bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–03–22
sixty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure.
  2. Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.
  3. Features of Mitochondrial Dynamics Changes in Large Pyramidal Neurons of the Human Motor Cortex during Aging.
  4. Investigating the Antidepressant Mechanism of Acupuncture with a Focus on Mitochondrial Homeostasis.
  5. Placental dysregulation of mitochondrial morphology and dynamics as a hallmark of maternal age-related adaptation.
  6. The m6A modification mediates the imbalance of mitochondrial homeostasis and apoptosis induced by Benzo[b]fluoranthene in mouse spermatocytes: mitophagy versus mitochondrial damage.
  7. [Protective effect of moxibustion on ovarian function in mice with premature ovarian insufficiency based on mitochondrial fission].
  8. Neuronal mitochondrial dynamics: roles in brain disorders and therapeutic potential.
  9. Effects of Acetyl-l-Carnitine on the Mitophagy in the Spinal Cord Injury Progression Through PINK/Parkin Pathway.
  10. Reproductive Toxicity Mechanisms of PNMC: Evidence from Mitochondrial Dysfunction and Hormone Synthesis Disruption in the KGN cells.
  11. O-GlcNAcylation of YAP1 promotes lung transplant ischemia-reperfusion injury via binding to HIF1α transcription factor and activating autophagy and mitophagy.
  12. Nanomaterials regulate cellular functions and influence cell fate through mitophagy.
  13. IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis.
  14. Excessive ER-mitochondria coupling: A DRP1-driven mechanism underlying mitochondrial dysfunction and impaired autophagy in stress-induced depression-like behavior in mice.
  15. Adverse outcome pathway analysis identifies DRP1-driven mitochondrial dysfunction as a central event in silver nanoparticle-induced hepatocyte ferroptosis.
  16. Correction to "Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics".
  17. P. gingivalis induces endothelial dysfunction via mitochondrial fission dependent VDAC1-HK2 disassociation.
  18. Dihuang Yinzi ameliorates post-stroke depression through Miro1 ubiquitination-dependent mitophagy.
  19. Tunable tau expression in C. elegans neurons reveals that early-AD tau phosphorylation selectively impacts behavior and mitochondrial quality control.
  20. Interleukin-6 Signaling Mediates Mitochondrial Fragmentation and Mitophagy Impairment to Induce Macrophages Ferroptosis in Atherosclerosis.
  21. Ginsenoside Rg1 alleviates MASH by targeting GLS2 to enhance PINK1/Parkin-mediated mitophagy and improve mitochondrial function.
  22. Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
  23. ZEB1 maintains mitochondrial fission and macrophage efferocytosis by restraining MFN2, thereby limiting inflammation and improving tendon‑bone healing.
  24. A potent icaritin derivative ameliorates Parkinson's disease via GPER-mediated mitophagy restoration and dopaminergic neuroprotection.
  25. Hippocampal mtDNA depletion promotes nicotine addiction by suppressing mitochondrial biogenesis through oxidative stress.
  26. Cyclophosphamide-induced iron homeostasis imbalance triggers ovarian toxicity through ferroptosis of ovarian granulosa cells in a mitophagy crosstalk manner.
  27. Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
  28. Mitochondrial dysfunction and mitochondrial unfolded protein response (UPRmt): unravelling their roles in autism spectrum disorder pathogenesis.
  29. Mfn1-mediated imbalanced mitochondrial dynamics promotes ovarian cancer stemness by inducing metabolic reprogramming.
  30. Sevoflurane activates ATF4/NSUN7/PRKCD axis to induce neurotoxicity and cognitive impairment by promoting neuron mitochondrial fission.
  31. FGF21-Mediated Upregulation of SIRT1 Delays Intervertebral Disc Degeneration by Promoting PINK1/Parkin Dependent Mitophagy Through Deacetylation of FOXO3.
  32. Targeting the PINK1/Parkin-FNDC5 pathway: a novel mechanism of icariin in regulating muscle-bone metabolic coupling in osteosarcopenia.
  33. Corrigendum to "Rg1 improves Alzheimer's disease by regulating mitochondrial dynamics mediated by the AMPK/Drp1 signaling pathway" [J. Ethnopharmacol. 340 (2025) 119285].
  34. Resveratrol inhibits NLRP3 inflammasome activation to alleviate bovine mastitis by promoting PINK1-mediated mitophagy.
  35. Correction: Erythropoietin mitigates diabetic nephropathy by restoring PINK1/Parkin-mediated mitophagy.
  36. ECSIT facilitates exercise-induced amelioration of skeletal muscle atrophy by maintaining mitochondrial quality control in Middle-aged mice.
  37. Mitochondrial metabolism in cancer stem cells (CSCs): molecular and diagnostic implications.
  38. Quercetin enhances skin flap survival via SIRT1-regulated mitophagy promotion and pyroptosis inhibition.
  39. Nobiletin from Xiaoyu Xiezhuo Decoction: Restoring Mitochondrial Dynamics and Alleviating Renal Ischemia-Reperfusion Injury via M1 Macrophage Modulation.
  40. Study of the Mechanism by Which Shenfu Injection Regulates Cardiomyocyte Hypertrophy Based on Dopamine Receptor D2-Mediated Mitochondrial Fission.
  41. Effect of yeast selenium on autophagy and PINK1/Parkin expression in Diquat-induced chicken liver and kidney cells.
  42. Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities.
  43. Extracellular vesicle-mediated transcellular mitophagy as a modulatory target for moderate hyperoxia-induced alveolar developmental arrest in bronchopulmonary dysplasia.
  44. [A preliminary study on the role of platelet mitochondria in the proliferation and metabolism of multiple myeloma cells].
  45. Thioredoxin protects against diabetic hearing loss by regulating TOMM22 mediated mitochondrial autophagy in hair cells and inhibiting microglial M1 polarization.
  46. Nrf2 attenuates epithelial-mesenchymal transition of lens epithelial cells in fibrotic cataract via PINK1-mediated mitophagy.
  47. Aerobic exercise improve physical endurance and muscle function by ameliorating oxidative stress and modulating mitochondrial dynamics in aged skeletal muscle.
  48. DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.
  49. MFF budding from mitochondria regulates melanosome size and maturation.
  50. Current perspectives on circadian regulation of mitochondrial dynamics in mood disorders and perioperative stress.
  51. Oncogenic GPRIN1 sustains proliferation and mitochondrial homeostasis via dual‑layer CDK1-PI3K/Akt signalling in gallbladder cancer.
  52. IL-15 Links Muscle-Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy.
  53. Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression.
  54. Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
  55. Precision Neurodegeneration: Integrating Molecular Mechanisms, Biomarkers, and Targeted Therapeutics.
  56. Decoding the mitochondrial metabolic engine for tumor metastasis and clinical therapeutic opportunities.
  57. Identification of alterations of immunometabolism associated with Pompe disease.
  58. SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
  59. A Rsv@HMnO2-HA nanozyme for AKI therapy via targeting inflammatory storm and activating SIRT1/PGC-1α to restore mitochondrial homeostasis.
  60. Corrigendum to "Melatonin improves spermatogenesis and alleviates oxidative stress in cryopreserved testicular tissue through suppression of the ROS/PINK1-Parkin mitophagy axis" [Free Radic. Biol. Med. 248 (2026) 238-254].
  61. Purslane (Portulaca oleracea L.) Extract Attenuates Obesity-Induced Inflammation and Enhances Mitochondrial Biogenesis via the miR-221/222 and AMPK/SIRT1 Axis in Rats.
  62. Hepatic STEAP4 promotes liver regeneration by regulating lysosomal iron homeostasis and membrane integrity in acetaminophen-induced liver injury.
  63. Mitochondria "Shackled" by Mutant Huntingtin: Analysis of Morphological Alterations and Disruptions of Intracellular Transport.
  64. LncRNA-HLX-2-7/HLX axis-dependent metabolic reprogramming drives cancer progression in group 3 medulloblastoma.
  1. Biochem Biophys Res Commun. 2026 Mar 09. pii: S0006-291X(26)00356-6. [Epub ahead of print]812 153592
    PGC-1α exacerbates apoptosis to induce HIF-1α/BNIP3 mediated mitophagy in heart failure.
    Chengyao Ni, Peng Hu, Yiming Ni.
      Heart failure (HF) is associated with mitochondrial quality control, a key process in quality control. Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) regulates mitophagy, but its role in HF remains unclear. This study investigates the role of PGC-1α in HF and its mechanism in mitophagy. Myocardial injury was induced in AC16 cells using pentobarbital, followed by PGC-1α overexpression and treatment with apoptosis inhibitor HY-19696 and mitophagy inhibitor Mdivi-1. A rat HF model was established via aortic constriction, with PGC-1α overexpressed through lentiviral injection. In the cell model, PGC-1α overexpression increased Creatine kinase isoenzyme MB (CK-MB), cardiac troponin T (cTnT), lactate dehydrogenase (LDH) levels, reduced cell viability and mitochondrial membrane potential, enhanced apoptosis and ROS production. These effects were attenuated by apoptosis inhibitor HY-19696. PGC 1α also promoted mitophagy related changes, including an increased LC3 II to LC3 I ratio, and this response was suppressed by Mdivi 1. In the rat model, PGC-1α overexpression aggravated myocardial injury, apoptosis, and damage markers, whereas pharmacological inhibition of apoptosis or mitophagy alleviated these effects. PGC-1α exacerbates HF by promoting apoptosis and enhancing mitophagy through the Hypoxia-inducible factor-1 (HIF-1)/BCL2 interacting protein 3 (BNIP3) pathway. Therefore, PGC-1α changed mitochondrial dynamic homeostasis and promoted HIF-1α/BNIP3-dependent mitophagy in HF.
    Keywords:  Apoptosis; BNIP3; HIF-1α; Heart failure; Mitophagy; PGC-1α
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153592
  2. J Diabetes Res. 2026 ;2026(1): e1498605
    Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.
