.
  34. Coenzyme Q10 improves redox homeostasis, mitochondrial biogenesis, and Irisin signaling in fast- and slow-twitch muscle fibers in a reserpine-induced fibromyalgia-like myalgia model.
  35. [Effect of mitochondrial quality control on osteoclast differentiation and its research progress in oral diseases].
  36. Transcriptomic analysis reveals the critical role and mechanisms of Shenxian zhou in preventing age-related cognitive impairment.
  37. Pathological microtubule dynamics in Parkinson's disease: Mechanisms and therapeutic implications.
  38. Melatonin postconditioning attenuates myocardial ischemia/reperfusion injury by activating YAP to decrease DRP1-mediated mitochondrial fission.
  39. Targeting PSAT1 in diabetic kidney disease: a ferroptosis-driven strategy for precision therapy.
  40. Time-Controlled Refrigerated Stem Cell Therapy Mitigates Scleroderma Fibrosis via Modulation of Mitochondrial Autophagy and Gut Metabolism.
  41. Role of the UHRF1-KLHL6-CORO2B axis in obesity-related insulin resistance.
  42. Exercise-related microRNAs in Caenorhabditis elegans regulate calcium homeostasis and mitochondrial dynamics: Conserved pathways, divergent microRNAs.
  43. Integrated Machine Learning and Multi-Omics Analysis Identifies Mitophagy-Related Core Genes and Mechanisms in Non-Alcoholic Fatty Liver Disease.
  44. Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
  45. A conserved mammalian mecciRNA, mecciATP6, regulates mitochondrial homeostasis through interaction with HNRNPA3.
  46. [Expression of Concern] Electroacupuncture at GV20‑GB7 regulates mitophagy to protect against neurological deficits following intracerebral hemorrhage via inhibition of apoptosis.
  47. Cardiomyocyte-derived GPX4 stabilizes BNIP3 to facilitate mitophagy and mitigate myocardial ischemia/reperfusion injury.
  48. PAK5 drives vascular remodeling in hypoxic pulmonary hypertension via Drp1-dependent mitochondrial midzone division.
  49. Research based on serine metabolism indicates mesenchymal stem cells alleviate psoriasis by regulating the PSPH-PINK1-Parkin-NLRP3 pathway in HaCaT.
  50. Corrigendum to 'Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis' [Cell Signal. 2025 Aug, 132:111824].
  51. Mitochondrial genomes on a string of pearls.
  52. Multimodal therapeutic potential of Reinwardtia indica Dumort. in rodent model of cerebral ischemia: Attenuations of oxidative and neuroinflammatory stress, restoration of neurotransmitter and mitochondrial homeostasis, suppression of apoptotic signaling and preservation of blood-brain barrier integrity.
  53. Lonp1 Inhibition Disrupts Mitochondrial Function in the hippocampus and Drives an Aging-Like Synaptic and Cognitive Phenotype in adult SAMP8 mice.
  54. Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD.
  55. Mitochondria orchestrated immune microenvironment and response in health and disease-clinically relevant outlook and recommendations.
  56. Airborne PM2.5 from pig houses induces piglet respiratory epithelial barrier injury by activating the NLRP3 inflammasome through Drp1-mediated mitochondrial dysfunction.
  57. Mitochondrial Localization Around Central Nuclei in Regenerating Skeletal Muscle Following Eccentric Contraction in Rat Model.
  58. Specialized high-capacity mitochondria fuel cell invasion.
  1. Trends Biochem Sci. 2026 Mar 28. pii: S0968-0004(26)00007-1. [Epub ahead of print]
    Cytosolic AcCoA: a metabolic signal bridging nutrient sensing and mitophagy.
    Jiayi Chen, Xin Pan.
      How cells sense energy status to precisely regulate organelle fate is a central question in life sciences. Recent work by Zhang et al. reframes cytosolic acetyl-coenzyme A (AcCoA) from a metabolic substrate into a signaling metabolite that directly regulates mitophagy, thereby establishing a molecular link between nutrient sensing and mitochondrial homeostasis.
    Keywords:  NLRX1; cytosolic AcCoA; mitophagy
    DOI:  https://doi.org/10.1016/j.tibs.2026.01.007
  2. Mitochondrion. 2026 Apr 01. pii: S1567-7249(26)00041-3. [Epub ahead of print] 102151
    Overexpression of miR-455-3p enhances mitophagy, synaptic and mitochondrial proteins in Alzheimer's disease.
    Jangampalli Adi Pradeepkiran, Madhuri Bandaru, Md Ariful Islam, Sudhir Kshirsagar, Rainier Vladlen Alvir, Upasana Mukherjee, P Hemachandra Reddy.
      MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression, neural development and plasticity in Alzheimer's disease (AD). Our lab recently discovered molecular links between miR-455-3p and AD. miR-455-3p is known to regulate APP expression, thereby influencing amyloid beta (Aβ) generation. Using pronuclear injection and CRISPR/Cas9 technologies, we created miR-455-3p transgenic (TG) and knockout (KO) mice. Remarkably, the miR-455-3p TG mice displayed an extended lifespan (by approximately 5 months) compared to wild-type (WT) mice, whereas miR-455-3p KO mice had a reduced lifespan (by 4 months). Behaviorally, miR-455-3p TG mice outperformed cognitive tasks such as the Morris water maze and Y-maze, indicating improved spatial memory and learning. To explore miR-455-3p's role in AD progression, we crossed miR-455-3p TG and miR-455-3p KO mice with the humanized amyloid beta knock-in (hAbKI) mouse model, which mimics late-onset AD features. The resulting experimental groups included WT, miR-455-3p TG, miR-455-3p KO, hAbKI, miR-455-3p TG X hAbKI, and miR-455-3p KO X hAbKI. In the current study, we investigated mitochondrial dynamics, mitochondrial biogenesis, mitophagy and synaptic proteins in all six groups of 12-month-old male and female mice. We focused on examining the expression of, mitophagy regulators (PINK1, Parkin), and synaptic markers (PSD95, Synaptophysin), mitochondrial biogenesis regulators (PGC1α, NRF1, TFAM) and dynamic proteins (DRP1, FIS1, Mfn1/2, OPA1) in the cortex of 12-month-old animals using western blot and immunofluorescence analyses. We also studied spine density in hippocampal sections for the mice groups in a Golgi-cox staining assay. We found miR-455-3p overexpression enhances mitophagy, mitochondrial biogenesis, dynamics proteins and spine density, in hAbKI mice. Depleted miR-455-3p exacerbates mitochondrial defects, defective mitophagy and synaptic loss in hAbKI mice. Our findings highlight miR-455-3p as a promising therapeutic target that modulates multiple pathological pathways in AD. This is the first genetic crossing study of miR-455-3p TG/KO mice with late onset AD, hAbKI mice.
    Keywords:  Alzheimer’s disease; Humanized Abeta knockin mice; Mir-455-3p transgenic mice; Mitochondria; Mitochondrial biogenesis; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2026.102151
  3. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00261-5. [Epub ahead of print]45(4): 117183
    STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
    Jin-Yi Lin, Ze-Bo Huang, Shi-Qi Zhang, Yong Wu, Ling-Jun Cheng, Xiangzheng Gao, Sofie Lautrup, Shu-Qin Cao, Junping Pan, Dade Rong, Ruixue Ai, Hayden Weng Siong Tan, Liming Wang, Haihe Wang, Han-Ming Shen, Evandro F Fang, Guang Lu.
      PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes ubiquitination and proteasomal degradation during mitophagy through the coordinated action of STUB1 and VCP/p97. Depletion of STUB1 stabilizes full-length PINK1, which paradoxically impairs mitophagy through the acceleration of parkin degradation. At the organismal level, the STUB1-VCP axis plays an important role in neuronal mitophagy-related memory and learning capacities in the roundworm C. elegans. Congruently, this axis is impaired in the postmortem brain tissues from patients with Alzheimer's disease compared with cognitively normal controls. Collectively, our findings support STUB1-VCP as a molecular calibrator that fine-tunes full-length PINK1 levels to enable efficient mitophagy and maintain mitochondrial homeostasis.
    Keywords:  Alzheimer’s disease; CP: metabolism; CP: molecular biology; PINK1; STUB1; VCP/p97; autophagy; mitophagy; parkin; ubiquitination-proteasome system
    DOI:  https://doi.org/10.1016/j.celrep.2026.117183
  4. Biochem Pharmacol. 2026 Mar 29. pii: S0006-2952(26)00268-6. [Epub ahead of print] 117935
    Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
    Jimna Mohamed Ameer, Sneha Mary Alexander, K Navya, Rajesh A Shenoi, Goutam Chandra.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the midbrain substantia nigra, resulting in debilitating motor and non-motor symptoms. No disease modifying therapy is currently available for PD patients. Mounting evidence implicates impaired mitochondrial quality control (MQC) as a central driver of PD pathogenesis. MQC maintains mitochondrial integrity and function through coordinated mechanisms such as mitochondrial biogenesis, dynamics, mitophagy, the ubiquitin-proteasome system, and the formation of mitochondria-derived vesicles (MDVs). MDVs are small vesicular structures that selectively sequester and transport damaged mitochondrial components to lysosomes for degradation, representing a rapid and localized quality control pathway distinct from mitophagy. Beyond their degradative role, MDVs also participate in inter-organelle signalling and intercellular communication, suggesting a broader influence on neuronal homeostasis. Disruption of MDV biogenesis, trafficking, or clearance has been emerging as a key contributor of mitochondrial dysfunction and neurodegeneration in PD. This review synthesizes current understanding of MDV biology, its integration within the MQC network, role in PD pathogenesis and explores how targeting MDV pathways may offer novel diagnostic and therapeutic strategies to modify disease progression in PD.
    Keywords:  Endolysosome; Mitochondrial dynamics; Mitophagy; SNARE proteins; Transport vesicles; Ubiquitin-protein ligases
    DOI:  https://doi.org/10.1016/j.bcp.2026.117935
  5. Aging (Albany NY). 2026 Mar 27. 18(1): 213-233
    ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
    Victoria C Sanfrancesco, David A Hood.
      In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.
    Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response
    DOI:  https://doi.org/10.18632/aging.206365
  6. Hepatology. 2026 Apr 01.
    HSP72 interacts with PRDX6 to deubiquitinate mitochondrial PINK1, activating mitophagy to treat MASLD.
    Yong Rao, Rui Su, Wen-Jie Cao, Yue Chen, Shu-Heng Huang, Jun-Jie Wu, Darren C Henstridge, Lin-Sheng Huang, Jin Liu, Fei-Fei Liu, Zhong-Ping Jiang, Cong-Jun Xu, Zhi-Shu Huang, Ji-Ming Ye, Ling Huang.
       BACKGROUND AIMS: Mitophagy dysfunction in hepatocytes impedes energy homeostasis in the liver and exacerbates metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the novel role of heat shock protein 72 (HSP72), a classic chaperone protein, in controlling mitophagy in the livers of MASLD mice and isolated primary mouse hepatocytes.
    APPROACH: Mitophagy and HSP72 expression levels in the livers of MASLD mice and humans were determined. Global or liver specific Hsp72-/- and HSP72 +/+ mice, or primary mouse hepatocytes were used to unravel the role of HSP72 in regulating mitophagy and MASLD. Co-immunoprecipitation and LC-MS joint analysis was performed to identify HSP72 interacting protein involving mitophagy; its effect on the ubiquitination level of PINK1 and the crucial ubiquitinated site within PINK1 were explored and confirmed.
    RESULTS: Liver mitophagy was suppressed in MASLD mice and patients as the level of HSP72 decreased. Global or liver-specific deletion of HSP72 specifically exacerbated MASLD and suppressed mitophagy. Restoring HSP72 level in the liver activated mitophagy and ameliorated MASLD. The observations further confirmed in isolated primary mouse hepatocytes with genetic manipulation of HSP72. Peroxiredoxin 6 (PRDX6) is identified as an interactive protein of HSP72 and is correlated with mitophagy. PRDX6 deletion ubiquitinated PINK1 and inhibited mitophagy, thereby exacerbating MASLD. Instead, restoring PRDX6 efficiently deubiquitinated PINK1, thus activating mitophagy. More importantly, residue Lys318 (K318) of PINK1 was revealed as a priority site for its ubiquitination in response to PRDX6 regulation.
    CONCLUSIONS: These data suggest that the HSP72/PRDX6 axis is indispensable for PINK1/Parkin-dependent mitophagy to counteract MASLD.
    Keywords:  HSP72; MASLD; PINK1; PRDX6; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1097/HEP.0000000000001763
  7. bioRxiv. 2026 Mar 25. pii: 2026.03.20.711686. [Epub ahead of print]
    Activation of the protective arm of renin-angiotensin system enhances mitochondrial turnover improving respiration and decreasing integrated stress response in a human Complex III deficiency model.
    Lucía Fernández-Del-Río, Andrea Eastes, David Rincón Fernández Pacheco, Nikole Scillitani, Jasmine Garza, Matthew Dugan, Matheus Pinto de Oliveira, Pradnya Kadam, Iman Gauhar, Karel Erion, Kathleen Rodgers, Kevin Gaffney, Amy Wang, Marc Liesa, Cristiane Benincá, Orian Shaul Shirihai.