    Tianlei Chen, Min Yang.
      Diabetic nephropathy (DN), a predominant cause of end-stage renal disease (ESRD), is primarily driven bfigolic disturbances and mitochondrial dysfunction. Apolipoprotein M (ApoM), a protein associated with high-density lipoprotein (HDL), is notably downregulated in DN and is correlated with a decline in renal function. Recent studies have identified a protective bidirectional axis between ApoM and mitophagy, the selective autophagy of mitochondria. ApoM, chiefly through its role as a carrier for sphingosine-1-phosphate (S1P), enhances mitophagy by activating the silent information regulator 1 (SIRT1) and parkin induced kinase 1 (PINK1)/Parkin pathways, thereby improving mitochondrial quality control. Conversely, mitophagy facilitates ApoM synthesis by supplying sufficient adenosine triphosphate (ATP) for its production and the assembly of HDL. In the context of DN, hyperglycemia disrupts this reciprocal relationship, leading to a detrimental cycle of impaired mitophagy and reduced ApoM, which exacerbates renal injury. Targeting the ApoM-mitophagy axis through ApoM enhancement or mitophagy activation emerges as a promising therapeutic approach for personalized renal protection in DN. This review synthesizes the mechanistic interplay between lipid metabolism and mitochondrial quality control, emphasizing its translational potential and the necessity for further investigation.
    Keywords:  apolipoprotein m; diabetic nephropathy; lipid metabolism; mitophagy; sphingosine-1-phosphate
    DOI:  https://doi.org/10.1155/jdr/1498605
  3. Biochemistry (Mosc). 2026 Feb;91(2): 380-387
    Features of Mitochondrial Dynamics Changes in Large Pyramidal Neurons of the Human Motor Cortex during Aging.
    Tatiana I Baranich, Dmitry N Voronkov, Kseniia M Okulova, Ekaterina V Shcherbak, Anna V Egorova, Olga V Velts, Maria S Ryabova, Kristina A Skvortsova, Zainab M Omarova, Dmitry A Kharlamov, Valeria V Glinkina, Vladimir S Sukhorukov.
      Brain aging is a physiological process characterized by various neurodegenerative manifestations, largely driven by mitochondrial dysfunctions, including changes in mitochondrial metabolism and dynamics. Conflicting reports in the literature regarding mitochondrial fusion and fission in the human cerebral cortex during aging underscore the need to elucidate the mechanisms of this dysfunction. The aim of this study was to assess features of mitochondrial dynamics in the large pyramidal neurons of the human motor cortex during aging. The study was conducted on autopsy material from the motor cortex of individuals aged 75 years and older. The control group consisted of similar material from individuals aged 35-44 years who died from sudden cardiac death. Intensity of immunohistochemical staining for TOMM20, Drp1, Mfn1, Mfn2, and Opa1 proteins in the large pyramidal neurons of the human motor cortex was evaluated. Decrease in the staining intensity of TOMM20 and Opa1 markers and increase in the staining intensity of the Drp1 marker were observed, indicating enhanced mitochondrial fragmentation in the pyramidal neurons of layer V of the motor cortex, possibly associated with reduction in the mitochondrial pool volume due to dysfunction in the mitochondrial fusion process, which impedes organelle growth.
    Keywords:  adaptation; aging; brain; fission; fusion; mitochondrial dynamics; motor cortex; neurodegeneration
    DOI:  https://doi.org/10.1134/S0006297925604447
  4. Int J Gen Med. 2026 ;19 584012
    Investigating the Antidepressant Mechanism of Acupuncture with a Focus on Mitochondrial Homeostasis.
    Yongnan Wei, Zijun Ma, Ning Xu, Yue He, Mengru Cao, Long Wang.
       Background: Major depressive disorder (MDD) is a complex neuropsychiatric condition characterized by persistent low mood, reduced voluntary activity, and cognitive impairment. Mitochondria, often described as cellular power plants, play a fundamental role in maintaining normal neuronal function and emotional stability. Mitochondrial homeostasis encompasses multiple dimensions, including oxidative stress, apoptosis, biogenesis, and dynamics. Accumulating evidence indicates significant impairment of neuronal mitochondrial function in depressive patients, manifested as aberrant energy metabolism, exacerbated oxidative stress, and disrupted mitochondrial dynamics.
    Discussion: This narrative review synthesizes current evidence from both clinical and preclinical studies aims to explore the mechanisms by which acupuncture therapy restores mitochondrial homeostasis. Specifically, acupuncture ameliorates mitochondrial membrane permeability and structural integrity, enhances energy metabolism, attenuates damage induced by oxidative stress and mitophagy, and regulates mitochondrial dynamic processes (such as fission and fusion). These coordinated effects collectively constitute a key biological mechanism through which acupuncture exerts its antidepressant actions.
    Conclusion: This study elucidates a mechanism-based therapeutic strategy, clarifying how acupuncture counteracts depression through multi-target regulation of mitochondrial function. These findings underscore the translational value of acupuncture in clinical treatment regimens for major depressive disorder, offering a theoretical framework.
    Keywords:  acupuncture; major depressive disorder; mitochondria; mitochondrial stability; review
    DOI:  https://doi.org/10.2147/IJGM.S584012
  5. Life Sci. 2026 Mar 19. pii: S0024-3205(26)00147-5. [Epub ahead of print]393 124338
    Placental dysregulation of mitochondrial morphology and dynamics as a hallmark of maternal age-related adaptation.
    Juan M Toledano, Maria Puche-Juarez, María Paz Carrillo, Javier Diaz-Castro, Javier Sanchez-Romero, Francisco Manuel Ocaña-Peinado, Catalina de Paco Matallana, Estefania Martín-Alavarez, Jorge Moreno-Fernandez, Julio J Ochoa.
       AIMS: Advanced maternal age (AMA), increasingly prevalent worldwide, is linked to obstetric risk even in clinically uncomplicated pregnancies. Mitochondria are essential for trophoblast metabolism and stress adaptation, and their alteration is associated with gestational pathologies. However, it remains unclear whether maternal age alone alters placental mitochondrial homeostasis.
    MATERIALS AND METHODS: Human placentas from AMA and control pregnancies were analysed by transmission electron microscopy (TEM) to assess mitochondrial ultrastructure and mitochondria-endoplasmic reticulum contacts (MERCs). Western blotting was used to evaluate regulators of mitochondrial fusion, fission, and mitophagy.
    KEY FINDINGS: placentas from AMA pregnancies showed a significant increase in mitochondrial number in both syncytiotrophoblast and cytotrophoblast cells, with regional variation between maternal and foetal sides. Despite increased abundance, mitochondria were smaller (reduced area and perimeter), indicating a fragmented phenotype, while circularity was unchanged. MERCs exhibited decreased distance and increased ER coverage, suggesting enhanced stress signaling and fission. Western blotting revealed decreased MFN1 with increased OPA1 and DRP1 expression, whereas MFN2, FIS1, and DNM2 remained unchanged. Mitophagy markers were dysregulated, with reduced OPTN and BNIP3 but elevated FUNDC1.
    SIGNIFICANCE: AMA is associated with fragmented and stress-adapted placental mitochondria, showing structural imbalance in dynamics and altered quality control even in the absence of clinical pathology. These features may reflect reduced placental capacity to buffer metabolic and stress challenges and contribute to increased vulnerability in pregnancies of older mothers, positioning mitochondria as a potential target for monitoring and improving outcomes in this population.
    Keywords:  Advanced maternal age; Mitochondria; Mitochondrial dynamics; Placenta; Pregnancy; Transmission electron microscopy
    DOI:  https://doi.org/10.1016/j.lfs.2026.124338
  6. J Adv Res. 2026 Mar 16. pii: S2090-1232(26)00252-3. [Epub ahead of print]
    The m6A modification mediates the imbalance of mitochondrial homeostasis and apoptosis induced by Benzo[b]fluoranthene in mouse spermatocytes: mitophagy versus mitochondrial damage.
    Chao-Feng Shi, Fei Han, Xiao Jiang, Lei Sun, Kang-le Liu, Sheng-Qi Sun, Ying-Qing Li, Jian-Kang Wang, Lin Ao, Jia Cao, Qing Chen, Jin-Yi Liu.
       INTRODUCTION: Mitochondrial homeostasis is intimately associated with the toxic effects of exogenous chemicals, as well as the onset and progression of various diseases. Benzo[b]fluoranthene (BbF) is ubiquitously distributed across various environmental media. The association between BbF exposure and male reproductive damage has been recently discovered. However, the relevant mechanisms remain unexplored.
    OBJECTIVES: To investigate the male reproductive toxicity and mechanisms of BbF.
    METHODS: We established BbF exposure models in both mice and GC-2 mouse spermatocyte cell lines to investigate BbF-associated reproductive toxicity. By integrating transcriptomic sequencing, bioinformatics analysis, and experimental validation, we demonstrated that disruption of mitochondrial homeostasis was the central mechanism. Furthermore, through N6-methyladenosine (m6A) sequencing combined with functional validation, we revealed the regulatory role of m6A modification in modulating mitochondrial homeostasis.
    RESULTS: BbF exposure triggered mitochondrial homeostasis disruption in spermatocytes and contributed to male reproductive toxicity. Specifically, BbF impaired mitochondrial biogenesis and oxidative phosphorylation via the p53/PGC-1α/TFAM signaling pathway. As a compensatory response, PINK1/Parkin-associated mitophagy was activated, thereby partially alleviating cellular damage. To further investigate the regulatory mechanisms of m6A modification in the aforementioned mitochondrial dysfunction process, we observed that BbF exposure resulted in reduced expression of YTHDF2 in spermatocytes. The downregulation of YTHDF2 slowed the degradation of Trp53 mRNA, leading to elevated levels of both Trp53 mRNA and p53 protein, thereby inducing the p53/PGC-1α/TFAM-mediated mitochondrial damage. On the other hand, we demonstrated that METTL3 exerted a crucial protective effect by regulating mitophagy. Particularly, METTL3 enhanced the m6A modification of Mark4 mRNA, thereby stabilizing the transcript, increasing both mRNA and protein levels of MARK4. Furthermore, the METTL3/MARK4 signaling axis promoted PINK1/Parkin-associated mitophagy, which served as a protective mechanism.
    CONCLUSION: As a result of the confrontation between YTHDF2/p53/PGC-1α/TFAM-mediated mitochondrial damage and PINK1/Parkin-associated mitophagy regulated by METTL3/MARK4, BbF disrupted mitochondrial homeostasis, ultimately leading to mitochondrial dysfunction and spermatocyte apoptosis.
    Keywords:  Benzo[b]fluoranthene; M(6)A modification; Mitochondrial homeostasis; Reproductive toxicity; Spermatocytes
    DOI:  https://doi.org/10.1016/j.jare.2026.03.031
  7. Zhongguo Zhen Jiu. 2026 Mar 12. 46(3): 411-420
    [Protective effect of moxibustion on ovarian function in mice with premature ovarian insufficiency based on mitochondrial fission].
    Jia Luo, Yaoli Yin, Meihong Shen, Yansu Fang, Chenge Zhu, Yanliang Fan.
       Objective: To investigate whether the protective effect of moxibustion on ovarian function in mice with premature ovarian insufficiency (POI) was associated with mitochondrial dynamics and function in ovarian granulosa cells, using a mitochondrial fission activator.
    Methods: Eighty female ICR mice with regular estrous cycles were randomly divided into a blank group, a tripterygium glycosides group (TG group), a moxibustion group, and a carbonyl cyanide m-chlorophenyl hydrazone plus moxibustion group (CCCP+moxibustion group), with 20 mice in each group. Except for the blank group, POI model was established in the remained groups by intragastric administration of TG suspension for 14 consecutive days. In the moxibustion group, moxibustion was applied at bilateral "Shenshu" (BL23) or alternately at "Zhongwan" (CV12) and "Guanyuan" (CV4) 1 hour after TG administration, once every day for 14 days. The CCCP+moxibustion group received intraperitoneal injection of CCCP (2.9 mg·kg-1·d-1) after TG administration, followed by the same moxibustion protocol as the moxibustion group. Estrous cycles were recorded, and the ovarian index was calculated. Ovarian morphology was observed with HE staining, and follicle counts were conducted. Serum levels of follicle-stimulating hormone (FSH), estradiol (E2), and anti-Müllerian hormone (AMH) were measured using ELISA. Immunohistochemistry and real-time quantitative PCR were used to detect the protein and mRNA expression of mitochondrial dynamics-related factors (dynamin-related protein 1 [Drp1], mitochondrial fission factor [Mff], optic atrophy 1 [Opa1], and mitofusin 1 [Mfn1]) in the ovaries, respectively. ATP concentration in granulosa cells was determined by luciferase assay, and reactive oxygen species (ROS) fluorescence intensity was detected using DCFH-DA fluorescent probe method.
    Results: Compared with the blank group, the mice in the TG group showed a significantly higher rate of estrous cycle disorder (P<0.01), smaller ovarian volume, lower ovarian index (P<0.01), reduced numbers of primordial, growing, and antral follicles (P<0.01), increased number of atretic follicles (P<0.01), and loose and disordered arrangement of granulosa cells; serum FSH level was elevated (P<0.01), while serum AMH and E2 levels were reduced (P<0.01). Drp1 and Mff protein staining in ovarian granulosa cells was intensified, while Opa1 and Mfn1 protein staining was lighter. The average optical densities of Drp1 and Mff and the mRNA expression of Drp1 and Mff were significantly increased (P<0.01), while the average optical densities of Opa1 and Mfn1 and the mRNA expression of Opa1 and Mfn1 were significantly decreased (P<0.01). ATP concentration was reduced (P<0.01), and ROS fluorescence intensity was decreased (P<0.01). Compared with the TG group, the mice in the moxibustion group exhibited lower rate of estrous cycle disorder (P<0.01), larger ovarian volume, higher ovarian index (P<0.01), increased numbers of primordial, growing, and antral follicles (P<0.01), reduced number of atretic follicles (P<0.01), and a more compact and orderly arrangement of granulosa cells; serum FSH level was decreased (P<0.01), while serum AMH and E2 levels were increased (P<0.01). Opa1 and Mfn1 protein staining was deepened, Drp1 and Mff protein staining was lightened, average optical densities and mRNA expression of Opa1 and Mfn1 were increased (P<0.01, P<0.05), and those of Drp1 and Mff were decreased (P<0.05, P<0.01). ATP concentration was increased (P<0.01), and ROS fluorescence intensity was decreased (P<0.01). Compared with the moxibustion group, the mice in the CCCP+moxibustion group showed an increased estrous cycle disorder rate (P<0.05) and a decreased ovarian index (P<0.05). The numbers of primordial, growing, and antral follicles were reduced (P<0.01, P<0.05), while the number of atretic follicles was increased (P<0.01). The arrangement of ovarian granulosa cells became looser and more disordered. Serum FSH level was elevated (P<0.01), while serum E2 and AMH levels were decreased (P<0.05). In the ovaries of mice in the CCCP+moxibustion group, Drp1 and Mff protein staining was intensified, whereas Opa1 and Mfn1 protein staining was lighter. The average optical densities of Drp1 and Mff, as well as the mRNA expression levels of Drp1 and Mff in granulosa cells, were increased (P<0.05), while the average optical densities of Opa1 and Mfn1 and the mRNA expression levels of Opa1 and Mfn1 in granulosa cells were decreased (P<0.05, P<0.01). Additionally, the ATP concentration in ovarian granulosa cells was reduced (P<0.01), and the ROS fluorescence intensity was elevated (P<0.01).
    Conclusion: Moxibustion may alleviate TG-induced ovarian damage by inhibiting mitochondrial fission and promoting mitochondrial fusion, thereby improving impaired mitochondrial function; this protective effect can be blocked by CCCP.
    Keywords:  granulosa cells; mitochondrial dynamics; mitochondrial fission; moxibustion; premature ovarian insufficiency (POI)
    DOI:  https://doi.org/10.13703/j.0255-2930.20241126-k0006
  8. Acta Pharmacol Sin. 2026 Mar 16.
    Neuronal mitochondrial dynamics: roles in brain disorders and therapeutic potential.
    Xing-Xian Zhang, Jia-Min Du, Shen-Zhan Wang, Xin-Lei Mo, Xiang-Nan Zhang.
      Mitochondrial dynamics - processes that include fission, fusion, transport, and mitophagy - are essential for shaping mitochondrial form and function to meet neuronal homeostatic demands. Growing evidence links imbalances in these processes to the pathogenesis of multiple brain disorders. In this review we comprehensively summarize the molecular mechanisms that govern mitochondrial dynamics and clarify their roles in key neuronal functions, including synaptic transmission, vesicle recycling, and calcium buffering. We also examine how disruptions in mitochondrial dynamics drive synaptic dysfunction and neuronal injury, with specific implications for neurodegenerative and psychiatric disorders. Finally, we evaluate emerging therapeutic strategies that target mitochondrial dynamics - both pharmacological and genetic - and highlight their promise as novel therapies for brain disorders. This synthesis provides an in-depth perspective on mitochondrial dynamics in brain health and disease and aims to guide future research and drug development.
    Keywords:  mitochondrial dynamics; neurodegenerations; neuron; neuropsychiatric disorders; therapeutic strategy
    DOI:  https://doi.org/10.1038/s41401-025-01746-w
  9. J Biochem Mol Toxicol. 2026 Mar;40(3): e70778
    Effects of Acetyl-l-Carnitine on the Mitophagy in the Spinal Cord Injury Progression Through PINK/Parkin Pathway.
    Juan Shen, Lin Zhao, Guangxiang He.
      Spinal cord injury (SCI) is a serious disease of the nervous system. Acetyl-l-carnitine-carnitine (ALC) is an acetylated product of l-carnitine, and exerts neuroprotection. The aim of this study was to investigate the effects of acetyl-l-carnitineALC) on mitophagy in rats with SCI and in PC12 cells injured by H2O2. By establishing SCI in vivo and in vitro, the levels of oxidative stress and mitophagy related factors were detected after ALC treatment. Cell viability was detected by CCK-8 assay, apoptosis was detected by TUNEL and flow cytometry. The mitochondria of PC12 cells after injury were observed by transmission electron microscopy (TEM). The activation of mitophagy related pathway PINK1/Parkin in ALC treated cells was detected. The results showed that ALC can protect neuronal cells in vivo and in vitro by promoting the normal growth of neuronal cells while inhibiting oxidative stress and promoting mitophagy. In addition, ALC can promote mitophagy by activating the PINK1/Parkin pathway and play a neuroprotective role. This study preliminarily demonstrated that the mechanism of action of ALC against SCI may be related to promotion of mitophagy.
    Keywords:  PINK1; Parkin; acetyl‐l‐carnitine; mitophagy; spinal cord injury
    DOI:  https://doi.org/10.1002/jbt.70778
  10. Reprod Toxicol. 2026 Mar 17. pii: S0890-6238(26)00066-3. [Epub ahead of print] 109223
    Reproductive Toxicity Mechanisms of PNMC: Evidence from Mitochondrial Dysfunction and Hormone Synthesis Disruption in the KGN cells.
    Jingyi Xie, Zixuan Pan, Yuhan Du, Kexue Li, Yuning Liu, Qiang Weng, Haolin Zhang.