      Primary mitochondrial diseases are clinically and genetically heterogeneous disorders, commonly caused by defects in the oxidative phosphorylation system. This heterogeneity presents major challenges for therapeutic development; however, a shared hallmark across these diseases is the accumulation of dysfunctional mitochondria. Enhancing mitochondrial turnover, by activating the selective degradation of dysfunctional mitochondria via mitophagy, concurrently with the activation of mitochondrial biogenesis, could represent a shared therapeutic strategy for mitochondrial diseases. Here, we describe a novel mitophagy inducer, CAP-1902. CAP-1902 is a new agonist of the MAS G-Protein Coupled Receptor (MasR). In fibroblasts from patients carrying a BCS1L mutation that impairs complex III (CIII) assembly, CAP-1902 increased mitochondrial turnover by promoting both mitophagy and biogenesis. Specifically, MasR activation triggered the AMPK/ULK1/FUNDC1 mitophagy pathway. Knockdown of FUNDC1 blocked mitophagy but not AMPK activation, confirming pathway specificity. Additionally, a decrease in the occurrence of depolarized mitochondria with treatment indicated the selective targeting of accumulated damaged mitochondria in the disease context. MasR activation by CAP-1902 also stimulated the nuclear translocation of PGC-1α, promoting increased expression of transcripts associated with mitochondrial biogenesis, respiratory chain components, and mitochondrial translation. Remarkably, CAP-1902 was ultimately able to restore key defects in CIII-deficient fibroblasts by rescuing bioenergetics and correcting both the aberrant lysosomal distribution and the elevated integrated stress response markers, which is consistent with a shift toward a healthier mitochondrial population. In summary, we describe the first potential GPCR-mediated treatment of mitochondrial diseases and demonstrate that MasR activation by CAP-1902 induces mitochondrial turnover and improves mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.03.20.711686
  8. Cell Death Discov. 2026 Mar 28.
    TUFM: a central regulator in mitochondrial quality control and beyond.
    Xuanyi Li, Liangjie Dong, Tian Xiao, Jiayi Chen, Hang Ye, Siyi Zhu, Fulin Chen, Yuan Yu.
      Tu translation elongation factor, mitochondrial (TUFM) is a highly conserved, nuclear-encoded GTPase that is indispensable for mitochondrial protein synthesis. Beyond this canonical function, TUFM has emerged as a central regulator of mitochondrial quality control (MQC), orchestrating mitochondrial biogenesis, dynamics, and mitophagy through a location-dictates-function paradigm. Its subcellular localization and activity are precisely regulated by post-translational modifications, including phosphorylation, lactylation, ubiquitination, and acetylation, which collectively dictate its functional outputs in cellular homeostasis and stress responses. TUFM also serves as a critical interface in host-pathogen interactions, where viruses often hijack its pro-mitophagic function to evade mitochondrial antiviral signaling. Functioning as a cellular fate switch, the TUFM-MQC axis determines context-dependent pathological outcomes: its hyperactivation promotes cell growth and fuels oncogenesis, whereas its deficiency exacerbates cell death and contributes to neurodegeneration, inflammatory damage, and metabolic dysfunction. This review synthesizes current mechanistic insights into TUFM as a central MQC coordinator and delineates how its functional imbalance redirects cellular trajectories toward survival or death. Deciphering the regulatory logic and spatiotemporal dynamics of this pivotal hub offers promising avenues for developing targeted strategies to restore cellular homeostasis across a spectrum of diseases.
    DOI:  https://doi.org/10.1038/s41420-026-03075-1
  9. Acta Physiol (Oxf). 2026 May;242(5): e70204
    Preoperative Beta-Hydroxy-Beta-Methyl-Butyrate Supplementation Reduces Mitochondrial Dynamics Proteins and Preserves Hepatic Mitochondrial Function After Partial Hepatectomy in Mice.
    A L Vieira-da-Silva, M V Esteca, F A Silva, I A Divino, F S Carneiro, E R Ropelle, A S Torsoni, I L Baptista.
       AIM: The liver exhibits a remarkable regenerative capacity, enabling this organ to maintain homeostasis even after significant injury. However, hepatic regeneration requires sufficient energy to sustain cellular hypertrophy and proliferation, thus ensuring efficient tissue repair. Therefore, dietary modulation of pathways regulating mitochondrial quality may enhance liver regeneration. This study aimed to investigate the effects of preoperative beta-hydroxy-beta-methylbutyrate (HMB) supplementation on mitochondrial quality control pathways and its impact on the liver regeneration process in mice undergoing partial hepatectomy (PHx).
    METHODS: Male C57BL/6J mice were supplemented with 600 mg/kg HMB via gavage for 10 days. On the 10th day, supplementation was discontinued, and the mice underwent a ⅔ liver resection. The subsequent 7 days have constituted the liver regeneration period. For a second injury induction, at the end of the 7th day of regeneration, acetaminophen (APAP) overdose was administered via gavage. We then analyzed several markers of mitochondrial quality and liver function.
    RESULTS: Our results indicate that preoperative HMB supplementation modulates cell cycle progression, preventing excessive hepatic mass accumulation. Additionally, HMB regulates mitochondrial dynamics by decreasing Parkin, Mfn2, and DRP1 protein levels while increasing the mitochondrial markers VDAC2 and Tom20. Following a second injury from an APAP overdose, the HMB-supplemented group demonstrated increased mtDNA content and enhanced mitochondrial capacity, both critical for effective tissue recovery.
    CONCLUSION: Our findings suggest that preoperative HMB supplementation preserves hepatic mitochondrial capacity after PHx.
    Keywords:  liver mass recovery; liver metabolism; liver regeneration; mitochondrial network; mitochondrial protein; mtDNA content
    DOI:  https://doi.org/10.1111/apha.70204
  10. Int J Biol Macromol. 2026 Apr 01. pii: S0141-8130(26)01700-9. [Epub ahead of print] 151774
    Dysregulation of Drp1 and Mfn2 is associated with reduced PSD-95, synaptophysin, and BDNF expression in a rat model of Alzheimer's disease.
    Mohamad Alfateh, Carlos Vasconcelos, Ali Hussein Choker, Helia Mohammadaein.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and mitochondrial abnormalities. Mitochondrial dynamics, especially the balance between fusion and fission processes regulated by proteins like mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1), play critical roles in neuronal health. However, the relationship between mitochondrial dynamics and synaptic integrity, and cognitive deficits remains incompletely understood. This study aimed to investigate the alterations in Mfn2 and Drp1 expression and their association with synaptic protein levels and also behavioral outcomes in a rat model of AD. Thirty adult male Wistar rats were randomly assigned to control and AD groups. AD was induced through bilateral hippocampal injection of Aβ1-42. Behavioral assessments including the Morris Water Maze, Novel Object Recognition, and Y-maze were conducted to evaluate spatial learning and memory. On day 21 post-induction, gene expression of Drp1, Mfn2, PSD-95, synaptophysin, BDNF, Bax, and Bcl2 in the hippocampus and cortex was measured using real-time PCR. Oxidative stress markers (MDA, SOD, CAT) and inflammatory cytokines (NF-κB, IL-1β) were evaluated in serum using ELISA kits. Results showed significant downregulation of Mfn2 and synaptic proteins, with increased Drp1 and Bax expression in AD rats. These molecular changes were accompanied with increase of oxidative and inflammatory markers and altered cognitive performance. In conclusion, the findings suggest that disrupted mitochondrial dynamics contribute to synaptic loss and cognitive decline in AD. Targeting mitochondrial function and neuroinflammation may represent potential therapeutic targets for AD management.
    Keywords:  Alzheimer's disease; BDNF; Cognitive impairment; Mitochondrial dynamics; PSD-95; Synaptophysin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151774
  11. Theriogenology. 2026 Mar 28. pii: S0093-691X(26)00106-8. [Epub ahead of print]259 117916
    Mitochondrial fission process 1 is required for bovine oocyte maturation through regulation of mitochondrial function and dynamics.
    Tiancang Han, Yuhan Zhao, Zhaoyang Sun, Anhui Jiao, Bingbing Wang, Qingshan Gao.
      Oocyte maturation is a complex process that is regulated by a variety of factors. Mitochondria are a key factor affecting oocyte maturation in vitro. Mitochondrial fission process 1 (MTFP1) is located on the inner mitochondrial membrane and mediates the fission of this membrane. However, the role and mechanism of MTFP1 in bovine oocyte maturation are still unclear. Therefore, we performed siRNA-mediated MTFP1 knockdown during in vitro maturation of bovine oocytes and assessed its effects on oocyte maturation as well as mitochondrial function and dynamics. We found that MTFP1 is expressed at all stages of bovine oocyte maturation. Moreover, MTFP1 knockdown decreased oocyte maturation efficiency. These observations, combined with our transcriptome sequencing results, showed that MTFP1 knockdown caused mitochondrial dysfunction, impaired nuclear and cytoplasmic maturation, promoted mitochondrial fusion, induced mitophagy and decreased oocyte apoptosis. In summary, the inner mitochondrial membrane protein MTFP1 plays a crucial role in bovine oocyte maturation. The results provide a reference and theoretical basis for improving the quality of in vitro oocyte maturation and breeding efficiency in beef cattle.
    Keywords:  MTFP1; Mitochondrial dynamics; Oocytes; RNA-seq
    DOI:  https://doi.org/10.1016/j.theriogenology.2026.117916
  12. BMC Nephrol. 2026 Apr 01.
    The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.
    Limiao Yang, Hongle Yang, Mingming Zhang, Feifei Zhang, Xiaomei Liu, Zhiping Zhang, Jing Wang, Xiaolu Chen, Yuexuan Wang, Rui Zhang, Weihao Li.
      
    Keywords:  Membranous nephropathy; Mitochondrial translocation; Mitophagy; Telomerase reverse transcriptase; The outer mitochondrial membrane 20
    DOI:  https://doi.org/10.1186/s12882-026-04910-4
  13. FEBS J. 2026 Apr 01.
    Decidual protein induced by progesterone enhances HIF-1α stability to promote mitophagy and glycolysis.
    Baopeng Tian, Jie Shen, Xuanning Chu, Yannan Zhou, Hao Li, Lei Wang, Min Guo, Jie Dou.
      Mitophagy, the process of removing mitochondria through the autophagy-lysosome pathway, is crucial for maintaining cellular homeostasis. However, its regulatory mechanisms and pathological implications remain poorly understood. In our study, we revealed that decidual protein induced by progesterone (DEPP) plays a significant role in mitophagy through the DEPP-HIF-1α-BNIP3/NIX axis. Our findings indicate that interaction between DEPP and hypoxia-inducible factor 1-alpha (HIF-1α) enhances HIF-1α stability, thereby promoting the transcription of HIF-1 target genes. The enhanced protein stability of HIF-1α not only activates mitophagy by stimulating the transcription of BCL2-interacting protein 3 (BNIP3) and BCL2-interacting protein 3-like (BNIP3L; also known as NIX) mRNA but also influences cellular metabolic reprogramming by promoting the transcription of glycolysis-related genes. In conclusion, our findings suggest that DEPP may act as a potential regulator of mitophagy and HIF-1α, playing an important role in maintaining cellular metabolic and energy homeostasis.
    Keywords:  BNIP3; DEPP; HIF‐1α; NIX; glycolysis; mitophagy
    DOI:  https://doi.org/10.1111/febs.70489
  14. Free Radic Biol Med. 2026 Mar 29. pii: S0891-5849(26)00254-6. [Epub ahead of print]250 203-215
    Caveolin-1 deficiency exacerbates liver fibrosis by driving lipid metabolic reprogramming in hepatic stellate cells via DRP1-mediated mitochondrial fission.
    Yong Wang, Xingyu Wang, Jingxue Lin, Wenhui Zhang, Yuquan Sun, Qianqian Geng, Shuo Chen, Chao Zhang, Lei Jin, Chengmu Hu.
      Liver fibrosis represents a prevalent pathological outcome of sustained hepatic injury and is largely driven by aberrant activation of hepatic stellate cells (HSCs). Emerging evidence suggests that mitochondrial dynamics and lipid metabolic remodeling play critical roles in HSC activation; however, the upstream regulatory mechanisms remain incompletely understood. Here, we identify Caveolin-1 (CAV1) as a critical suppressor of HSC activation. CAV1 deficiency enhances DRP1-mediated mitochondrial fission, elevating mitochondrial reactive oxygen species (mtROS) and shifting lipid metabolism toward fatty acid oxidation, thereby fueling HSC activation. Inhibition of DRP1 with Mdivi-1 restored mitochondrial homeostasis, reduced mtROS, normalized lipid metabolism, and suppressed HSC activation. In vivo, CAV1 knockout aggravated CCl4-induced liver fibrosis via DRP1-dependent mitochondrial fission and metabolic reprogramming, while Mdivi-1 treatment alleviated fibrosis. Collectively, these findings identify CAV1 as a critical upstream regulator of HSC activation and liver fibrosis through modulation of DRP1-mediated mitochondrial fission, mtROS generation, and lipid metabolic reprogramming, highlighting a potential therapeutic target for liver fibrosis.
    Keywords:  Caveolin-1; DRP1; Hepatic stellate cells; Lipid metabolism reprogramming; Mitochondrial fission; mtROS
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.063
  15. Pain Res Manag. 2026 ;2026(1): e5584799
    Oxidative Stress and Mitophagy in Rats With Nitroglycerin/Inflammatory Soup-Induced Migraine: A Comparative Study.
    Wen-Xiu Sun, Ting-Yan Chen, Mao-Mei Song, Ying-Jie Gao, Sui-Yi Xu.
       OBJECTIVE: Oxidative stress leads to mitochondrial DNA, protein, and lipid damage, ultimately resulting in mitochondrial dysfunction. Decreased mitophagy leads to the continuous accumulation of damaged mitochondria, which further induces oxidative stress and cellular damage. Mitochondrial dysfunction and an imbalance between energy supply and demand may lead to increased migraine susceptibility. However, there have been no comparative studies from the perspective of oxidative stress and mitophagy.