      3-methyl-4-nitrophenol (PNMC), a widespread environmental endocrine-disrupting compound derived from diesel particulate matter and degradation of fenitrothion, poses a potential risk to ovarian function. This study investigated the concentration-dependent effects of PNMC on mitochondrial homeostasis and steroidogenesis using the human ovarian granulosa KGN cell line. Cells were treated with PNMC across a wide range of concentration (1nM to 1mM) for 48hours and mitochondrial dynamics and functions as well as steroidogenesis were evaluated. Transcriptional and immunofluorescence analyses showed that 100μM PNMC treatment significantly upregulated the expression of mitochondrial dynamics-related genes (MFN1/2, OPA1 and DRP1), mitophagy-related genes (PINK1 and PARK2) and antioxidant defense-related genes (SOD1/2 and GPX1). These changes were associated with increased mtDNA copy number, reduced intracellular ROS and increased mitochondrial membrane potential. By contrast, 1mM PNMC treatment provoked overt mitochondrial toxicity, characterized by diminished mtDNA content, elevated mitochondrial ROS, loss of membrane potential and significant decrease in cell viability. These results indicated that PNMC significantly altered the expression of genes related to mitochondrial dynamics, antioxidant defense, and mitophagy. The expression of CYP19A1 shows significant upregulation at 100µM PNMC treatment, while the maximal response for other genes (CYP17A1, CYP11A1, HSD3B) is observed at 1µM PNMC treatment. Correspondingly, the levels of 17β-estradiol and progesterone increased in the culture medium at 100µM or 1µM PNMC treatment, respectively. Collectively, these findings reveal that PNMC-associated dysregulation of steroidogenic function is closely linked to concomitant alterations in mitochondrial activity, providing important mechanistic insights into its potential reproductive toxicity.
    Keywords:  3-methyl-4-nitrophenol (PNMC); Endocrine-disrupting chemicals (EDCs); KGN cells; Mitochondrial dynamics; Oxidative stress; Steroidogenic enzymes
    DOI:  https://doi.org/10.1016/j.reprotox.2026.109223
  11. Cell Death Dis. 2026 Mar 15.
    O-GlcNAcylation of YAP1 promotes lung transplant ischemia-reperfusion injury via binding to HIF1α transcription factor and activating autophagy and mitophagy.
    Shaohua Dai, Xuemei Wan, Lingchun Xia, Lei Xu, Chunfan Xie, Guohui Wang, Jian Tang.
      Lung transplant ischemia-reperfusion injury poses a significant challenge in transplantation medicine, often causing severe complications and poor patient outcomes. Our study focused on the role of O-GlcNAcylation of Yes-associated protein 1 (YAP1) in exacerbating this injury by regulating autophagy and mitochondrial autophagy pathways. We found that hypoxia-reoxygenation robustly activated the Hippo-YAP1 signaling pathway, leading to increased damage in lung epithelial cells. Concurrently, autophagy and mitochondrial autophagy levels were significantly upregulated, indicating cellular stress responses. During actual lung transplantation, ischemia-reperfusion resulted in a marked increase in autophagy and mitochondrial autophagy levels, accompanied by elevated tissue damage. Notably, YAP1 played a crucial role in orchestrating these processes, as its knockdown reduced autophagy and mitochondrial autophagy levels under both hypoxia-reoxygenation and ischemia-reperfusion conditions. We further elucidated that OGT-mediated O-GlcNAc modification of YAP1 enhanced its interaction with HIF1α, activating downstream hypoxia-responsive molecules. Knockdown of the key enzyme OGT significantly mitigated autophagy, mitophagy, and associated damage in lung epithelial cells and transplant tissues subjected to hypoxia-reoxygenation and ischemia-reperfusion. These findings reveal the intricate interplay between O-GlcNAcylation of YAP1, HIF1α binding, autophagy activation, and mitochondrial autophagy in driving lung transplant ischemia-reperfusion injury, suggesting potential therapeutic targets for ameliorating its detrimental effects.
    DOI:  https://doi.org/10.1038/s41419-026-08548-w
  12. J Control Release. 2026 Mar 12. pii: S0168-3659(26)00218-X. [Epub ahead of print]393 114816
    Nanomaterials regulate cellular functions and influence cell fate through mitophagy.
    Yan Wang, Dan Li, Zhen Ai, YuJia Tian, Chao Zhang.
      Mitophagy plays a crucial role in maintaining mitochondrial quality control, energy metabolism, redox homeostasis, and cell fate regulation. Its dysregulation is considered a key mechanism underlying the onset and progression of various metabolic disorder- and cell fate abnormality-associated diseases. In recent years, nanomaterials have emerged as ideal tools for modulating mitophagy owing to their designability, targeting capability, and multidimensional regulatory potential. Moreover, moderate activation of mitophagy helps to remove damaged mitochondria, alleviate oxidative stress, and restore metabolic balance, whereas excess or impaired mitophagy may trigger energy crises and lead to cellular injury. However, the bidirectional mechanisms and biosafety issues associated with nanomaterial-mediated mitophagy regulation remain poorly understood. This review highlights recent advances in how nanomaterials regulate cellular functions through mitophagy, focusing on their roles in energy metabolism, oxidative stress, senescence, programmed cell death, and diverse disease models, and summarizes the major signaling pathways involved. This study aimed to provide a theoretical framework for understanding the biological basis of nanomaterial-mediated mitophagy modulation and offer guidance for future nanomedicine design, disease intervention, and safety evaluation.
    Keywords:  Cell fate regulation; Mitophagy; Nanomaterial-based therapy; Nanomaterials; Redox balance
    DOI:  https://doi.org/10.1016/j.jconrel.2026.114816
  13. Oncogenesis. 2026 Mar 17.
    IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis.
    Huaxia Cai, Jianjun He.
      Accumulating evidence indicates that mitochondrial dynamics are closely linked to the biological behaviors of tumor cells, with increased mitochondrial fission being recognized as a phenotype that promotes tumor growth. Although intermediate filament family orphan 1 (IFFO1) has been implicated in mitochondrial dynamics, its specific role and molecular mechanisms in regulating mitochondrial fission during breast cancer (BC) progression remain unclear. In this study, analysis of tumor and adjacent normal tissues from 30 BC patients revealed significant downregulation of IFFO1 in tumor tissues, and low IFFO1 expression predicted poor prognosis in patients. In vitro experiments demonstrated that IFFO1 overexpression suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of BC cells by inhibiting mitochondrial fission and fatty acid synthesis. Mechanistically, IFFO1 interacts with LaminA/C to promote its expression, which subsequently upregulates PGC1α, thereby suppressing mitochondrial fission and fatty acid synthesis in BC cells. Consistent with this mechanism, both LaminA/C and PGC1α were downregulated in BC tissues. Silencing LMNA reversed the inhibitory effects of IFFO1 overexpression on mitochondrial fission and fatty acid synthesis, whereas overexpression of PGC1α effectively counteracted the consequences of LMNA knockdown. In vivo studies confirmed that upregulation of IFFO1 inhibited tumor growth in xenograft models and reduced lung metastasis in a lung metastasis mouse model. These findings underscore the significance of the IFFO1/LaminA/C/PGC1α pathway as a key regulator of mitochondrial fission and fatty acid synthesis during BC progression and highlight its potential as a therapeutic target for breast cancer.
    DOI:  https://doi.org/10.1038/s41389-026-00609-1
  14. Redox Biol. 2026 Mar 10. pii: S2213-2317(26)00119-9. [Epub ahead of print]92 104121
    Excessive ER-mitochondria coupling: A DRP1-driven mechanism underlying mitochondrial dysfunction and impaired autophagy in stress-induced depression-like behavior in mice.
    Jia-Rui Zhang, Jia-Yan Zhang, Qing-Ya Sun, Chang Chen, Jing-Wei Yang, Nan Cheng, Zi-Wen Guo, Ruo-Nan Shuang, Wei Gu, Meng-Ying Zhai, Jin-Ao Duan, Wei-Wei Tao.
       BACKGROUND: Depression is a common psychiatric disorder characterized by heightened stress exposure and disruptions in neuronal signaling. Growing evidence suggests that mitochondrial dysfunction contributes to its pathophysiology. In particular, mitochondrial dynamics regulated by Dnm1l/Drp1 are critical for neuronal homeostasis, and their dysregulation may lead to cellular impairment. Additionally, mitochondrial-endoplasmic reticulum contact sites (MERCs) are crucial for maintaining cellular function and require precise regulation. However, the role of Drp1 in modulating MERC structure and function in the context of depression remains unclear.
    METHODS: We quantified protein changes via 4D-FastDIA proteomics. MERC alterations were examined using transmission electron microscopy (TEM) and proximity ligation assay (PLA). Mitochondrial metabolism was assessed with the Seahorse XF Analyzer. Autophagy was visualized through tyramine signal amplification and Imaris-based 3D reconstruction. The causal relationship was tested using Vglut2-Cre mice combined with specific flox-virus mediated Drp1 manipulation and pharmacological inhibition of autophagy. Depression-like behaviors were evaluated after chronic social defeat stress (CSDS).
    RESULTS: Drp1 activation disrupts mitochondrial-endoplasmic reticulum contact sites (MERCs), leading to mitochondrial dysfunction and impaired autophagy, and ultimately promoting depressive-like behaviors. Inhibiting the MERC tethering protein GRP75 or enhancing mitophagy pharmacologically alleviated these neuronal and behavioral deficits. These findings identify Drp1-mediated MERC disruption as a key mechanism in depression and suggest therapeutic strategies targeting MERC integrity and autophagy.
    CONCLUSION: Our results provide novel mechanistic evidence that Drp1-mediated dysfunction at MERCs and impaired mitochondrial quality control contribute to the pathogenesis of depression. These findings underscore the importance of endoplasmic reticulum-mitochondrial crosstalk in depression and suggest potential therapeutic targets for modulating cellular resilience in stress-related disorders.
    Keywords:  Depression; Mitochondrial-endoplasmic reticulum contact sites (MERCs); Mitochondrion; Mitophagy; drp1
    DOI:  https://doi.org/10.1016/j.redox.2026.104121
  15. Apoptosis. 2026 Mar 19. pii: 103. [Epub ahead of print]31(3):
    Adverse outcome pathway analysis identifies DRP1-driven mitochondrial dysfunction as a central event in silver nanoparticle-induced hepatocyte ferroptosis.
    Jiangyan Li, Jiaqi Lan, Zhiwen Liu, Yujia Zhang, Zhuang Duan, Xinyue Wang, Zhijun Geng, Bao Zhao, Hezuo Lü, Qiang Fang, Fengchao Wang.
       BACKGROUND: Silver nanoparticles (AgNPs) are increasingly employed across diverse applications, raising concerns regarding their potential biosafety risks. The liver plays a pivotal role as a target organ upon exposure to AgNPs. The adverse outcome pathway (AOP) framework provides a structured, mechanism-based approach for assessing and managing toxicological risks.
    RESULTS: In this study, we applied the AOP framework to construct a mechanistic relationship map of AgNP-induced hepatotoxicity. Using in vitro (HepG2 cells) and in vivo (C57BL/6 mice) models, we identified mitochondrial dysfunction as a molecular initiating event (MIE), characterized by excessive dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and increased mitochondrial reactive oxygen species (mtROS), which serve as key events (KEs). The cascade ultimately leads to programmed cell death and structural/functional liver injury, which constitute the AO. Further mechanistic investigations revealed that DRP1 phosphorylation at the Ser616 site activated sequestration 1 (p62)/PTEN-induced kinase 1 (PINK1)-dependent mitophagy, which partially mitigated the severity of the AO by preserving mitochondrial integrity and reducing oxidative damage.
    CONCLUSION: These findings not only demonstrate the critical role of DRP1 activation in linking mitochondrial dynamics to hepatocellular ferroptosis, but also highlight the value of the AOP framework as a tool for predicting NPs risk assessment and regulatory decision-making.
    Keywords:  Lipid peroxidation; Mitochondria; Mitochondrial reactive oxygen species; Nanomaterials; Toxic effects
    DOI:  https://doi.org/10.1007/s10495-026-02265-7
  16. J Neurochem. 2026 Mar;170(3): e70411
    Correction to "Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics".
      
    DOI:  https://doi.org/10.1111/jnc.70411
  17. J Oral Microbiol. 2026 ;18(1): 2643035
    P. gingivalis induces endothelial dysfunction via mitochondrial fission dependent VDAC1-HK2 disassociation.
    Yi Wang, Shengming Xu, Zichao Zhuang, Congyi Tu, Zhe Zhou, Tianhao Chen, Mengting Wu, Bin Lu, Pengcheng Ye, Xia Fan, Rongdang Hu, Hui Deng.
       Background: Mitochondrial dysfunction contributes to Porphyromonas gingivalis (P. gingivalis)-impaired endothelial function. Given the critical role of the mitochondrial permeability transition pore (mPTP) in mitochondrial homeostasis, this study explored how P. gingivalis promotes dynamin-related protein 1 (Drp1)-dependent mPTP overactivation, leading to mitochondrial damage and endothelial dysfunction.
    Materials and methods: Mitochondrial and endothelial functions were evaluated in P. gingivalis-infected human aortic endothelial cells (HAECs) and C57BL/6 mice. Western blotting, immunofluorescence, and co-immunoprecipitation were used to assess the mitochondrial dynamics and mPTP-related protein interactions. Aortic vasodilation and endothelial integrity were examined following treatment with the Drp1 inhibitor Mdivi-1 or mPTP inhibitor cyclosporin A (CsA).
    Results: P. gingivalis infection induced significant mitochondrial fragmentation, excessive mPTP opening, and impaired endothelium-dependent vasorelaxation. These changes were associated with enhanced p-Drp1 and its translocation to mitochondria. Mechanistically, P. gingivalis promoted voltage-dependent anion channel 1 (VDAC1) oligomerization in the out membrane of mitochondrial via p-Drp1 activation, which in turn disrupted the VDAC1-hexokinase 2 (HK2) interaction, facilitating mPTP opening. Inhibition of Drp1 and mPTP opening significantly alleviated mitochondrial dysfunction and restored endothelial function both in vitro and in vivo.
    Conclusion: P. gingivalis impairs endothelial function via Drp1-VDAC1-HK2-mediated mPTP overactivation, highlighting a potential therapeutic target against vascular injury in periodontal infection.
    Keywords:  Drp1; Endothelial dysfunction; Porphyromonas gingivalis; mPTP; mitochondria
    DOI:  https://doi.org/10.1080/20002297.2026.2643035
  18. J Ethnopharmacol. 2026 Mar 16. pii: S0378-8741(26)00389-2. [Epub ahead of print]364 121538
    Dihuang Yinzi ameliorates post-stroke depression through Miro1 ubiquitination-dependent mitophagy.
    Hui Chang, Zhiping Ji, Qingya Sun, Shan Zhou, Zhou Yang, Xiaodong Qu, Yongqu Jiang, Xiaolan Cheng, Yanling Wang, Yongxia Jiang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Dihuang Yinzi (DY) is a classic formula traditionally used for stroke-related disorders. Its potential therapeutic effect on post-stroke depression (PSD), however, remains to be investigated.
    AIM OF THE STUDY: This study aims to evaluate the antidepressant effects of DY in a rat model of PSD and to explore the underlying mechanisms involving mitophagy and neuroinflammation.
    MATERIALS AND METHODS: PSD was induced in rats by middle cerebral artery occlusion combined with chronic unpredictable mild stress. DY extract was administered daily for two weeks. Neurofunctional deficits and depressive-like behaviors were assessed. Cerebral infarction volume was measured by TTC staining. Hippocampal tissues were collected for transcriptomic analysis, qPCR, Western blot, immunoprecipitation, and ELISA to detect mitophagy-related genes (RHOT1, MAP1LC3B, PINK1, PRKN) and proteins as well as inflammatory factors. A specific mitophagy inhibitor was used to verify whether the anti-inflammatory effects of DY depend on mitophagy. Subcellular fractionation and immunofluorescence co-localization with the mitochondrial marker Tom20 were performed to confirm mitochondrial localization of overexpressed Miro1. The role of Miro1 was further validated using adenovirus-mediated overexpression.
    RESULTS: DY significantly alleviated depressive-like behaviors and reduced cerebral infarction volume in PSD rats. qPCR analysis showed that DY downregulated RHOT1 (Miro1) and upregulated MAP1LC3B, PINK1, and PRKN mRNA expression. Transcriptomic and mechanistic analyses revealed that DY promoted Miro1 degradation, thereby enhancing PINK1-mediated mitophagy. Subcellular fractionation and immunofluorescence confirmed that overexpressed Miro1 was correctly localized to mitochondria. Inhibition of mitophagy abolished the anti-inflammatory effects of DY, as evidenced by increased NF-κB activation and elevated pro-inflammatory cytokine levels. Notably, adenovirus-mediated Miro1 overexpression reversed the therapeutic effects of DY.
    CONCLUSIONS: DY improves PSD by promoting Miro1 degradation to facilitate mitophagy and suppress NF-κB-mediated neuroinflammation. These findings provide a scientific basis for the clinical application of DY in PSD and identify Miro1 as a potential therapeutic target.
    Keywords:  Dihuang Yinzi; Miro1; Mitophagy; NF-κB pathway; Post-stroke depression
    DOI:  https://doi.org/10.1016/j.jep.2026.121538
  19. Neurobiol Dis. 2026 Mar 13. pii: S0969-9961(26)00095-1. [Epub ahead of print] 107350
    Tunable tau expression in C. elegans neurons reveals that early-AD tau phosphorylation selectively impacts behavior and mitochondrial quality control.
    T Carroll, D Pfendler, H Alhaj Arhayem, R Thoma, A Müller-Eigner, A Straut, G V W Johnson, K Nehrke.
      Tau protein accumulates myriad post-translational modifications as Alzheimer's disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of "tunable tau" strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1, a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis.
    Keywords:  Alzheimer's disease; Auxin inducible degron; C. elegans; Mitochondrial quality control; Mitochondrial unfolded protein response; Phosphorylation; Tau
    DOI:  https://doi.org/10.1016/j.nbd.2026.107350
  20. Inflammation. 2026 Mar 16.
    Interleukin-6 Signaling Mediates Mitochondrial Fragmentation and Mitophagy Impairment to Induce Macrophages Ferroptosis in Atherosclerosis.
    Minhui Li, Lin Zheng, Xiao Tang, Haifeng Liu, Xiaotong Qi, Zhenyu Zhou, Jiaqi Zhu, Changpo Lin, Yongbin Shi, Tonglei Han, Hanfei Tang, Daqiao Guo.
      
    Keywords:  Atherosclerosis; Ferroptosis; Interleukin-6; Macrophages; Mitochondrial fission; Mitophagy
    DOI:  https://doi.org/10.1007/s10753-025-02359-5
  21. Biochem Pharmacol. 2026 Mar 13. pii: S0006-2952(26)00224-8. [Epub ahead of print]249 117891
    Ginsenoside Rg1 alleviates MASH by targeting GLS2 to enhance PINK1/Parkin-mediated mitophagy and improve mitochondrial function.