    METHOD: Male Sprague-Dawley rats were divided into control, NTG (10 mg/kg, intraperitoneal, Days 1/3/5/7), and IS (epidural infusion, 7 days) groups (n = 10, per group). Paw mechanical thresholds, migraine-like behaviors (head-face scratching, body grooming, exploration, and freezing time), and oxidative markers (malondialdehyde, catalase, reduced glutathione, and superoxide dismutase) in the trigeminal nucleus caudalis were assessed. The expressions of PINK1, Parkin, LC3II/I, TOMM20, and COXIV were evaluated to quantify levels of mitophagy.
    RESULTS: Both NTG/IS models reduced mechanical thresholds, but NTG induced stronger head scratching and freezing time. Oxidative stress markers diverged: NTG elevated malondialdehyde and depleted reduced glutathione/superoxide dismutase, while IS primarily reduced superoxide dismutase. Both models exhibited a decreased LC3II/I ratio as well as reduced PINK1 and Parkin.
    CONCLUSION: NTG/IS administration comparatively decreased the mechanical threshold, increased the level of oxidative stress, and decreased the level of mitophagy in the trigeminal nucleus caudalis in migraine rats.
    Keywords:  antioxidant; mitochondrial metabolism; oxidative stress; rat migraine model; trigeminal nuclear caudalis
    DOI:  https://doi.org/10.1155/prm/5584799
  16. Exp Cell Res. 2026 Apr 01. pii: S0014-4827(26)00124-2. [Epub ahead of print] 115007
    Zn2+-Dependent Modulation of the Mitochondrial Ca2+ Uniporter Underlies Resveratrol-Mediated Protection against Myocardial Ischemia-Reperfusion Injury.
    Bohan Xing, Xiaoyi Li, Bingyu Wang, Luyao Huang, Qiuyu Wang, Xi Chen, Huan Zheng, Yonggui He, Jinkun Xi.
       PURPOSE: This study aims to determine whether resveratrol (Res) regulates the mitochondrial calcium uniporter (MCU) in a Zn2+-dependent manner to influence mitochondrial biogenesis and dynamics, thereby alleviating myocardial ischemia-reperfusion injury (MIRI) and conferring cardioprotective effects.
    METHODS: H9c2 cardiomyocytes were cultured to establish an in vitro ischemia/reperfusion (I/R) model. Biochemical assays and transmission electron microscopy were used to assess cellular injury and mitochondrial ultrastructure after I/R. Protein structure prediction and molecular docking analyses were conducted to explore Res-protein interactions. Western blot, immunofluorescence staining, and RT-qPCR were performed to determine the expression of MCU, mitochondrial biogenesis and dynamics-related proteins. Confocal microscopy was used to measure mitochondrial membrane potential changes, and intracellular Zn2+ and Ca2+ fluorescence intensities.
    RESULTS: Compared with Control group, I/R significantly reduced myocardial viability, increased cytotoxicity, and decreased intracellular Zn2+ levels, ATP content, and NAD+/NADH ratio. The expression of mitochondrial biogenesis regulators (SIRT1, PGC-1α, NRF1, TFAM) and fusion-related proteins (OPA1, Mfn1, Mfn2) were downregulated, whereas fission-related proteins (Drp1, Fis1) were upregulated. MCU protein and mRNA levels were increased, alongside reduced PGC-1α/TFAM mRNA levels and decreased mitochondrial DNA copy number. In addition, MMP and Zn2+ fluorescence intensities decreased, while Ca2+ intensity increased. Res treatment attenuated I/R-induced cellular and mitochondrial injuries; however, the zinc chelator TPEN reversed these effects. Furthermore, MCU silencing by siRNA further enhanced the protective effects of Res.
    CONCLUSIONS: Resveratrol exerts cardioprotective effects against MIRI by increasing intracellular Zn2+ to modulate MCU activity, thereby promoting mitochondrial biogenesis and fusion, inhibiting excessive fission, improving mitochondrial function, and ultimately attenuating MIRI.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Myocardial ischemia reperfusion injury; Zn(2+); resveratrol
    DOI:  https://doi.org/10.1016/j.yexcr.2026.115007
  17. Cancer Metab. 2026 Apr 03.
    Measurement of mitochondria amount and clearance using flow cytometry: effect of mitophagy inhibitors in leukemia cells.
    Tereza Kořánová, Dana Grebeňová, Kateřina Kuželová.
      
    Keywords:  Chloroquine; HS-5; Leukemia; Mitophagy; SQSTM1; TP53; XRK3F2; mDivi-1
    DOI:  https://doi.org/10.1186/s40170-026-00429-2
  18. Chin Med. 2026 Apr 03. pii: 110. [Epub ahead of print]21(1):
    Electroacupuncture inhibited neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy after ischemic stroke.
    Li Zhou, Yicheng Peng, Mingchao Fu, Mei Zhou, Chengcai Zhang, Xichen Yang, Yongdan Cun, Simei Zhang, Na Chen, Rong Ning, Yaju Jin, Zuhong Wang, Hong Xin, Pengyue Zhang.
      Neuronal apoptosis persists throughout ischemic stroke. This leads to massive neuron loss and severely impairs recovery of neurological function. Clinical evidence has confirmed that electroacupuncture (EA) effectively improves neurological function after ischemic stroke; however, the underlying mechanism remains to be fully elucidated. In this study, we found that apoptosis and autophagy were activated after ischemic stroke. EA further upregulated autophagy and inhibited neuronal apoptosis in the ischemic stroke model. Furthermore, EA's neuroprotective effect was linked to mitophagy activation by upregulating PGAM5 expression, which promoted FUNDC1 dephosphorylation and enhanced the interaction between FUNDC1 and LC3, ultimately activating PGAM5/FUNDC1-dependent mitophagy. Enhanced mitochondrial autophagy reduced ROS production and Cyt c release from damaged mitochondria, thereby inhibiting Caspase3 activation and subsequent neuronal apoptosis. Meanwhile, EA also upregulated the level of FUNDC1 and further promoted mitophagy through the PGAM5/FUNDC1 pathway. Notably, lateral ventricle injection of 3-MA inhibited mitophagy and significantly reversed the neuroprotective effect of EA. In summary, the neuroprotective effect of EA against ischemic stroke might be achieved by inhibiting neuronal apoptosis through PGAM5/FUNDC1-dependent mitophagy.
    Keywords:  Apoptosis; Autophagy; Electroacupuncture; Ischemic stroke; Mitophagy; PGAM5/FUNDC1 pathway
    DOI:  https://doi.org/10.1186/s13020-026-01383-3
  19. Cancer Sci. 2026 Mar 30.
    SOD2-Superoxide Metabolic Axis Regulates Mitophagy and Modulates TKIs Sensitivity in Head and Neck Squamous Cell Carcinoma.
    Wan-Hang Zhou, Shuo-Jin Huang, An-Xun Wang.
      Superoxide dismutase 2 (SOD2) has been implicated in head and neck squamous cell carcinoma (HNSCC), yet its mechanistic contribution in regulating tumor responses to tyrosine kinase inhibitors (TKIs) remains unclear. Here, we investigated whether SOD2 shapes TKI sensitivity in HNSCC through a mitochondrial superoxide-mitophagy axis. Bioinformatic analyses revealed that elevated SOD2 expression was negatively correlated with mitophagy signatures in HNSCC. Functional experiments showed that SOD2 silencing led to mitochondrial superoxide accumulation, impaired mitochondrial function, and significant mitophagy activation in HNSCC cells. Pharmacological modulation further supported a superoxide-dependent mechanism, as Mito-TEMPO suppressed mitochondrial superoxide and mitophagy induction, whereas rotenone enhanced mitochondrial superoxide and mitophagy activity. Importantly, SOD2 knockdown increased apoptotic susceptibility and sensitized HNSCC cells to TKI treatment, which was partially reversed by superoxide scavenging but reinforced by superoxide elevation. Consistently, SOD2 knockout xenograft models exhibited enhanced antitumor responsiveness to TKIs in vivo. Collectively, these findings identified SOD2 as a key regulator of mitochondrial redox homeostasis and mitophagy, thereby modulating therapeutic sensitivity in HNSCC, and suggest that targeting the SOD2-superoxide metabolic axis may represent a promising strategy to improve TKIs efficacy in HNSCC.
    Keywords:  anlotinib; head and neck squamous cell carcinoma; mitophagy; superoxide; superoxide dismutase 2
    DOI:  https://doi.org/10.1111/cas.70374
  20. Neurosci Bull. 2026 Mar 28.
    Decode the Ubiquitinome in Parkinson's Disease: From Pathological Aggregates to Targeted DUB Therapeutics.
    Xi Yu, Qinshuai Ni, Litong Han, Shenghan Zhang, Huamin Xu, Junxia Xie, Yingjuan Liu.
      Parkinson's disease (PD), a neurodegenerative disorder, is significantly influenced by genetic predispositions, aging, and environmental factors. Central to PD pathology are mechanisms such as aberrant α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, and ferroptosis, all of which are closely associated with dysregulated protein post-translational modifications. Ubiquitination, a critical reversible modification, acts as a pivotal bridge connecting the ubiquitin-proteasome system and the lysosomal-autophagy pathway, with its dynamics finely counterbalanced by deubiquitinating enzymes (DUBs). Notably, under pathological conditions, many DUBs exacerbate disease by stabilizing toxic α-syn aggregates and suppressing mitophagy. This review synthesizes current knowledge on how ubiquitin signaling orchestrates PD pathogenesis and highlights the emerging therapeutic potential of targeting specific DUBs with small molecule inhibitors to restore proteostasis and mitochondrial quality control, offering novel strategies for disease modification in PD.
    Keywords:  Deubiquitinating enzymes; Mitophagy; Parkinson disease; Ubiquitination; α-synuclein
    DOI:  https://doi.org/10.1007/s12264-026-01613-6
  21. Cancer Lett. 2026 Mar 26. pii: S0304-3835(26)00220-X. [Epub ahead of print]647 218457
    Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression.
    Nicolás Georges-Calderón, Camila Fuentes, Yessia Hidalgo, Felipe Grunenwald, José Corrales-Bermúdez, Aliosha I Figueroa-Valdés, Mirliana Ramírez-Pereira, Gloria Arriagada, Fernando J Bustos, Constanza Ahumada-Marchant, Mercedes López, Francisca Alcayaga-Miranda.
      Recent evidence establishes that melanoma cells actively uptake mitochondria from stromal cells; however, the mitochondrial release in a physiological context remains unstudied. Here, we show that melanoma cells release dysfunctional mitochondria into the extracellular space through a predominantly non-vesicular route. Using melanocyte Melan-a and melanoma B16-F1 and B16-F10 cell lines, we observed increased extracellular mitochondrial release in malignant cells. Electron microscopy revealed these mitochondria lacked cristae and were primarily free organelles. Membrane potential analysis confirmed their dysfunctional state. Mitophagy analysis using mtKeima showed that, under oxidative stress, melanoma cells failed to activate canonical mitophagy and instead upregulated mitochondrial release as an alternative MQC mechanism. Western blot analysis revealed a fission-biased mitochondrial network in melanoma cells, with elevated phospho-DRP1/DRP1 ratio, and a tendency to reduce MFN1 and OPA1. Together with PINK1/ATG7 downregulation and BNIP3/NIX upregulation, suggest a secretory mitophagy phenotype. Tumor-derived mitochondria were detected in both the tumor microenvironment and plasma of melanoma-bearing mice, with extracellular mitochondria levels correlating with tumor burden. Plasma from melanoma patients exhibited elevated levels of TOMM20+ mitochondria compared to healthy donors. Transcriptomic analysis of The Cancer Genome Atlas melanoma cohort revealed that high expression of MQC-related genes DRP1 and BNIP3L was associated with worse prognosis. Collectively, our findings uncover a tumor-intrinsic, non-canonical MQC pathway that releases dysfunctional mitochondria. This mechanism establishes a new paradigm of tumor-host systemic communication, wherein circulating tumor-derived mitochondria might actively influence disease progression. These findings open avenues for developing non-invasive biomarkers and therapeutic strategies targeting mitochondrial release.
    Keywords:  Biomarkers; Extracellular mitochondria; Melanoma; Mitochondrial quality control; Secretory mitophagy
    DOI:  https://doi.org/10.1016/j.canlet.2026.218457
  22. Tissue Cell. 2026 Mar 26. pii: S0040-8166(26)00191-6. [Epub ahead of print]101 103498
    Mitophagy at the intersection of ferroptosis and cuproptosis in osteosarcoma: Molecular interactions and therapeutic implications.
    Haizhou Fang, Meng Zhang, Shuangshuang Yang, Jinxi Yue, Lijun Cui.
      Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. Its pronounced aggressiveness, metabolic reprogramming features, and the development of acquired resistance to chemotherapy severely limit the long-term efficacy of current therapeutic strategies. In recent years, the concept of metal ion-dependent regulated cell death has provided a novel theoretical framework for understanding cell fate regulation in osteosarcoma. Among these mechanisms, ferroptosis and cuproptosis are characterized by iron homeostasis-driven uncontrolled lipid peroxidation and copper-dependent mitochondrial proteotoxic stress, respectively. Both processes are closely associated with the metabolic phenotype, invasive behavior, and therapeutic responsiveness of osteosarcoma. However, the potential synergistic or antagonistic interactions between ferroptosis and cuproptosis, as well as their upstream regulatory networks in osteosarcoma, remain insufficiently integrated and systematically elucidated. Mitophagy, a critical process for maintaining mitochondrial quality control and metabolic homeostasis, is increasingly recognized as a central hub linking multiple forms of metal-dependent cell death. On the one hand, mitophagy dynamically modulates the threshold of ferroptosis by regulating mitochondrial ROS production, intracellular iron pool distribution, and lipid metabolic pathways. On the other hand, through its regulation of tricarboxylic acid cycle activity, lipoylated protein homeostasis, and mitochondrial metal-buffering capacity, mitophagy may exert bidirectional regulatory effects on cuproptosis as well. Under specific metabolic contexts, dysregulated mitophagy may serve as a critical prerequisite for amplifying the crosstalk between ferroptosis and cuproptosis. This review systematically summarizes recent advances in the study of mitophagy, ferroptosis, and cuproptosis in osteosarcoma. By focusing on mitochondrial metabolic reprogramming, metal homeostasis regulation, and programmed cell death networks, we comprehensively dissect the molecular mechanisms underlying the interplay among these processes. Furthermore, we discuss the potential therapeutic value of targeting the mitophagy-ferroptosis-cuproptosis axis to overcome osteosarcoma aggressiveness and chemoresistance, thereby providing a theoretical basis and conceptual framework for precision therapeutic strategies centered on mitochondrial and metal metabolism reprogramming.