    Zhijian Wang, Yinuo Wang, Peiyun Peng, Huating Luo, Liuling Xiao, Wenxiang Huang.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by profound metabolic dysregulation and hepatic inflammation and represents a major global health burden with limited effective therapeutic options. Increasing evidence suggests that improving mitochondrial function and enhancing mitophagy may offer promising strategies for MASH treatment. Ginsenoside Rg1 (G-Rg1) has been reported to exert potent anti-inflammatory and antioxidant effects; however, its precise molecular mechanisms and targets in MASH remain unclear. In this study, we investigated whether G-Rg1 ameliorates diet-induced MASH by promoting mitophagy and sought to identify its direct molecular target. Mice treated with G-Rg1 were evaluated using histological, biochemical, and indirect calorimetric analyses to assess hepatic steatosis, fibrosis, inflammation, and energy metabolism. Transcriptomic profiling and transmission electron microscopy revealed enhanced mitophagy and improved mitochondrial ultrastructure following G-Rg1 treatment. Virtual screening and molecular docking identified glutaminase 2 (GLS2) as a potential target of G-Rg1, which was subsequently confirmed by drug affinity-responsive target stability, cellular thermal shift, and binding assays. Mechanistically, G-Rg1 activated the GLS2/PINK1/Parkin pathway, leading to increased mitophagy, reduced hepatocellular lipid accumulation, restoration of mitochondrial function, and attenuation of oxidative stress. Notably, GLS2 overexpression recapitulated the protective effects of G-Rg1 both in vitro and in vivo. Collectively, these findings demonstrate that G-Rg1 alleviates MASH by targeting GLS2 to activate PINK1/Parkin-mediated mitophagy, highlighting GLS2-regulated mitophagy as a potential therapeutic target for MASH.
    Keywords:  GLS2; Gene therapy; Ginsenoside Rg1; MASH; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.bcp.2026.117891
  22. FEBS J. 2026 Mar 19.
    Oxidative phosphorylation and mitochondrial dynamics are regulated by Sestrin2 to maintain cellular function.
    Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.
      The stress-inducible protein Sestrin2 (SESN2) has recently emerged as an orchestrator of mitochondrial signaling. The regulation of mitochondria-related pathways, such as aerobic respiration, is thought to be mediated by SESN2, but the underlying mechanisms are not fully understood. Here, we characterized mitochondria in Sesn2-knockdown myoblasts under physiological conditions using oxygen consumption rate measurements, fluorescence microscopy, and protein content analysis. We discovered that SESN2 is essential for sustaining oxidative phosphorylation and maintaining the mitochondrial network organization. SESN2 loss diminished ATP production, decreased the levels of nuclear- and mitochondrial-encoded complex IV subunits, and increased superoxide generation. Moreover, the assessment of mitochondrial distribution in Sesn2-knockdown cells revealed a more fragmented network. This was associated with an increased ratio of short to long optic atrophy 1 (OPA1) forms. Remarkably, disruption of mitochondrial signaling suppressed cellular proliferation and altered both cell and nuclear morphology. In summary, our findings suggest that SESN2 plays an important role in maintaining cellular homeostasis, partly through its impact on mitochondrial function.
    Keywords:  SESN2; mitochondria; mitochondrial dynamics; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/febs.70497
  23. Int J Mol Med. 2026 May;pii: 134. [Epub ahead of print]57(5):
    ZEB1 maintains mitochondrial fission and macrophage efferocytosis by restraining MFN2, thereby limiting inflammation and improving tendon‑bone healing.
    Yan Zhao, Yuankai Zhang, Tian Lei, Shangqing Zhang, Kai Nan, Xin Zhang, Li-Hong Fan.
      Excessive inflammation and scar formation at the tendon‑bone interface (TBI) hinder effective healing. Macrophage efferocytosis is critical for resolving inflammation, yet its regulatory mechanisms in TBI healing remain unclear. The present study investigated the role of zinc finger E‑box binding homeobox 1 (ZEB1) in macrophage efferocytosis and rotator cuff repair. Zeb1 knockdown in rats was achieved using short hairpin RNA (shRNA). Bone marrow‑derived macrophages co‑cultured with apoptotic Jurkat cells were used to evaluate efferocytosis efficiency. Mechanistically, ZEB1 was demonstrated to function as a critical regulator of mitochondrial dynamics by transcriptionally repressing Mitofusin‑2 (MFN2), thereby maintaining the mitochondrial fission necessary for efficient efferocytosis. ZEB1‑knockdown relieved MFN2 suppression, leading to excessive mitochondrial fusion and a subsequent decrease in apoptotic cell clearance. In vivo, ZEB1 deficiency resulted in the accumulation of secondary necrotic cells, aggravated the inflammatory microenvironment (increased M1/decreased M2 polarization), and impaired histological and biomechanical healing of the tendon‑bone interface. These findings indicate a novel ZEB1/MFN2/mitochondrial fission axis that governs macrophage efferocytosis. Targeting this axis to restore the immune microenvironment offers a potential therapeutic strategy for improving tendon‑bone healing.
    Keywords:  ZEB1; efferocytosis; inflammatory microenvironment; rotator cuff injury; tendon and bone healing
    DOI:  https://doi.org/10.3892/ijmm.2026.5805
  24. Bioorg Chem. 2026 Mar 15. pii: S0045-2068(26)00295-6. [Epub ahead of print]174 109759
    A potent icaritin derivative ameliorates Parkinson's disease via GPER-mediated mitophagy restoration and dopaminergic neuroprotection.
    Xiaowen Wang, Xizhen Cao, Meiyun Cai, Ruiyue Zhao, Yangyang Zheng, Mei Zhang, Changlun Shao, Wenfang Chen.
      Icaritin (ICT), a major prenylated flavone from Epimedium with anti-osteoporosis, anti-cancer, and anti-inflammatory properties, is limited clinically by poor water solubility and low bioavailability. In this study, ICT derivatives were prepared via multi-step chemical reactions and five ICT derivatives (ICTA, ICTB, ICTC, ICTD and ICTE) were successfully synthesized. Compared with ICT, most derivatives exhibited improved solubility and reduced cytotoxicity. Notably, ICTC showed a significant improvement in aqueous solubility (at least 12-fold higher), favorable lower cytotoxicity (at least 2-fold lower at 20 μM), and prominent neuroprotective effects. Mechanistically, in vitro studies revealed that ICTC targets the G protein-coupled estrogen receptor (GPER) to rescue defective mitophagy by restoring MPP+-suppressed expression of mitophagy-related proteins (PINK1, Parkin) and attenuating MPP+-induced accumulation of autophagic substrates (LC3-II, P62). In vivo, intraperitoneal injection of ICTC (0.3-3 mg/kg) effectively protected against MPTP-induced damage to dopaminergic neurons and attenuated neuroinflammation. Molecular docking, pharmacological blockade and studies in GPER knockout mouse models of Parkinson's disease (PD) confirmed that the effects of ICTC depend on GPER. Moreover, intravenous injection of ICTC also provided effective dopaminergic neuron protection, addressing the limitations of oral formulation. Overall, ICTC is a promising prodrug with enhanced solubility that exerts anti-inflammatory and neuroprotective effects in experimental PD by targeting GPER to ameliorate abnormal mitophagy.
    Keywords:  G protein-coupled estrogen receptor; Icaritin derivatives; Mitophagy; Neuroprotection; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109759
  25. Neurobiol Dis. 2026 Mar 12. pii: S0969-9961(26)00098-7. [Epub ahead of print]222 107353
    Hippocampal mtDNA depletion promotes nicotine addiction by suppressing mitochondrial biogenesis through oxidative stress.
    Shuhong Zhang, Hongjuan Wang, Guanglin Liu, Huan Chen, Hongwei Hou.
      Nicotine addiction is a complex neurobiological process in which the hippocampus plays a pivotal role in consolidating drug-context associative memories. Although mitochondrial dysfunction has been implicated in addiction, the specific role and molecular mechanisms underlying changes in mitochondrial DNA (mtDNA) copy number during nicotine exposure remain poorly defined. This study aimed to elucidate the relationship between hippocampal mtDNA copy number alterations and nicotine addiction behaviors, as well as the molecular mechanisms driving mtDNA depletion. Using a nicotine-induced conditioned place preference (CPP) mouse model, we observed a marked reduction in mtDNA copy number specifically in the hippocampus, but not in the nucleus accumbens (NAc) or ventral tegmental area (VTA). To determine causality, recombinant adeno-associated virus (rAAV)-mediated genetic manipulation was employed to selectively overexpress (TFAM-OE) or knock down (TFAM-KD) mitochondrial transcription factor A (TFAM) in the hippocampus. TFAM-OE, which significantly increased baseline mtDNA copy number, completely abolished the development of nicotine-induced CPP, establishing a direct causal link between hippocampal mtDNA copy number and nicotine reward behavior. Mechanistically, chronic nicotine exposure induced a time-dependent reduction in mtDNA copy number and pronounced mitochondrial ultrastructural damage in hippocampal neurons. This depletion was primarily driven by suppression of the mitochondrial biogenesis pathway-particularly the Sirt1-Nrf1-Tfam signaling axis-rather than activation of mitophagy. Notably, oxidative stress, evidenced by depleted glutathione (GSH) levels, was identified as the upstream trigger mediating this suppression. Pharmacological intervention with mitochondrial-targeted antioxidants (melatonin and mito-TEMPO) restored mitochondrial biogenesis, prevented mtDNA copy number loss, and normalized ATP production. Melatonin can further significantly inhibit the formation of nicotine CPP behavior. Collectively, these findings establish a causal link between hippocampal mtDNA depletion and nicotine reward memory, demonstrating that nicotine suppresses mitochondrial biogenesis via oxidative stress-mediated inhibition of the Sirt1-Nrf1-Tfam axis. This work identifies a previously unrecognized metabolic mechanism underlying nicotine addiction and may also advance our understanding of mitochondrial contributions to other substance use disorders.
    Keywords:  CPP; Hippocampus; Mitochondrial biogenesis; Nicotine; Oxidative stress; mtDNA copy number
    DOI:  https://doi.org/10.1016/j.nbd.2026.107353
  26. Chem Biol Interact. 2026 Mar 18. pii: S0009-2797(26)00155-9. [Epub ahead of print] 112047
    Cyclophosphamide-induced iron homeostasis imbalance triggers ovarian toxicity through ferroptosis of ovarian granulosa cells in a mitophagy crosstalk manner.
    Bo Xu, Xiaoqiang Luo, Tengjiao He, Yu Deng, Yitong Shang, Hang Han, Xufeng Fu.
      Chemotherapy, while effective in targeting cancerous cells, often results in collateral damage to normal cells with high proliferative capacity, leading to iatrogenic ovarian injury. Ferroptosis has been implicated as a key driver of ovarian injury caused by chemotherapy drugs. However, the underlying molecular mechanisms remain incompletely understood. Therefore, this study was designed to elucidate the mechanism by which chemotherapy drugs induce ovarian injury through ferroptosis. Our findings demonstrate that the chemotherapeutic drug cyclophosphamide (CTX) impairs ovarian function and disrupts follicular development. Further analysis revealed characteristic features of ferroptosis within CTX-induced atretic follicular granulosa cells (GCs), including elevated Fe2+ accumulation, increased lipid peroxidation, and dysregulation of key ferroptosis-related molecules. Consistently, in vitro experiments demonstrated that treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) significantly alleviated CTX-induced cytotoxicity in KGN cells. Moreover, using the iron chelator deferoxamine (DFO) and the iron supplement ferric ammonium citrate (FAC), we demonstrated that modulating iron homeostasis could attenuate or aggravate CTX-induced ferroptosis in GCs, thereby confirming that disrupted iron homeostasis is a primary trigger for CTX-induced ferroptosis in GCs. Notably, we observed that Fe2+ accumulation occurred within mitochondria and subsequently triggered excessive mitophagy. This heightened mitophagy response exacerbated mitochondrial damage, thereby establishing a vicious cycle of persistent mitochondrial impairment that ultimately sensitized GCs to ferroptosis. Conversely, treatment with the mitophagy inhibitor cyclosporin A (CSA) alleviated CTX-induced ferroptosis in GCs. In conclusion, our study reveals that mitophagy-mediated ferroptosis is a critical mechanism underlying CTX-induced ovarian injury. These findings suggest that therapeutic strategies targeting mitophagy or ferroptosis hold promise for the treatment and prevention of chemotherapy-associated ovarian toxicity.
    Keywords:  Ferroptosis; Iron overload; Ovarian Granulosa Cells; Oxidative stress; mitophagy
    DOI:  https://doi.org/10.1016/j.cbi.2026.112047
  27. Biogerontology. 2026 Mar 15. pii: 71. [Epub ahead of print]27(2):
    Noncanonical role of MTP-18 in mitochondrial function and aging via electron transport chain interactions in Caenorhabditis elegans.
    Jyothi Priyanka Ghantasala, Timothy Wai, Writoban Basu Ball, Manjunatha Thondamal.
      Mitochondria provide energy and maintain homeostasis, and their dysfunction relates to aging. Disrupted structure and function of mitochondria are linked to age-related diseases, but the roles of many mitochondrial proteins in mitochondrial dynamics and aging remain unclear. We studied the role of the mitochondrial fission protein MTP-18 in mitochondrial dynamics and aging in C. elegans. Our data show that loss of mtp-18 increases longevity and stress resistance, alongside changes in key physiological processes. We tested whether mtp-18-mediated longevity is linked to the PI3K-dependent insulin/IGF-1 signaling (IIS) pathway. mtp-18-mediated longevity requires the Forkhead transcription factor DAF-16, a primary effector of the IIS pathway, but is not mediated by the canonical IIS cascade. We also observed unique interactions between mtp-18 and genes encoding components of the mobile electron carrier system in mitochondria, such as coenzyme Q and cytochrome c. Our study reveals that mtp-18 is an evolutionarily conserved, key aging regulator that maintains mitochondrial morphology. What sets this study apart from previous research is the identification of a novel mechanism by which MTP-18 affects these processes independently of the canonical IIS pathway, particularly through unique interactions with genes encoding components of the electron transport chain.
    Keywords:   C. elegans ; Electron transport chain; Insulin signlling pathway; Longevity; Mitochondrial fission; ROS
    DOI:  https://doi.org/10.1007/s10522-026-10415-2
  28. Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00038-3. [Epub ahead of print] 102148
    Mitochondrial dysfunction and mitochondrial unfolded protein response (UPRmt): unravelling their roles in autism spectrum disorder pathogenesis.
    Merlin Jeejo, Mrudula Mathew, Kochupurackal P Mohanakumar, Usha Rajamma.
      Autism spectrum disorders (ASD) is a complex neurodevelopmental condition characterized by a gamut of impairments in social interaction, communication, and behaviour. Emerging evidence implicates mitochondrial dysfunction, manifested through disruptions in ATP synthesis, mitochondrial DNA (mtDNA) mutations, and heightened oxidative stress, as a significant contributor to the pathophysiology of ASD. Notably, individuals with ASD demonstrate a higher prevalence of mitochondrial disorders compared to the general population, suggesting a potential pathogenic link. However, the relationship between mitochondrial dysfunction and ASD is heterogeneous and varies among individuals, reflecting the disorder's intrinsic complexity. Recent interest in the Mitochondrial Unfolded Protein Response (UPRmt), which is activated in response to mitochondrial stress and misfolded proteins, underscores its critical role in maintaining mitochondrial integrity. Yet, its specific implications in ASD have been insufficiently investigated. This review aims to consolidate the current literature on UPRmt-related biomarkers in the context of ASD, elucidating how disruptions in this pathway may exacerbate mitochondrial dysfunction and contribute to ASD pathogenesis. In this narrative review, based on our literature search from academic databases such as PubMed, Scopus, Web of Science, and Google Scholar, and also grey literature, we present a conceptual framework to enhance our understanding of ASD pathophysiology that integrates mitochondrial stress, UPRmt activation, and neurodevelopmental outcomes. This review aims to expand the existing knowledge of mitochondrial contributions to ASD and identify new research dimensions to explore the mechanisms underlying UPRmt deregulation in ASD pathophysiology, thereby highlighting the potential therapeutic directions for targeting mitochondria-mediated UPRmt dysfunction in ASD.
    Keywords:  Autism spectrum disorders; Gut-brain axis; Mitochondrial dysfunction; Mitochondrial unfolded protein response; Mitokine
    DOI:  https://doi.org/10.1016/j.mito.2026.102148
  29. J Physiol Biochem. 2026 Mar 18. pii: 28. [Epub ahead of print]82(1):
    Mfn1-mediated imbalanced mitochondrial dynamics promotes ovarian cancer stemness by inducing metabolic reprogramming.
    Rahail Ashraf, Kalpana Tankay, Manita Raina, Athira, Sanjay Kumar.
      
    Keywords:  2-Deoxy-D-glucose; CD133+ ; ETC complexes; Metabolic reprogramming; Mfn1; Mitochondrial fusion; Ovarian cancer stem cells
    DOI:  https://doi.org/10.1007/s13105-026-01172-4
  30. Chem Biol Interact. 2026 Mar 16. pii: S0009-2797(26)00151-1. [Epub ahead of print] 112043
    Sevoflurane activates ATF4/NSUN7/PRKCD axis to induce neurotoxicity and cognitive impairment by promoting neuron mitochondrial fission.
    Qiang Fu, Ling Chen, Xiong Zeng, Cuilin Lan, Guanhua Wang, Shujia Li, Tingmin Lv, Hanwen Chen.
      Sevoflurane (SEV) had been confirmed to induce mitochondrial dysfunction to accelerate neurotoxicity. NOL1/NOP2/Sun domain family member 7 (NSUN7) is involved in the regulation of the progression of neurological dysfunction. The present study aims to explore whether SEV mediates mitochondrial dynamics to exert neurotoxicity by regulating NSUN7-related pathway. Normal mice and NSUN7 knockout (KO) mice were exposed to SEV (obtained from Baxter Healthcare Corporation). Cognitive function of mice was assessed by morris water maze test. HE and Nissl staining, inflammatory factors and ROS levels were used to evaluate neuron injury. Western blot, qRT-PCR or immunofluorescence staining were used to detect the expression of NSUN7, mitochondrial fusion/fission-related markers, protein kinase C delta (PRKCD) and activating transcription factor 4 (ATF4). Neurons isolated from mice hippocampal tissues were treated with SEV, and cell viability and apoptosis were determined using CCK8 assay and flow cytometry. The regulation of NSUN7 on PRKCD, as well as ATF4 on NSUN7, was evaluated using dot blot, RIP, dual-luciferase reporter or ChIP assay. SEV stimulation could enhance mitochondrial fission and NSUN7 expression in hippocampal neurons of mice. NSUN7 knockdown repressed mitochondrial fission to relieve SEV-induced neuron injury, and NSUN7-KO ameliorated SEV-induced neurocognitive dysfunction in mice. Besides, NSUN7 facilitated the PRKCD stability and translation by 5-methylcytosine modification, and the suppressive effect of NSUN7 knockdown on SEV-induced neuron injury could be reversed by PRKCD overexpression. Also, ATF4 activated the transcription of NSUN7, and its knockdown alleviated SEV-induced neuron injury by inhibiting mitochondrial fission through downregulating NSUN7. Meanwhile, SEV aggravated neurotoxicity and cognitive impairment in mice by activating the ATF4/NSUN7/PRKCD axis. Collectively, SEV-induced neurotoxicity is associated with mitochondrial fission and ATF4/NSUN7/PRKCD pathway activation, providing new ideas for alleviating SEV-induced neurotoxicity.
    Keywords:  ATF4; Mitochondrial dynamics; NSUN7; Neurotoxicity; PRKCD; Sevoflurane
    DOI:  https://doi.org/10.1016/j.cbi.2026.112043
  31. Aging Cell. 2026 Apr;25(4): e70449
    FGF21-Mediated Upregulation of SIRT1 Delays Intervertebral Disc Degeneration by Promoting PINK1/Parkin Dependent Mitophagy Through Deacetylation of FOXO3.
    Zuo-Long Wu, Rui Ran, Qi-Qi Xie, Cong Zhang, Ya-Jun Chen, Peng Cheng, Ke-Ping Wang, Hai-Hong Zhang.