    Keywords:  Cuproptosis; Ferroptosis; Mitophagy; Osteosarcoma
    DOI:  https://doi.org/10.1016/j.tice.2026.103498
  23. Neurotherapeutics. 2026 Apr 02. pii: S1878-7479(26)00070-X. [Epub ahead of print]23(3): e00900
    Arginine ameliorates motor and survival deficits in MFN2-Deficient Drosophila models.
    Masahiro Ando, Yuji Okamoto, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Chikashi Yano, Risa Nagatomo, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Yusuke Sakiyama, Hiroshi Takashima.
      Charcot-Marie-Tooth disease type 2 A (CMT2A) is an inherited axonal neuropathy linked to mutations in MFN2, a key regulator of mitochondrial dynamics. Currently, no effective drug therapies exist. l-arginine has shown promise in treating mitochondrial disorders, though its effect on MFN2-associated neuropathy remains uncertain. To investigate this, we used Drosophila models with the neuron-specific knockdown of Marf, the fly ortholog of MFN2, employing a temporally controlled GAL4/UAS system. Flies were administered different doses of l-arginine to examine its influence on motor ability and lifespan. To evaluate responses under mitochondrial stress, flies were also treated with rotenone, a mitochondrial complex I inhibitor. l-arginine markedly improved climbing performance under baseline conditions and extended lifespan under both baseline and stress conditions. However under rotenone-induced mitochondrial stress, high-dose l-arginine improved survival without a corresponding improvement in locomotor performance. These results support a neuroprotective role for l-arginine in MFN2-deficient Drosophila, possibly through effects on mitochondrial dynamics involving complex I. l-arginine may hold therapeutic promise for CMT2A, meriting further investigation in vertebrate models.
    Keywords:  Drosophila; Mitochondrial dynamics; Mutation; Rotenone; l-arginine
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00900
  24. Curr Med Sci. 2026 Apr 02.
    Targeting the Gut-Liver Mitochondria Axis in MASLD: Mechanisms and Therapeutic Perspectives.
    Yu-Hang Wang, Xue-Song He, Li Lin, Lu-Lu Ning, Ya Zhao, Meng-Xiao Zhang, Le Chen, Min Chen.
      The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing continuously, posing a substantial threat to public health. This study examines the critical role of imbalanced interactions within the gut‒liver-mitochondrial axis in MASLD pathogenesis. Dysregulation of mitochondrial homeostasis, including metabolic disturbances, impaired quality control, and disrupted interorganelle interactions, significantly contributes to MASLD progression. Through the gut‒liver axis, the gut microbiota establishes a bidirectional regulatory network with mitochondria. Dysbiosis disrupts mitochondrial homeostasis via multiple pathways, while mitochondrial dysfunction aggravates imbalances in the gut microbiota, creating a vicious cycle. Therefore, in this study, the molecular basis of mitochondrial abnormalities was investigated, and the mechanisms of reciprocal regulation were clarified. Additionally, targeted intervention strategies, including the modulation of mitochondrial homeostasis and the regulation of the gut microbiota, are explored to provide novel therapeutic perspectives for MASLD.
    Keywords:  Gut microbiota; Gut-liver mitochondria axis; Metabolic dysfunction-associated steatotic liver disease (MASLD); Mitochondrial homeostasis; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s11596-026-00190-z
  25. Nat Commun. 2026 Apr 02.
    Targeting REV-ERBα/BNIP3 axis attenuates pulmonary arterial hypertension by repressing mitophagy in mice.
    Lejia Qiu, Tingting Lu, Jiayang Zhang, Min Liu, Hui Wang, Wenyu Li, Changxiao Ma, Shuyao Li, Baoyin Ren, Qiong Wang, Fenling Fan, Hu Xu, Feng Zheng, Youfei Guan, Xiaoyan Zhang, Guangrui Yang, Lihong Chen.
      Pulmonary arterial hypertension (PAH) is a life-threatening metabolic disorder. Nuclear receptors REV-ERBα and REV-ERBβ are established regulators of circadian rhythm and metabolic homeostasis, however their roles in PAH remain unclear. Using Rev-erbα+/-, VSMC-specific Rev-erbα-/-, and Rev-erbβ-/- mice (only male mice were used in the study), along with pharmacological activation and AAV-mediated overexpression, we found that Rev-erbα deficiency, particularly in vascular smooth muscle cells (VSMCs), exacerbates Su5416+hypoxia (SuHx)-induced PAH, whereas REV-ERBα activation or overexpression alleviates disease. In contrast, Rev-erbβ loss does not affect PAH. Notably, late-stage administration of REV-ERBα agonist significantly improves established PAH. Mechanistically, REV-ERBα directly represses Bnip3 transcription, thereby inhibiting BNIP3-driven mitophagy and improving mitochondrial function in hypoxic pulmonary artery smooth muscle cells (PASMCs). Bnip3 knockdown phenocopies REV-ERBα activation, while Bnip3 overexpression abrogates REV-ERBα's anti-proliferative effects and accelerates PAH. Collectively, REV-ERBα protects against PAH by inhibiting BNIP3-driven mitophagy and preserving mitochondrial homeostasis in PASMCs. Targeting the REV-ERBα/BNIP3 axis holds promise as a circadian-based therapeutic strategy for PAH.
    DOI:  https://doi.org/10.1038/s41467-026-71189-2
  26. J Diabetes. 2026 Apr;18(4): e70209
    Hydrogen-Enriched Hyaluronic Acid Dressing Ameliorates Diabetic Foot Ulcer via Promoting Mitophagy.
    Ziyu Xu, Xinyu Cui, Houbin Chu, Hao Wan, Yunbo Xie, Ying Wang, Qingbin Ni, Xiaolin Ding, Guohua Song.
       OBJECTIVE: Diabetic foot ulcer (DFU) is one of the most common chronic complications of diabetes. This study developed a hydrogen-enriched hyaluronic acid (HA) dressing and aimed to explore its therapeutic effects and mechanisms in DFU treatment.
    METHODS: A combination of vacuum-assisted closure (VSD) and hydrogen-rich saline was used to treat DFU patients and assess the clinical outcomes of wound repair. A rat model of DFU was established, and treatment with hydrogen-enriched HA dressing. Subsequently, the protective effects of the dressing were evaluated, including histological studies, the expression of inflammatory factors and angiogenesis markers. Western blot was used to analyze the expression levels of mitophagy-related proteins. In vitro, the role of HA and hydrogen on cell mitochondrial damage, apoptosis, migration, and markers associated with mitophagy pathways in human foreskin fibroblast-1 (HFF-1) was assessed.
    RESULTS: VSD combined with hydrogen-rich saline significantly enhanced wound healing in patients, while reducing inflammation and oxidative damage. In vivo studies showed that the dressing promoted wound healing, increased collagen deposition, reduced inflammatory cytokines, and enhanced neovascularization. In vitro studies, high glucose induced cell morphological damage and oxidative stress, disrupted mitochondrial membrane potential, leading to apoptosis and attenuating cell migration. However, both HA and hydrogen significantly induced SIRT3 expression and activated the downstream FOXO3A/PINK1-PARKIN signaling pathway, promoting mitochondrial autophagy and reducing cell apoptosis. Furthermore, the SIRT3/SOD2 pathway was also activated, decreasing reactive oxygen species (ROS) production and enhancing migration.
    CONCLUSION: This study confirmed that the hydrogen-enriched HA dressing has the potential to enhance diabetic wound repair.
    Keywords:  SIRT3; diabetic foot ulcer; hydrogen‐enriched hyaluronic acid dressing; mitophagy
    DOI:  https://doi.org/10.1111/1753-0407.70209
  27. Phytomedicine. 2026 Mar 27. pii: S0944-7113(26)00366-1. [Epub ahead of print]155 158131
    Danshensu ameliorates doxorubicin cardiotoxicity by attenuating oxidative stress and JNK-mediated mitochondrial dysfunction.
    Xuemei Wang, Wenjing Huang, Lin Shen, Li Zheng, Lunda Gu, Lan Lin, Lingyu Li, Linling Liu, Yingling Wang, Xinyue Li, Yan Mao, Xiao Liu, YiXin Chen, Jiayi Kong, Qiying Jiang, Xin Yan, Ruli Li, He Li, Junyan Zhang, Ran Zhang, Fan Wang, Yingqiang Guo, Wei Jiang.
       BACKGROUND: Doxorubicin (DOX) is a potent chemotherapeutic widely used in cancer treatment, but its clinical application is limited by dose-dependent cardiotoxicity. The underlying mechanisms involve oxidative stress, mitochondrial dysfunction, and apoptosis; however, effective cardioprotective strategies remain inadequate.
    PURPOSE: To evaluate the cardioprotective effects of Danshensu (DSS), a bioactive compound from Salvia miltiorrhiza, against DOX-induced cardiotoxicity and to delineate the mechanisms by which it restores DOX-impaired mitochondrial quality control.
    METHODS: Cardiotoxicity models were established in vivo using DOX-treated C57BL/6 J mice and in vitro using neonatal rat cardiomyocytes (NRCMs). The publicly available snRNA-seq dataset GSE292067 was analyzed to delineate DOX-associated transcriptional alterations in human cardiomyocytes. Molecular docking and cellular thermal shift assay were used to identify the targets of DSS. DSS was administered at multiple doses and compared with the FDA-approved cardioprotective agent, dexrazoxane (ICRF-187). Cardiac function was assessed by echocardiography and invasive hemodynamics. Histopathology, immunoblotting, flow cytometry, fluorescence imaging, and mitochondrial functional assays were used to evaluate apoptosis, oxidative stress, mitochondrial dynamics, and mitophagy.
    RESULTS: DSS supplementation improved survival, ameliorated ventricular dysfunction, and attenuated cardiac atrophy and fibrosis in DOX-treated mice. In DOX-exposed NRCMs, DSS increased cell viability and area, mitigated oxidative stress, and suppressed apoptosis. Mechanistically, mitochondrial injury-associated pathways were significantly enriched in DOX-treated human cardiomyocytes. DSS directly bonded to JNK and inhibited ROS-stirred c-Jun N-terminal kinase (JNK) phosphorylation, thereby restoring Mfn1/2 expression and limiting Drp1 phosphorylation to rebalance mitochondrial fission-fusion dynamics; It also restrained excessive, Drp1-facilitated and PINK1/Parkin-mediated mitophagy. Collectively, these effects preserved mitochondrial integrity, lowered ROS, and ultimately reduced cardiomyocyte apoptosis.
    CONCLUSION: DSS confers cardioprotection against DOX-induced injury by disrupting the vicious circle formed by ROS and JNK, which mediated impairment of mitochondrial quality control, attenuating oxidative stress, and reducing apoptosis. These findings highlight DSS as a promising therapeutic candidate for mitigating chemotherapy-associated cardiotoxicity.
    Keywords:  Cardiotoxicity; Danshensu; Doxorubicin; JNK signaling; Mitochondrial quality control; Oxidative stress
    DOI:  https://doi.org/10.1016/j.phymed.2026.158131
  28. Cell Signal. 2026 Apr 01. pii: S0898-6568(26)00169-5. [Epub ahead of print] 112517
    Mitochondrial IRF3 drives pulmonary fibrosis by impairing mitophagy and triggering ferroptosis.
    Zhang Jiashu, Liu Jingbao, Fang Hua, Sun Meiqi, Liu Jing, Wang Mengyao, Zhang Wei.
       BACKGROUND: Pulmonary fibrosis (PF) is a progressive, lethal lung disease with limited treatments. Although inflammation is involved, how it triggers specific oxidative cell death in epithelial cells remains unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is active in PF, but research has focused on its upstream inflammatory role. The function of its key effector, interferon regulatory factor 3 (IRF3), especially through non-canonical mechanisms, is largely unknown. We hypothesized that activated IRF3 translocates to mitochondria to disrupt quality control and promote ferroptosis, linking inflammation to fibrosis.
    METHODS: We employed a bleomycin-induced mouse PF model and TGF-β-stimulated A549 cells. Techniques included molecular analyses (western blot, RT-qPCR, Co-IP), imaging (TEM, immunofluorescence), mitophagy flux assays, and measurement of ferroptosis markers (Fe2+, MDA). Interventions involved H151, si-IRF3, Ferrostatin-1, and Mdivi-1.
    RESULTS: In PF, phosphorylated IRF3 translocated to mitochondria, interacting with PINK1 to impair mitophagy, shown by decreased PINK1, accumulated p62, and reduced LC3-II/LC3-I ratio. This triggered ferroptosis, evidenced by upregulated ACSL4, downregulated GPX4, elevated Fe2+/MDA, and mitochondrial damage. In TGF-β-stimulated A549 cells, IRF3 knockdown or STING inhibition restored mitophagy and suppressed ferroptosis. Mdivi-1 reversed si-IRF3's protection. In vivo, H151 treatment suppressed the IRF3-mitophagy-ferroptosis axis and alleviated PF.
    CONCLUSIONS: Mitochondrial IRF3 integrates cGAS-STING signaling with mitophagic dysfunction and ferroptosis to drive PF, revealing a novel therapeutic target.
    Keywords:  Alveolar epithelial cells; Ferroptosis; IRF3; Mitophagy; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112517
  29. Inflamm Res. 2026 Apr 01. pii: 78. [Epub ahead of print]75(1):
    NPC1L1, stabilized by PABPC1/IGF2BP1, accelerates atherosclerosis by enhancing CYP11A1-mediated mitophagy and ferroptosis.
    Guoan Zhang, Baoguo Song, Xiaoyan Huang, Jian Shi.
      In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. However, the regulation mode of its expression and the specific approaches by which it functions in lipid oxidative stress are still unclear. HUVECs and macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to induce endothelial cell injury. First, the effects of the RNA binding proteins IGF2BP1 and poly (A) binding protein cytoplasmic 1 (PABPC1) on the stability of NPC1L1 mRNA was evaluated. The interaction between NPC1L1 and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) was analyzed using Co-IP, and the co-localization of the two was detected using immunofluorescence. Combined with qPCR, Western blotting, CCK8, ferroptosis-related index and mitophagy-related index determination were performed to evaluate the expression of CYP11A1 in ox-LDL-treated HUVECs and its role of ferroptosis and mitophagy. Subsequently, pcDNA-NPC1L1 or CYP11A1 siRNA were individually or altogether transfected into ox-LDL-treated HUVECs to verify the involvement of CYP11A1 in NPC1L1-mediated ferroptosis and mitochondrial oxidative stress. Finally, ApoE-/- mice were fed with high-fat diet to establish an AS model in vivo and sh-NPC1L1 and/or Ad-CYP11A1 were injected via tail vein to verify the therapeutic effect of NPC1L1 knockdown on AS and reversal effect of CYP11A1. Either knockdown of IGF2BP1 or PABPC1 reduced NPC1L1 mRNA stability. Mechanistically, NPC1L1 interacted with CYP11A1 and promoted CYP11A1 protein expression. CYP11A1 was upregulated in ox-LDL-treated HUVECs and overexpression of CYP11A1 induced ferroptosis by activating excessive mitophagy, and knockdown of CYP11A1 reversed the promotion of NPC1L1 on mitophagy and ferroptosis in ox-LDL treated HUVECs. In vivo, injection of the sh-NPC1L1 lentiviral vector inhibited AS progression, while injection of the LV-CYP11A1 lentiviral vector attenuated the protective effect of sh-NPC1L1 on AS. PABPC1 and IGF2BP1 synergistically stabilized NPC1L1 mRNA, and NPC1L1 interacted with CYP11A1 to induce endothelial mitophagy and ferroptosis during AS.
    Keywords:  Atherosclerosis; CYP11A1; Ferroptosis and mitochondrial oxidative stress; NPC1L1; PABPC1/IGF2BP1
    DOI:  https://doi.org/10.1007/s00011-026-02229-2
  30. Phytomedicine. 2026 Mar 28. pii: S0944-7113(26)00352-1. [Epub ahead of print]155 158117
    The chemically defined herbal mixture ADAPT-232 delays mitochondrial dysfunction and promotes healthspan through mitophagy-related pathways mediated by the DAF-16/NHR-49 axis.
    Monika N Todorova, Martina S Savova, Biser K Binev, Milen I Georgiev.
       BACKGROUND: Mitochondrial dysfunction and metabolic imbalance are major contributors to the progression of age-related disorders, including cardiovascular diseases. Current therapeutic strategies increasingly focus on preserving mitochondrial integrity and promoting healthspan to reduce cardiometabolic burden. The standardized, chemically well-defined adaptogenic combination ADAPT-232 has a long history as a stress-protective remedy, enhancing cognitive and physical resilience. However, its effects on healthspan, particularly mitochondrial function, and the underlying molecular mechanisms remain insufficiently understood.
    PURPOSE: The current study investigated whether ADAPT-232 can mitigate glucose-induced metabolic and mitochondrial dysfunction in Caenorhabditis elegans and aimed to elucidate the molecular pathways involved in its biological activity.
    METHODS: Healthspan parameters, including lifespan, stress resistance, and body morphology, were evaluated following ADAPT-232 supplementation. To investigate the protective potential of the formula under metabolic stress, a glucose-induced dysfunction model was employed, analysing mitochondrial morphology and lipid accumulation. Expression of markers of mitophagy, autophagy, metabolic regulation, and stress-response was assessed through RT-qPCR and GFP- reporter strains.
    RESULTS: The herbal combination ADAPT-232 significantly extended lifespan and enhanced thermal and oxidative stress resistance. In glucose-stressed worms, the formula restored mitochondrial integrity and reduced lipid accumulation. At the molecular level, ADAPT-232 upregulated pink-1, dct-1, and lgg-2, indicating increased mitophagy and autophagic activity. Upregulation of NHR-49, ATGL-1, and lipl-4 supported improved lipid catabolism and metabolic flexibility. The ADAPT-232 reactivated DAF-16 and skn-1, consistent with enhanced stress-response signalling.
    CONCLUSION: The formula ADAPT-232 alleviates glucose-induced mitochondrial dysfunction by activating mitophagy-related pathways and improving metabolic homeostasis through coordinated regulation involving DAF-16 and NHR-49. These findings position ADAPT-232 as a promising plant-based intervention for promoting healthspan and potentially reducing cardiovascular risk.
    Keywords:  ADAPT-232; Caenorhabditis elegans; cardiovascular diseases; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1016/j.phymed.2026.158117
  31. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  32. Zhonghua Kou Qiang Yi Xue Za Zhi. 2026 Mar 31. 61(4): 515-524
    [Experimental study on the role of TRPM2 in regulating osteoblast differentiation through mitophagy in periodontitis].
    J L Chen, W X Cui, Y Jiang, S Y Guo, X Chen, H Q Gou, Y Xu.
      Objective: To explore the regulatory mechanism of transient receptor potential cation channel subfamily M member 2 (TRPM2) on the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BMSCs), and to clarify the role of TRPM2-regulated mitophagy in the progression of periodontitis. Methods: Twelve TRPM2 gene knockout (TRPM2-/-) mice and twelve wild-type (WT) mice were used in this study. A periodontitis model was established by silk ligation on the maxillary second molars of mice, with sham operation performed in the control group, and the modeling lasted for 10 days. The mice were divided into four groups (n=6 per group): WT sham operation group, WT periodontitis group, TRPM2-/- sham operation group, and TRPM2-/- periodontitis group. In the periodontitis group, silk ligation was performed on the maxillary second molars of mice, while no silk ligation was conducted in the sham operation group. Micro-CT was employed to collect imaging data for three-dimensional reconstruction. CTvox and CTAn v1.15.4.0 software were used to quantify the distance from the cementoenamel junction to the alveolar bone crest (CEJ-ABC) and bone volume fraction (BV/TV) in maxillary bone tissues of the mice in four groups. Statistical analysis was performed subsequently. Immunohistochemical staining was conducted to detect the expression intensity of Runt-related transcription factor 2 (RUNX2) in periodontal tissues in maxillary bone tissues of the mice in four groups. BMSCs were isolated from the femurs of the two types mice and cultured in vitro, followed by induction for osteogenic differentiation. Alizarin red S (ARS) staining and alkaline phosphatase (ALP) staining were used to evaluate the osteogenic differentiation potential of BMSCs. Western blotting (WB) was performed to determine the expression levels of osteogenic-related markers [RUNX2, bone morphogenetic protein 2 (BMP2), ALP, osteopontin (OPN)]. Meanwhile, transmission electron microscopy (TEM) was used to observe intracellular mitophagy status. WB was applied to detect the expression of autophagy-related proteins [Microtubule-associated proteins 1A/1B light chain 3 (LC3), PTEN-induced putative kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (Parkin)], and immunofluorescence colocalization labeling was used to assess the fluorescence intensity of LC3, Translocase of the outer mitochondrial membrane 20 (Tomm20), and Lysosomal-associated membrane protein (LAMP). Results: No statistically significant differences were observed in bone volume fraction, trabecular number, and trabecular separation between TRPM2-/- and WT mice (all P>0.05). However, the buccal and palatal CEJ-ABC values in the TRPM2-/- periodontitis group [(265.40±21.72) μm and (273.30±17.56) μm, respectively] were significantly lower than those in the WT periodontitis group [(416.50±20.90) μm and (428.00±17.59) μm, respectively] (both P<0.001). In addition, the relative expression level of RUNX2 in periodontal tissues of the TRPM2-/- periodontitis group [(15.03±0.48) %] was significantly higher than that of the WT periodontitis group [(11.95±0.40) %] (P<0.001). In vitro experiments (ALP and ARS staining) demonstrated that the osteogenic differentiation capacity of BMSCs derived from TRPM2-/- mice was significantly enhanced compared with that from WT mice. WB results showed that the expression levels of osteogenic-related markers (RUNX2, BMP2, ALP, OPN) in BMSCs from TRPM2-/- mice were all upregulated compared with WT mice (all P<0.05, respectively), and so as the protein levels of mitophagy-related indicators (LC3 and BECLIN1)(both P<0.001). Furthermore, TRPM2 deficiency remarkably upregulated the expression of proteins related to the PINK1/Parkin pathway (all P<0.001). Conclusions: TRPM2 regulates the osteogenic differentiation capacity of BMSCs through mitophagy, thereby participating in the progression of periodontitis. Therefore, targeting TRPM2 is expected to serve as a novel and effective strategy for the treatment of periodontitis.
    DOI:  https://doi.org/10.3760/cma.j.cn112144-20260108-00010
  33. J Am Heart Assoc. 2026 Mar 28. e048103
    Mitophagy in Macrophages: A Metabolic Checkpoint in Inflammation-to-Repair Transition in Atherosclerosis.
    Jie Zhou, Hanxiu Liu, Sen Ma, Haoyang Wang, Ni He, Xiaoling Zhang, Zhongwei Liu.
      Atherosclerosis is the leading cause of cardiovascular morbidity and mortality worldwide, driven not only by lipid accumulation but also by chronic inflammation and defective tissue repair. Among immune cells within plaques, macrophages orchestrate both inflammatory injury and reparative responses, and their fate is critically regulated by mitochondrial quality control. Damaged mitochondria release mitochondrial reactive oxygen species and mitochondrial DNA, which activate innate immune pathways, such as the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome and the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, thereby amplifying inflammation. Mitophagy, the selective clearance of dysfunctional mitochondria, has emerged as a metabolic checkpoint determining whether macrophages sustain inflammation or transition toward repair. Key signaling axes, including phosphatase and tensin homolog (PTEN)-induced kinase 1/Parkin, BNIP3 (BCL2/adenovirus E1B 19-kDa interacting protein 3)/NIX (NIP3-like protein X), and FUNDC1 (FUN14 domain-containing protein 1), converge to limit mitochondrial reactive oxygen species and mitochondrial DNA release, suppress innate immune activation, and preserve oxidative metabolism. By maintaining energy balance, mitophagy supports efferocytosis, extracellular matrix deposition, and fibrous cap stabilization, whereas its impairment drives necrotic core expansion and plaque vulnerability. Preclinical studies demonstrate that mitophagy can be therapeutically modulated by small molecules (metformin and resveratrol), natural products (salidroside), gene-based and nanoparticle approaches, and lifestyle interventions. This review summarizes mechanistic insights into macrophage mitophagy, emphasizes its role as a metabolic checkpoint in the inflammation-to-repair transition, and discusses translational opportunities and challenges in targeting this pathway to stabilize vulnerable plaques.
    Keywords:  atherosclerosis; inflammasome; macrophages; mitochondria; mitophagy
    DOI:  https://doi.org/10.1161/JAHA.125.048103
  34. Life Sci. 2026 Mar 30. pii: S0024-3205(26)00175-X. [Epub ahead of print] 124366
    Coenzyme Q10 improves redox homeostasis, mitochondrial biogenesis, and Irisin signaling in fast- and slow-twitch muscle fibers in a reserpine-induced fibromyalgia-like myalgia model.
    Muaz Belviranlı, Nilsel Okudan, Tuğba Sezer.
       AIMS: Fibromyalgia (FM) is a chronic pain syndrome frequently associated with muscular oxidative stress and mitochondrial dysfunction. This study investigated the therapeutic potential of Coenzyme Q10 (CoQ10) supplementation in a reserpine-induced FM rat model, focusing on its effects in gastrocnemius and soleus muscles.
    MATERIALS AND METHODS: Female Wistar rats were divided into Control, FM, CoQ10, and FM + CoQ10 groups. Reserpine (1 mg kg-1 day-1, s.c.) was administered for 3 days to induce FM; CoQ10 (150 mg kg-1 day-1, oral gavage) was given for 7 days. Cold hyperalgesia, serum TNF-α, muscular CoQ9/CoQ10 levels, oxidative stress markers (MDA, PC, TOS), antioxidant defenses (SOD, GSH, TAC), and mRNA expression of AMPK, SIRT1, PGC-1α, and FNDC5 were assessed.
    KEY FINDINGS: Reserpine successfully induced cold hyperalgesia and increased serum TNF-α. In both muscle types of FM rats, CoQ10 levels were depleted, oxidative damage markers were elevated, and antioxidant defenses (GSH, SOD) were compromised. CoQ10 supplementation attenuated cold hyperalgesia, normalized muscular CoQ10 (and influenced CoQ9), significantly reduced MDA, PC, and TOS levels, and partially restored GSH and SOD activity. Notably, CoQ10 robustly upregulated the mRNA expression of AMPK, SIRT1, and PGC-1α, key regulators of mitochondrial biogenesis, in both gastrocnemius and soleus muscles. Furthermore, CoQ10 significantly increased the expression of FNDC5, the precursor to the myokine irisin.
    SIGNIFICANCE: These findings suggest that CoQ10 ameliorates reserpine-induced FM-like pathology by mitigating oxidative stress, enhancing antioxidant capacity, promoting mitochondrial biogenesis, and stimulating the FNDC5/irisin pathway in skeletal muscle, highlighting its multifaceted therapeutic potential for FM.
    Keywords:  Coenzyme Q10; FNDC5/irisin; Fibromyalgia; Mitochondrial biogenesis; Oxidative stress; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.lfs.2026.124366
  35. Zhonghua Kou Qiang Yi Xue Za Zhi. 2026 Mar 31. 61(4): 603-610
    [Effect of mitochondrial quality control on osteoclast differentiation and its research progress in oral diseases].
    R Y Wang, L Y Dong, W An, X F Huang.
      Osteoclasts are the key cells in bone tissue that regulate bone resorption, and their homeostasis is crucial for maintaining the homeostasis of the oral and maxillofacial bone tissue. Mitochondria, known as the "powerhouses" of the cell, not only affect cellular energy supply but also modulate the levels of reactive oxygen species, thus becoming one of the key factors regulating osteoclast differentiation and maturation. This review elucidates the critical function and molecular mechanisms of mitochondrial quality control in osteoclasts, with a focus on how mitochondrial biogenesis, dynamics, and degradation are involved in differentiation of osteoclasts and bone resorption. It also discusses the association between mitochondrial dysfunction and pathological processes such as oral bone defects and periodontal disease, providing theoretical insights for developing mitochondria-targeted therapeutic strategies in oral bone disorders.
    DOI:  https://doi.org/10.3760/cma.j.cn112144-20251009-00392
  36. J Ethnopharmacol. 2026 Mar 31. pii: S0378-8741(26)00435-6. [Epub ahead of print] 121584
    Transcriptomic analysis reveals the critical role and mechanisms of Shenxian zhou in preventing age-related cognitive impairment.
    Xutong Jia, Mengya Liu, Yonglin Liang, Yugui Zhang, Shunyi Li, Min Bai, Yongqiang Duan.
       ETHNOPHARMACOLOGICAL RELEVANCE: Age-related cognitive impairment is a common neurodegenerative disease. Shenxian zhou (SXZ) is a Traditional Chinese Medicine formulation noted for its health-preserving properties, as documented in the Meditating-and-Breathing Methods, Dunhuang manuscript P.3810. Contemporary studies indicate that SXZ may possess anti-aging properties and enhance cognitive function. However, the specific effects and mechanisms of SXZ in addressing age-related cognitive impairment require further investigation.
    AIM OF THE STUDY: This study utilized aged rats to explore the therapeutic effects of SXZ on cognitive impairment and to elucidate its potential mechanisms.
    MATERIALS AND METHODS: This study investigated the main compounds of SXZ utilizing ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). Following the administration of SXZ to naturally aged rats, behavioral tests were conducted using maze tests, and histopathological changes in the hippocampus were observed using hematoxylin-eosin (H&E) staining and Nissl staining. Transcriptome sequencing technology was then employed to investigate the mechanism through which SXZ enhanced cognitive function in aged rats. Furthermore, immunofluorescence staining, Western blotting (WB), and quantitative real-time polymerase chain reaction (qRT-PCR) were utilized to confirm the findings of transcriptome sequencing.
    RESULTS: Behavioral test showed that SXZ could improve the learning and memory ability of aging rats; Pathological findings showed that SXZ ameliorated structural impairment in the hippocampus of aged rats and enhanced the number of Nissl bodies; In the transcriptome studies, Gene Ontology (GO) enrichment analysis suggested that SXZ modulated key biological processes, including lysosomal localization, mitochondrial membrane function, and the regulation of autophagosomes and autophagy. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, mitophagy and necroptosis might be critical mechanisms by which SXZ improved cognitive impairment in aged rats. Transmission electron microscopy (TEM) showed that SXZ alleviated mitochondrial structural impairment and increased the number of autolysosomes. Furthermore, molecular biology results indicated that SXZ significantly enhanced mitochondrial function, regulated the expression of key molecules in the mitophagy and necroptosis pathways, and consequently inhibited the inflammatory response.
    CONCLUSION: This study demonstrated that SXZ was effective in preventing and treating cognitive impairment in aged rats. Its specific mechanism was highly associate with the activation of mitophagy, alleviation of mitochondrial impairment-induced necroptosis, and the decrease of inflammatory damage in the hippocampus of aged rats.
    Keywords:  Age-related cognitive impairment; Mitochondrial function; Mitophagy; Necroptosis; Shenxian zhou
    DOI:  https://doi.org/10.1016/j.jep.2026.121584
  37. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00115-4. [Epub ahead of print]150 423-443
    Pathological microtubule dynamics in Parkinson's disease: Mechanisms and therapeutic implications.
    Kirti Baghel, Ateendra Kumar Dubey, Satyendra Singh, Vijay Kumar Prajapati.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily marked by the degeneration of dopaminergic neurons in the substantia nigra and the pathological accumulation of misfolded α-synuclein in Lewy bodies. This chapter explores the underrecognized role of microtubule (MT) dysregulation in PD pathogenesis, linking disruptions in cytoskeletal integrity to impaired axonal transport and neuronal survival. The fundamental biology of MTs, their dynamics, and their regulation by motor proteins and associated proteins like MT-associated proteins (MAPs), tau, and gamma-tubulin complexes. Special attention is given to how mutations linked to PD, such as those in SNCA (α-synuclein), Parkin, PINK1 (PTEN-induced kinase 1), and LRRK2 (leucine-rich repeat kinase 2), lead to MT destabilization, impaired mitophagy, and disruptions in axonal transport. A self-perpetuating cycle of MT disruption and α-synuclein aggregation is proposed, resulting in synaptic failure and dopaminergic neuron loss. The chapter also evaluates emerging therapeutic strategies targeting MT stabilization, including LRRK2 inhibitors, MT-stabilizing agents like Epothilone D, and approaches to modulate α-synuclein aggregation. Challenges such as the blood-brain barrier, off-target effects of MT-targeting drugs, and patient-specific variability in drug response are critically discussed. The future directions include CRISPR-Cas9-based gene therapies and personalized medicine, emphasizing the need for a deeper understanding of PD-related molecular pathways. This comprehensive overview highlights MT dynamics not just as collateral damage but as a central element in PD pathology, offering novel insights into potential avenues for intervention.
    Keywords:  Cytoskeletal integrity; Microtubule dysregulation; PINK1-parkin mitophagy pathway; Parkinson’s disease; α-synuclein aggregation
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.019
  38. Eur J Pharmacol. 2026 Mar 28. pii: S0014-2999(26)00309-2. [Epub ahead of print]1021 178827
    Melatonin postconditioning attenuates myocardial ischemia/reperfusion injury by activating YAP to decrease DRP1-mediated mitochondrial fission.
    Tian Tian, Bin Hu, Xin-Tao Li, Wen-He Yang, Xin-Yue Li, Yi Cheng, Mu Jin, Fu-Shan Xue.
      It remains unclear if Yes-associated protein (YAP) is involved in the protection of melatonin against myocardial ischemia/reperfusion (I/R) injury by regulating mitochondrial fission. In this experiment, an in vivo myocardial I/R injury model was used. Animals were randomly assigned to receive the different interventions: Sham, I/R, 10 mg melatonin, 20 mg melatonin, lysophosphatidic acid (LPA, a YAP agonist), LPA + melatonin, verteporfin (a YAP antagonist) and verteporfin + melatonin. Myocardial infarct size and serum cardiac enzyme levels were measured. Histopathological features, mitochondrial morphology, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, apoptosis, and dynamic-related protein 1 (DRP1) and YAP expressions of the I/R myocardium were also evaluated. We observed that melatonin postconditioning significantly reduced myocardial infarct size, ameliorated histological changes, and decreased oxidative stress and apoptosis in the I/R myocardium. These protective effects were associated with enhanced YAP nuclear translocation, increased p-DRP1 Ser637 expression and decreased p-DRP1 Ser616 expression. Activation of YAP with LPA demonstrated a protective effect against myocardial I/R injury, while inhibition of YAP with verteporfin exacerbated myocardial I/R injury and significantly attenuated the protective effect of melatonin postconditioning against myocardial I/R injury. These findings suggest that melatonin postconditioning confers cardioprotection by activating YAP to preserve mitochondrial ultrastructure and attenuate excessive DRP1-mediated fission. These structural changes may contribute to the observed reduction in myocardial injury. While these findings identify YAP activation as a potential therapeutic target, the limited dose range tested precludes determination of an optimal cardioprotective dose. Further studies defining the full dose-response relationship are still necessary to inform potential clinical translation.
    Keywords:  Dynamic-related protein 1; Ischemia/reperfusion injury; Melatonin; Mitochondrial fission; Yes-associated protein
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178827
  39. Mol Cell Biochem. 2026 Apr 02.
    Targeting PSAT1 in diabetic kidney disease: a ferroptosis-driven strategy for precision therapy.
    Yiling Wei, Cheng Yuan, Danqin Lu, Yuandi Xiang, Lihua Ni.
      
    Keywords:  Bioinformatics analysis; Biomarkers; Diabetic kidney disease; Ferroptosis; Immune cell infiltration; Mitophagy
    DOI:  https://doi.org/10.1007/s11010-026-05528-8
  40. Adv Sci (Weinh). 2026 Mar 31. e15505
    Time-Controlled Refrigerated Stem Cell Therapy Mitigates Scleroderma Fibrosis via Modulation of Mitochondrial Autophagy and Gut Metabolism.
    Xue Xia, Chenfei Kong, Xiaoming Zhao, Naixu Shi, Jinlan Jiang, Ping Li.
      Scleroderma is a chronic autoimmune disease characterized by progressive fibrosis, associated with high morbidity and mortality, limited therapeutic efficacy, and significant systemic side effects. Therefore, there is an urgent need to develop novel treatment strategies with improved tissue targeting and safety profiles. In this study, a refrigerated-treated mesenchymal stem cell (RT-MSCs) system was established by culturing human umbilical cord-derived MSCs under controlled low-temperature conditions. The antifibrotic effects of RT-MSCs were evaluated through both in vivo and in vitro experiments, together with an assessment of their regulatory role in mitochondrial autophagy. Their lesion-targeting capacity was also investigated. Furthermore, the effects of RT-MSCs on gut microbiota composition and metabolic pathways in model mice were comprehensively analyzed using 16S rRNA sequencing and intestinal content metabolomics, and the safety of RT-MSCs was systematically evaluated. The results demonstrated that RT-MSCs effectively attenuated fibrosis progression by modulating mitochondrial autophagy. Within 30 min after administration, RT-MSCs accumulated at lesion sites and persisted for up to 7 days. RT-MSCs significantly improved intestinal microbiota dysbiosis in scleroderma mice and regulated the expression of associated intestinal metabolites. In summary, as an optimized stem cell-based therapeutic strategy, RT-MSCs offer new insights and potential avenues for treating scleroderma.
    Keywords:  gut microbiota; intestinal content metabolomics; mesenchymal stem cells; mitophagy; targeting specificity
    DOI:  https://doi.org/10.1002/advs.202515505
  41. J Diabetes Investig. 2026 Mar 31.
    Role of the UHRF1-KLHL6-CORO2B axis in obesity-related insulin resistance.
    Xu Deng, Xiaoping Li, Jialuo Cai, Xinyu Chen, Zelin Xu, Yuntao Luo.
       BACKGROUND: Obesity-related insulin resistance (IR) involves mitochondrial dysfunction and ferroptosis dysregulation. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), an epigenetic regulator of DNA methylation, mediates crucial functions in disease progression, though its mechanisms in IR remain unclear.
    METHODS: Using murine IR models and tumor necrosis factor-α (TNF-α)-induced adipocyte systems, UHRF1's regulation of mitophagy and ferroptosis was assessed. Bioinformatics identified downstream targets Kelch-like protein 6 (KLHL6) and coronin 2B (CORO2B), prompting examination of the UHRF1-KLHL6-CORO2B axis in obesity-related IR.
    RESULTS: Obesity-related IR mice exhibited increased body weight, impaired glucose and insulin tolerance, adipose tissue inflammation, impaired mitophagy, and alterations in ferroptosis-related parameters, accompanied by reduced UHRF1 expression. In vitro, TNF-α-treated adipocytes showed decreased mitophagy, elevated oxidative stress, and changes consistent with ferroptosis, along with lower UHRF1 levels. UHRF1 overexpression was associated with changes in PINK1/Parkin-related markers, cell viability, oxidative stress indicators, ferroptosis-related parameters, and inflammatory responses. UHRF1 overexpression was associated with increased KLHL6 DNA methylation, decreased KLHL6 expression, and alterations in CORO2B ubiquitination.
    CONCLUSIONS: UHRF1 overexpression was associated with decreased KLHL6 expression, altered CORO2B ubiquitination, and changes in autophagy-, ferroptosis-, and inflammation-related markers. These results provide insights into potential pathogenic mechanisms and suggest that UHRF1, KLHL6, and CORO2B may serve as candidate targets for further investigation in obesity-related IR.
    Keywords:  ferroptosis; mitophagy; obesity‐related insulin resistance
    DOI:  https://doi.org/10.1111/jdi.70291
  42. FEBS J. 2026 Mar 30.
    Exercise-related microRNAs in Caenorhabditis elegans regulate calcium homeostasis and mitochondrial dynamics: Conserved pathways, divergent microRNAs.
    Qin Xia, Jiwang Tang, José C Casas-Martinez, Penglin Li, Maria Borja-Gonzalez, Leo R Quinlan, Katarzyna Goljanek-Whysall, Brian McDonagh.
      Exercise can help mitigate age-related muscle atrophy, promoting mitochondrial function, Ca2+ homeostasis and regulating gene expression. MicroRNAs (miRs) are crucial post-transcriptional regulators of gene expression, fine-tuning protein levels to maintain cellular homeostasis. In Caenorhabditis elegans, a 5-day swimming regimen increased mitochondrial content, lifespan and fitness. Small RNA sequencing identified exercise specific miRs, including increased levels of cel-miR-57-5p and cel-miR-249-3p, and decreased levels of cel-miR-72-3p and cel-miR-77-5p. mir-57 and mir-249 mutant strains had enhanced fertility, survival and lifespan, whereas mir-72 and mir-77 mutant strains had diminished fertility, survival and lifespan. The exercise-related miRs identified in C. elegans did not have conserved mammalian orthologs. Exercise regulated mammalian miRs were identified from the literature including mmu-miR-181a-5p, mmu-miR-199a-5p and mmu-miR-378a-3p. Treatment of murine myoblasts with mmu-miR-181a-5p and mmu-miR-378a-3p enhanced mitochondrial content, autophagy markers and myogenesis, while mmu-miR-199a-5p impaired these processes. Exercise-related miRs identified in C. elegans target genes regulating Ca2+ homeostasis such as ipp-5 (inositol Polyphosphate-5-phosphatase), sca-1 (Ca2+ transporting ATPase) and ncx-2 (mitochondrial Na+/Ca2+ antiporter). It was also confirmed that mmu-miR181a-5p targets Inpp5a and treatment with antogmiR-181a decreased Ca2+ handling in myotubes. Similarly, mmu-miR-378a-3p and cel-miR-249-3p target Kinase Suppressor of Ras (Ksr1)/ksr-2, involved in the MAPK pathway. Despite direct conservation of exercise-related miRs from nematodes to mammals, there are putative common regulatory pathways contributing to exercise-induced adaptations.
    Keywords:  Caenorhabditis elegans; DEAD‐box helicase 3 X‐linked (Ddx3x); Kinase Suppressor of Ras (Ksr1)/ksr‐2; exercise; inositol polyphosphate‐5‐phosphatase (Inpp5a); microRNA arm switching; peroxiredoxin 2
    DOI:  https://doi.org/10.1111/febs.70502
  43. J Inflamm Res. 2026 ;19 575586
    Integrated Machine Learning and Multi-Omics Analysis Identifies Mitophagy-Related Core Genes and Mechanisms in Non-Alcoholic Fatty Liver Disease.
    Yu Yuan, Tianyu Zhang, Chao Song, Chunli Lin, Yuewen Sun, Hongzhen Tang.
       Objective: This study aimed to systematically screen for mitophagy-related core genes in Non-alcoholic fatty liver disease (NAFLD), elucidate their specific molecular regulatory network, and investigate their functional mechanisms and roles within the immune microenvironment to provide novel targets for disease diagnosis and therapy.
    Methods: Multiple NAFLD transcriptomic datasets and single-cell RNA sequencing data from the GEO database were integrated. Bioinformatics analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and 11 machine learning algorithms were employed for core gene screening. Functional mechanisms and immune microenvironment characteristics were further investigated using SHAP model interpretability analysis, including detailed immune infiltration analysis, PPI network construction, GSEA, single-cell trajectory inference, and cell-cell communication analysis. Reverse network pharmacology and molecular docking predicted potential targeted compounds. In vitro experiments (Western Blot, qRT-PCR, JC-1 staining) validated core gene expression and mitophagy levels.
    Results: Five key genes-IGF1, MYH11, HYOU1, SPATA18, and SCD-were identified, demonstrating excellent disease discrimination across multiple cohorts (training set AUC=0.974). These genes were significantly enriched in processes like endoplasmic reticulum stress, mitophagy, and lipid metabolism. Critically, they played crucial roles in reshaping the NAFLD immune microenvironment, characterized by increased macrophage M2 polarization and T cell infiltration, linking mitochondrial dysfunction to inflammatory response. Single-cell analysis revealed their expression heterogeneity across hepatocytes, macrophages, and T cells, along with their involvement in intercellular communication patterns. Experimental validation confirmed aberrant core gene expression and altered mitophagy levels in NAFLD cell models.
    Conclusion: This study systematically delineates the regulatory network of mitophagy-related core genes in NAFLD and the resultant inflammatory immune microenvironment, offering novel insights and data support for elucidating disease mechanisms, developing early diagnostic biomarkers, and formulating precise therapeutic strategies.
    Keywords:  bioinformatics; machine learning; mitophagy; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.2147/JIR.S575586
  44. Autophagy. 2026 Mar 31. 1-3
    Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
    Polyxeni Papadea, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.
    Keywords:  Bottleneck; maternal transmission; mitochondria; mitophagy; mtDNA mutations
    DOI:  https://doi.org/10.1080/15548627.2026.2650772
  45. Noncoding RNA Res. 2026 Aug;19 28-39
    A conserved mammalian mecciRNA, mecciATP6, regulates mitochondrial homeostasis through interaction with HNRNPA3.
    Xiaoyang Cao, Juzheng Sui, Ge Shan, Xu Liu.
      Circular RNAs (circRNAs) are covalently closed, single-stranded RNA molecules generated from both nuclear and mitochondrial genomes. Several nuclear-encoded circRNAs have been reported to be conserved in sequence and function across animals. However, the evolutionary conservation and physiological significance of mitochondria-encoded circRNAs (mecciRNAs) remain largely unexplored. Here, by analyzing mitochondrial RNA sequencing data from human and mouse cells, we identify a conserved mecciRNA derived from the MT-ATP6 locus, termed mecciATP6. We show that mecciATP6 modulates mitochondrial homeostasis by binding and regulating the protein abundance of an evolutionarily conserved RNA-binding protein (RBP) HNRNPA3. Our data provide a conceptual framework for defining mecciRNA conservation across mammals and uncover a conserved mecciRNA-protein regulatory mechanism linked to mitochondrial homeostasis.
    Keywords:  HNRNPA3; Mitochondria-encoded circRNA; Mitochondrial homeostasis; RNA stability; circRNA
    DOI:  https://doi.org/10.1016/j.ncrna.2026.03.002
  46. Mol Med Rep. 2026 06;pii: 160. [Epub ahead of print]33(6):
    [Expression of Concern] Electroacupuncture at GV20‑GB7 regulates mitophagy to protect against neurological deficits following intracerebral hemorrhage via inhibition of apoptosis.
    Ruiqiao Guan, Zhihao Li, Xiaohong Dai, Wei Zou, Xueping Yu, Hao Liu, Qiuxin Chen, Wei Teng, Peng Liu, Xiaoying Liu, Shanshan Dong.
      Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, in comparing the bar charts shown in Fig. 2D and F on p. 5 representing the quantification of the western blot data featured in Fig. 2C and E respectively, these bar charts were strikingly similar, suggesting that the same chart may have erroneously been included in this figure twice to represent the different experimental conditions. The authors have been contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper, and we are awaiting their response. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of these potential problems while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 24: 492, 2021; DOI: 10.3892/mmr.2021.12131].
    Keywords:  apoptosis; autophagy; electroacupuncture; intracerebral hemorrhage; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2026.13870
  47. Nat Commun. 2026 Mar 29.
    Cardiomyocyte-derived GPX4 stabilizes BNIP3 to facilitate mitophagy and mitigate myocardial ischemia/reperfusion injury.
    Lingfeng Zhong, Zhenfeng Cheng, Yucong Zhang, Xiaoxi Fan, Yixin Zhou, Fan Yu, Ruihan Zheng, Derong Chen, Keke Ye, Jiahui Lin, Xi Chen, Zhouqing Huang, Chan Chen, Deling Yin, Weijian Huang, Bozhi Ye.
      GPX4 is a crucial regulator of ferroptosis, yet its role in mitochondrial dysfunction during myocardial ischemia/reperfusion injury (MI/RI) is unclear. This study aims to clarify the effect and molecular mechanisms of GPX4 in MI/RI. We analyzed the spatiotemporal dynamics of GPX4 during MI/RI and observed high expression levels in border and normal areas but a significant reduction in the ischemic region utilizing spatial transcriptomics, spatial proteomics, and single-cell sequencing. Cardiomyocyte-derived GPX4 notably reduces myocardial damage and mitochondrial dysfunction in MI/RI while also alleviating long-term ventricular remodeling. Mechanistically, our findings reveal that GPX4, through its critical U46 active site, enhances the interaction between BNIP3 and USP20, decreasing ubiquitination at K131 of BNIP3. This process stabilizes BNIP3, promotes mitophagy, improves mitochondrial function, and ultimately preserves cardiac function. Our research defines the role of the GPX4/BNIP3/USP20 complex in MI/RI and uncovers a mechanism linking GPX4 to ferroptosis-related mitochondrial damage, providing valuable insights for advancing ferroptosis studies.
    DOI:  https://doi.org/10.1038/s41467-026-71232-2
  48. Sci Rep. 2026 Apr 02.
    PAK5 drives vascular remodeling in hypoxic pulmonary hypertension via Drp1-dependent mitochondrial midzone division.
    Junming Zhang, Huimin Yan, Yan Wang, Yuwen Dai, Chenfei Zhao, Yukun Gan, Limin Liu, Qiong Liu, Lan Wang, Zhichao Li.
      
    Keywords:  Drp1; HPH; Midzone division; PAK5; PASMCs proliferation
    DOI:  https://doi.org/10.1038/s41598-026-46809-y
  49. Stem Cell Res Ther. 2026 Mar 28.
    Research based on serine metabolism indicates mesenchymal stem cells alleviate psoriasis by regulating the PSPH-PINK1-Parkin-NLRP3 pathway in HaCaT.
    Qing Lin, Yunfei Ji, Bin Yang, Rongjia Zhu, Ping Song, Robert Chunhua Zhao.
       BACKGROUND: Psoriasis is a refractory immune-related disease. In recent years, it has been discovered that mesenchymal stem cells (MSCs) can be used as a new therapeutic approach for psoriasis, but their potential therapeutic mechanism remains unclear. This study aims to explore the role of MSCs in the treatment of psoriasis.
    METHODS: We employed a mouse psoriasis model induced by imiquimod (IMQ) in vivo and a co-culture system of MSCs and HaCaT keratinocytes (KCs) cell line in vitro. These approaches allowed us to investigate the effect of MSCs on the levels of inflammatory factors and the activation of inflammasomes in both contexts. Mouse-targeted amino acid sequencing, transmission electron microscopy for in vitro observation, immunofluorescence for both in vivo and in vitro analyses, and siRNA transfection in vitro were employed in this study.
    RESULTS: Our results showed that MSCs significantly improved the skin lesion of mice with psoriasis, and reduced the levels of inflammatory factors and chemokines including IL-1β, IL-6, IL-8, TNF-α, MCP-1, CCL7, CCL20 and CCL27 in the mouse skin lesion areas and M5- induced psoriatic KCs models in vitro. Likewise, MSCs repaired the skin barrier by enhancing claudin-1 expression in vivo. In addition, MSCs increased KRT1 and decreased KRT6 levels in vivo and in vitro. Amino acid metabolism analysis showed that MSCs could improve the serine metabolism level in the mouse skins and upregulated the key enzyme phosphoserine phosphatase (PSPH) in serine metabolism. In vitro experiments demonstrated that knockdown of PSPH could reverse the therapeutic effects of MSCs on psoriasis. Furthermore, studies in vitro and in vivo revealed that MSCs can activate the PINK1-Parkin pathway. It was specifically manifested by elevated levels of PINK1, Parkin, p-Parkin, Beclin-1, and LC3B-II/I, coupled with a reduction in P62 protein. Subsequently, the activation of PINK1-Parkin led to decreased expressions of IL-1β, IL-6, IL-8, TNF-α, CCL7, CCL20, CCL27, and MCP-1. In vitro and in vivo experiments indicated that MSCs can reduce the levels of IL-1β, IL-6, IL-8, TNF-α, CCL7, CCL20, CCL27, and MCP-1 by inhibiting the activation of NLRP3 inflammasomes. Meanwhile, PSPH knockdown in vitro can reverse the activating effects of MSCs on the PINK1-Parkin, as shown by decreased levels of PINK, Parkin, p-Parkin, Beclin-1, and LC3B-II/I, concurrently with an elevation in P62..
    CONCLUSIONS: The results of this study indicated that MSCs can alleviate IMQ-induced psoriasiform dermatitis in mice by upregulating serine metabolism. The key serine metabolism enzyme PSPH may enhance PINK1/Parkin-mediated mitochondrial autophagy in psoriatic HaCaT and inhibit NLRP3 inflammasome activation in HaCaT cells, thereby alleviating skin inflammatory responses and suppressing skin p roliferation in psoriatic mice.
    Keywords:  Mesenchymal stem cells; NLRP3; PINK1-Parkin mitophagy; PSPH; Psoriasis; Serine metabolism
    DOI:  https://doi.org/10.1186/s13287-026-04964-z
  50. Cell Signal. 2026 Mar 27. pii: S0898-6568(26)00152-X. [Epub ahead of print] 112500
    Corrigendum to 'Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis' [Cell Signal. 2025 Aug, 132:111824].
    Yi Zhu, Jin Yang, Jia-Li Zhang, Hao Liu, Xue-Jiao Yan, Ji-Yong Ge, Fang-Fang Wang.
      
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112500
  51. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  52. Inflammopharmacology. 2026 Mar 30.
    Multimodal therapeutic potential of Reinwardtia indica Dumort. in rodent model of cerebral ischemia: Attenuations of oxidative and neuroinflammatory stress, restoration of neurotransmitter and mitochondrial homeostasis, suppression of apoptotic signaling and preservation of blood-brain barrier integrity.
    Karan Wadhwa, Payal Chauhan, Govind Singh.
      
    Keywords:   Reinwardtia indica Dumort; Cerebral ischemia; MCAo; Multi-target neuroprotection; Plant-based therapeutics
    DOI:  https://doi.org/10.1007/s10787-026-02192-8
  53. Free Radic Biol Med. 2026 Mar 26. pii: S0891-5849(26)00250-9. [Epub ahead of print]
    Lonp1 Inhibition Disrupts Mitochondrial Function in the hippocampus and Drives an Aging-Like Synaptic and Cognitive Phenotype in adult SAMP8 mice.
    Daniela Cortés-Díaz, Claudia Jara, Ítalo Fuentes, Jesús Llanquinao, Matías Lira, Micaela Ricca, Sebastián Valenzuela, Carolina A Oliva, Cheril Tapia-Rojas.
      Lonp1 is the main mitochondrial matrix protease responsible for maintaining mitochondrial proteostasis through the degradation of damaged or misfolded proteins. Although impaired Lonp1 expression or activity has been linked to mitochondrial dysfunction and oxidative stress in peripheral tissues and non-neuronal cells, its role in the brain, and particularly in hippocampal function, remains unexplored. Here, we provide the first in vivo evidence that Lonp1 activity is a critical regulator of mitochondrial redox homeostasis, synaptic integrity, and learning in the hippocampus. We administered the Lonp1 inhibitor Sesamin intranasally to 4-month-old adult Senescent-Acelerated Mouse Prone 8 (SAMP8) mice for 6 weeks. Subsequently, we conducted cognitive tests to assess hippocampal-dependent learning and memory. We also examined Lonp1 proteolytic activity using the FITC-Casein assay, performed Golgi staining to evaluate dendritic spines, and used fluorescent and luminescent probes to investigate mitochondrial function. Interestingly, we selectively impaired Lonp1 function at an early stage of age-related brain vulnerability. Lonp1 inhibition led to the accumulation of mitochondrial Lonp1 substrates and a marked reduction in mitochondrial bioenergetic capacity, as reflected by decreased ATP production and a robust increase in mitochondrial reactive oxygen species (ROS). These redox alterations were accompanied by selective synaptic remodeling, characterized by a reduction in thin dendritic spines without changes in total spine density, and by impaired hippocampus-dependent learning, while memory retention remained preserved. Thus, our findings identify Lonp1 as a previously unrecognized regulator of mitochondrial redox balance and synaptic structure in the hippocampus. Importantly, Lonp1 inhibition recapitulates key features of brain aging, linking defective mitochondrial proteostasis to ROS-driven synaptic vulnerability and cognitive dysfunction. This study establishes Lonp1-dependent mitochondrial quality control as a central node connecting redox dysregulation to synaptic failure and highlights Lonp1 as a novel target for strategies aimed at preserving mitochondrial and cognitive function during aging.
    Keywords:  Lonp1; Mitochondrial dysfunction; SAMP8 mice; hippocampal-dependent learning
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.059
  54. Sci Adv. 2026 Apr 03. 12(14): eadz3398
    Copper deficiency impairs oligodendrocyte maturation and social behavior via mitophagy and mTOR suppression in ASD.
    Noriyoshi Usui, Miyuki Doi, Stefano Berto, Kiwamu Matsuoka, Rio Ishida, Hana Miyauchi, Yuuki Fujiwara, Koichiro Irie, Michihiro Toritsuka, Takahira Yamauchi, Takaharu Hirai, Min-Jue Xie, Yoshinori Kayashima, Naoko Umeda, Keiko Iwata, Kazuki Okumura, Taeko Harada, Taiichi Katayama, Masatsugu Tsujii, Hideo Matsuzaki, Manabu Makinodan, Shoichi Shimada.
      Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and restricted repetitive behaviors, yet the contribution of trace elements remains poorly defined. We profiled 21 trace elements in individuals with ASD and identified significantly reduced copper levels, which negatively correlated with social symptom severity. Magnetic resonance imaging revealed decreased white matter volume in ASD, which also correlated with social impairment. To explore the mechanisms, we generated a copper-deficient mouse model that displayed ASD-like behaviors and impaired oligodendrocyte (OL) development. Copper deficiency disrupted hypoxia-inducible factor 1α (HIF1α)-dependent angiogenesis and metabolic regulation in the embryonic brain, leading to oxidative stress, mitochondrial dysfunction, and BCL2 interacting protein 3 (BNIP3)-mediated mitophagy in oligodendrocyte progenitor cells. These processes suppressed mechanistic target of rapamycin kinase (mTOR) signaling, reduced OL-lineage cells, and caused hypomyelination. Restoring mTOR activity rescued OL maturation and improved social behavior in copper-deficient mice. These findings identify a copper-HIF1α-BNIP3-mTOR signaling axis that links trace element imbalance to glial dysfunction and ASD-relevant behavioral phenotypes, providing mechanistic insight into neurodevelopment.
    DOI:  https://doi.org/10.1126/sciadv.adz3398
  55. J Adv Res. 2026 Mar 27. pii: S2090-1232(26)00269-9. [Epub ahead of print]
    Mitochondria orchestrated immune microenvironment and response in health and disease-clinically relevant outlook and recommendations.
    Kai Yang, Junlong Bi, Yu Cao, Dewei He, Shoupeng Fu, Wenjin Guo.
       BACKGROUND: The homeostatic balance of the immune microenvironment is key to maintaining bodily health, and its disorder is closely related to the occurrence and development of various major diseases such as cardiovascular diseases, autoimmune diseases, tumors, and aging. In recent years, mitochondria have gradually become a research hotspot, breaking the traditional perception of mitochondria solely as the cell's energy factory. Mitochondria precisely regulate the polarization, activation, proliferation, and functional fate of various immune cells through various means such as metabolic reprogramming, dynamics remodeling, autophagy regulation, and intercellular communication. Under pathological conditions, metabolic reprogramming abnormalities, abnormal release of mitochondrial damage-associated molecular patterns (mtDAMPs), and intercellular mitochondrial transfer (IMT) dysfunction can drive pathological remodeling of the immune microenvironment.
    AIM OF REVIEW: This article provides a systematic review centered on the interaction between mitochondria and the immune microenvironment, comprehensively elaborating on aspects such as the regulatory patterns of mitochondria in immune cells, intercellular mitochondrial communication mechanisms, mitochondrial-immune remodeling pathological mechanisms in diseases, novel analytical technologies, and targeted therapeutic strategies. It analyzes the translational feasibility and challenges of mitochondria-targeted therapies, aiming to offer theoretical support and clinical reference for a deeper understanding of the immune regulatory functions of mitochondria and the development of new immunotherapeutic strategies.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: The review highlights that immune cell function relies on cell-type-specific mitochondrial metabolism, alongside the balance of mitochondrial dynamics and mitophagy. Furthermore, IMT and extracellular vesicle (EV)-mediated mtDAMPs signaling form a crucial intercellular communication network that regulates the energy metabolism and immune phenotype of recipient cells. Across various diseases, mitochondrial-immune remodeling points to three conserved checkpoints, providing universal therapeutic targets. Driven by breakthroughs in single-cell sequencing and multi-omics analysis, the decoding of mitochondrial heterogeneity has facilitated a paradigm shift from reactive to predictive and proactive medicine. Finally, this review integrates extensive studies on mitochondria-targeted therapeutic strategies, providing highly translatable avenues for personalized immunotherapy.
    Keywords:  Immune microenvironment; Individualized immunotherapy; Intercellular mitochondrial transfer; Mitochondrial dynamics; Mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.jare.2026.03.048
  56. Ecotoxicol Environ Saf. 2026 Mar 28. pii: S0147-6513(26)00401-X. [Epub ahead of print]314 120072
    Airborne PM2.5 from pig houses induces piglet respiratory epithelial barrier injury by activating the NLRP3 inflammasome through Drp1-mediated mitochondrial dysfunction.
    Qian Tang, Chuang Wang, Yu Wang, Huihua Mao, Kaidong Deng, Dan Shen, Minyang Zhang, Chunmei Li.
      Airborne PM2.5 in pig houses contains diverse toxic substances and pathogenic microorganisms, which can induce respiratory inflammation and act as a major vector for disease transmission, posing a serious threat to swine health and productivity. The respiratory epithelial barrier serves as the first line of defense against environmental pollutants. This study employed a whole-body exposure model in piglets and primary tracheal epithelial cells from neonatal piglets (PTEC) to investigate the effects of PM2.5 on the respiratory epithelial barrier and its underlying mechanisms. PM2.5 exposure did not significantly influence growth performance or organ indices in piglets, but caused pronounced alveolar damage, inflammatory cell infiltration, goblet cell hyperplasia, and aggravated pulmonary fibrosis. These lesions were accompanied by decreased expression of tight junction proteins, increased apoptosis, and elevated proinflammatory cytokines. Further analyses revealed a dose-dependent upregulation of the NLRP3 inflammasome components and the mitochondrial fission protein Drp1 in lung tissues. In vitro, PM2.5 decreased PTEC viability and barrier integrity, evidenced by reduced transepithelial electrical resistance and increased FITC-dextran permeability. PM2.5 exposure also induced mitochondrial dysfunction, including elevated intracellular ROS levels, decreased mitochondrial membrane potential, and severe ultrastructural damage. Inhibition of NLRP3 alleviated PM2.5-induced barrier disruption and inflammation, while Drp1 inhibition suppressed NLRP3 activation, suggesting that Drp1-mediated mitochondrial dysfunction acts upstream of NLRP3 activation. Collectively, these findings demonstrate that pig-house PM2.5 compromises respiratory epithelial barrier structure and function by activating the NLRP3 inflammasome through Drp1-mediated mitochondrial dysfunction, providing novel insights and potential therapeutic targets for respiratory disorders associated with PM2.5 pollution in intensive livestock production systems.
    Keywords:  Mitochondrial dysfunction; PM(2.5); Pig house; Respiratory epithelial barrier function
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120072
  57. Am J Physiol Cell Physiol. 2026 Apr 03.
    Mitochondrial Localization Around Central Nuclei in Regenerating Skeletal Muscle Following Eccentric Contraction in Rat Model.
    Reiya Murakami, Ayaka Tabuchi, Takayoshi Kobayashi, Kazuyoshi Yagishita, Daisuke Hoshino, David C Poole, Yutaka Kano.
      This study aimed to characterize the spatial distribution and ultrastructural changes of mitochondria in regenerating muscle following ECC-induced injury, utilizing photothermal microscopy (PTM) and transmission electron microscopy (TEM). ECC was applied to the gastrocnemius muscles of male rats (13 weeks old, 284.8 ± 8.9 g), and regenerating muscles were harvested seven days post-injury. PTM, featuring a high-sensitivity optical system, was employed to visualize the wide-range and three-dimensional distribution of mitochondria within the white gastrocnemius muscle region. Concurrently, TEM was used for quantitative analysis of mitochondrial ultrastructural morphology, including cristae density. In regenerating muscle, the regular lattice-like network observed in normal tissue was disrupted and replaced by fragmented, randomly distributed mitochondria. Notably, both PTM and TEM analyses revealed a high concentration of mitochondria specifically around "central nuclei", a hallmark of regenerating muscle (i.e. within 0.1- 1.0 µm: Normal 1.8 ± 2.0% vs. Regeneration 5.5 ± 3.6%, p < 0.0001, by TEM data). Detailed morphological analysis further demonstrated that mitochondria in the immediate vicinity of the central nucleus (< 0.1 µm) had significantly lower cristae density (inner and outer membranes ratio, 1.10 ± 0.43) compared to those in distal regions (> 2.0 µm) (1.80 ± 0.65, p < 0.0001), indicating that they may be structurally immature. In conclusion, during the muscle regeneration process, mitochondria specifically localize around the central nucleus. Given their low cristae density, these potentially represent newly synthesized (biogenesis-derived) mitochondria. This perinuclear accumulation is thought to function as a critical energy source for the nuclear transcriptional and translational activities required for muscle differentiation, while also serving as a hub for organelle coordination during the regeneration process.
    Keywords:  Central nuclei; Eccentric contraction; Mitochondrial biogenesis; Photothermal microscopy; Skeletal muscle regeneration
    DOI:  https://doi.org/10.1152/ajpcell.00115.2026
  58. Curr Biol. 2026 Apr 01. pii: S0960-9822(26)00310-6. [Epub ahead of print]
    Specialized high-capacity mitochondria fuel cell invasion.
    Isabel W Kenny-Ganzert, Lena P Basta, Lianzijun Wang, Qiuyi Chi, Laura C Kelley, Caitlin Y Su, Jake Leyhr, Katherine S Morton, Joel N Meyer, David R Sherwood.
      Cell invasion through basement membrane (BM) is energetically intensive. How cells produce high ATP levels to power invasion is understudied. By endogenously tagging 20 mitochondrial proteins, we identified a specialized mitochondrial subpopulation within the C. elegans anchor cell (AC) that localizes to the BM breaching site and generates elevated ATP levels to fuel invasion. These electron transport chain (ETC)-enriched high-capacity mitochondria are compositionally unique, harboring increased protein import machinery and dense cristae enriched with ETC components. High-capacity mitochondria emerge at the time of AC specification and depend on the AC pro-invasive transcriptional program. Finally, we show that netrin signaling through an Src kinase directs microtubule polarization, facilitating metaxin adaptor complex-dependent ETC-enriched mitochondrial trafficking to the AC invasive front. Our studies reveal that an invasive cell produces high ATP levels by generating and localizing high-capacity mitochondria. This might be a common strategy used by other cells to meet the energetically demanding processes.
    Keywords:  ATP; basement membrane; cell invasion; cell specification; electron transport chain; live imaging; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.cub.2026.03.023
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