      Intervertebral Disc Degeneration (IDD) is a common degenerative spinal disease and a leading cause of low back pain and disability. The senescence of nucleus pulposus cells (NPCs) is a central mechanism driving the pathological progression of IDD, though its regulatory mechanisms remain unclear. Bioinformatic analysis identified FGF21 as a key gene regulating NPCs senescence. In both human and rat degenerated intervertebral discs, FGF21 expression was significantly downregulated and closely associated with the upregulation of senescence markers (P16, P21, and P53) and clinical pathological features (age, symptom duration, and Pfirrmann grading). In vitro experiments demonstrated that FGF21 intervention significantly alleviated tert-butyl hydroperoxide (TBHP)-induced NPCs senescence and mitochondrial damage. Mechanistically, FGF21 upregulated SIRT1 and promoted the deacetylation of FOXO3 at lysine sites K241, K258, K289, and K568, thereby enhancing mitophagy and inhibiting NPCs senescence. In vivo, FGF21 treatment significantly improved disc height and histological scores in a rat IDD model, whereas SIRT1 knockdown attenuated these protective effects. In summary, FGF21 inhibits NPCs senescence and delays IDD progression by activating SIRT1-mediated FOXO3 deacetylation and enhancing PINK1-Parkin pathway-dependent mitophagy. Therefore, the FGF21-targeted SIRT1/FOXO3/PINK1/Parkin axis may represent a promising new therapeutic strategy for IDD.
    Keywords:  FGF21; FOXO3; SIRT1; cellular senescence; intervertebral disc degeneration; mitophagy
    DOI:  https://doi.org/10.1111/acel.70449
  32. J Transl Med. 2026 Mar 17. pii: 389. [Epub ahead of print]24(1):
    Targeting the PINK1/Parkin-FNDC5 pathway: a novel mechanism of icariin in regulating muscle-bone metabolic coupling in osteosarcopenia.
    Mengyan Zhao, Fei Yuan, Chaoyang Liu, Tao Guo.
      
    Keywords:  FNDC5; Icariin; Mitochondrial autophagy; Muscle-bone metabolic coupling; Osteosarcopenia; PINK1/Parkin; SMR
    DOI:  https://doi.org/10.1186/s12967-026-08017-0
  33. J Ethnopharmacol. 2026 Mar 17. pii: S0378-8741(25)01197-3. [Epub ahead of print] 120505
    Corrigendum to "Rg1 improves Alzheimer's disease by regulating mitochondrial dynamics mediated by the AMPK/Drp1 signaling pathway" [J. Ethnopharmacol. 340 (2025) 119285].
    Yini Zhang, Shangzhi Liu, Di Cao, Min Zhao, Haifei Lu, Ping Wang.
      
    DOI:  https://doi.org/10.1016/j.jep.2025.120505
  34. Anim Biosci. 2026 Mar 11.
    Resveratrol inhibits NLRP3 inflammasome activation to alleviate bovine mastitis by promoting PINK1-mediated mitophagy.
    Junpen Huang, Longwei Sun, Shujing Tan, Ran Yu, Weiguo Zhao, Chengmin Li.
       Objective: Negative energy balance in transition cows elevates the circulating concentrations of non-esterified fatty acids (NEFA), which can trigger mastitis and pose a severe threat to the dairy industry. Resveratrol is a polyphenolic compound with anti-inflammatory properties, yet its role in NEFA-induced inflammation in bovine mammary epithelial cells (BMECs) remains unclear. This study aimed to investigate the protective effects of resveratrol on mastitis and elucidate its underlying mechanisms.
    Methods: BMECs were pre-treated 100 µM RES for 24 h and then treated 0.9 mM NEFAs for 4 h, and a PINK1 inhibitor was used to assess the underlying mechanisms. Furthermore, a mouse model of mastitis was utilized to further evaluate the hepatoprotective effects of resveratrol against mastitis in vivo.
    Results: Resveratrol significantly attenuated the NEFA-induced inflammatory response, as evidenced by reduced levels of NLRP3 inflammasome components (NLRP3, caspase1, IL-1β) and pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Mechanistically, resveratrol promoted mitophagy by upregulating levels of LC3-II, PINK1, and Parkin, and downregulating P62 expression. Crucially, the anti-inflammatory effect of resveratrol was reversed upon inhibition of PINK1. The in vivo experiments confirmed that resveratrol alleviated mammary gland inflammation and enhanced PINK1-mediated mitophagy.
    Conclusion: This study demonstrates that resveratrol mitigates NLRP3-mediated inflammatory responses by activating PINK1-mediated mitophagy, suggesting its potential as a promising therapeutic candidate for mastitis in perinatal dairy cows experiencing negative energy balance.
    Keywords:  Mastitis; Mitophagy; NLRP3 inflammasome; Resveratrol; Transition dairy cow
    DOI:  https://doi.org/10.5713/ab.250935
  35. Front Pharmacol. 2026 ;17 1781741
    Correction: Erythropoietin mitigates diabetic nephropathy by restoring PINK1/Parkin-mediated mitophagy.
    Xinyao Yi, Wenhui Yan, Tingli Guo, Na Liu, Zhuanzhuan Wang, Jia Shang, Xiaotong Wei, Xin Cui, Yuzhuo Sun, Shuting Ren, Lina Chen.
      [This corrects the article DOI: 10.3389/fphar.2022.883057.].
    Keywords:  EPO; LC3; Pink1/Parkin; diabetic nephropathy; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1781741
  36. J Gerontol A Biol Sci Med Sci. 2026 Mar 15. pii: glag065. [Epub ahead of print]
    ECSIT facilitates exercise-induced amelioration of skeletal muscle atrophy by maintaining mitochondrial quality control in Middle-aged mice.
    Jingcheng Fan, Xin Wen, Xuemei Duan, Xue Zhang, Tan Zhang.
      Although exercise is well-established in alleviating aging-associated skeletal muscle atrophy, the underlying mechanism is not fully understood. Evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) has been shown to be a crucial adaptor for inflammation and mitochondrial function, however, little is known about the action of ECSIT in skeletal muscle atrophy. Firstly, the young and middle-aged mice were performed with exercise training, skeletal muscle atrophy, mitochondrial quality control, and mitochondrial complex in skeletal muscle were detected. Then, we analyzed the Gene Expression Omnibus (GEO) database and performed in vivo experiments to determine the effect of exercise on ECSIT expression. Furthermore, ECSIT was knockdown in myoblasts to examine its effects on muscle atrophy, mitochondrial quality control and mitochondrial complex. Compared with young mice, middle-aged mice exhibited significant reductions in relative weights of skeletal muscles, grip strength, hang time, and exhaustion exercise performance, while exercise restored these deficits dramatically. Consistently, exercise promoted protein synthesis and inhibited protein degradation in the gastrocnemius of middle-aged mice. Therefore, exercise significantly mitigated skeletal muscle atrophy in middle-aged mice. Concomitantly, exercise alleviated the impaired mitophagy in the gastrocnemius of middle-aged mice. ECSIT expression was elevated in the gastrocnemius of middle-aged mice but was reversed by exercise intervention. Mechanistically, ECSIT knockdown impaired myoblast differentiation, mitochondrial complex and mitochondrial quality control in myoblasts. Collectively, this study reveals, for the first time, that ECSIT is important for myogenesis by maintaining mitochondrial quality control, thereby facilitating exercise-induced amelioration of skeletal muscle atrophy during aging.
    Keywords:  ECSIT; anti-aging; exercise; mitochondria
    DOI:  https://doi.org/10.1093/gerona/glag065
  37. Front Mol Biosci. 2026 ;13 1741800
    Mitochondrial metabolism in cancer stem cells (CSCs): molecular and diagnostic implications.
    Charan Psvv, Sona Sunil, Nandana Thuyyath, Rekha Rani Kokkanti, Kousalya Lavudi.
      Cancer stem cells (CSCs) are a self-renewing population often linked to tumor initiation, metastasis, relapse, and resistance to therapy. While bulk tumor cells are often dependent on glycolysis, CSCs demonstrate metabolic plasticity can switch between glycolysis and OXPHOS (oxidative phosphorylation) depending on context. Mitochondria buffer against stress and allow for a metabolic reprogramming towards apoptosis evasiveness, making mitochondrial function crucial to CSC survival. The acquisition of stem-like traits coincides with the rewiring of mitochondrial metabolism, as newly emerging CSCs intermittently upregulate respiration, ROS detoxification, and metabolic plasticity to satisfy cellular demands. Several regulators converge on this mitochondrial metabolism axis. For instance, the co-activator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and partner estrogen-related receptor α (ERRα) promote mitochondria biogenesis and OXPHOS while promoting tumor sphere formation and expression of stemness genes. Conversely, knockdown of PGC-1α reduces sphere formation and stemness. Similarly, a crucial process - mitophagy via AMP-activated protein kinase (AMPK) and related kinases regulate organelle turnover and quality control to promote CSC viability against stress. Mitochondrial dynamics (fission/fusion) also decides the fate of CSCs. The CSC metabolism is further influenced by the tumor microenvironment (TME). Hypoxia-inducible transcription factors, along with tumor stromal signals such as CAF-derived metabolites induce metabolic rewiring and strengthen antioxidant defenses in CSCs, thereby making it easier for CSCs to survive in unfavourable niches. The abundance of mitochondrial DNA and basal respiratory activity has been linked to CSC features such as increased ATP, stem cell markers and chemoresistance. Over the past few years, significant progress has been made in targeting mitochondrial metabolism of CSCs, yet is still a developing area with tremendous therapeutic scope. More research is required to identify mitochondrial vulnerabilities that are specific to therapy and then translate those findings into effective, precision-based cancer treatments. In this review, we try to provide a comprehensive overview of mitochondrial metabolism in regulating behaviour of CSCs, origin and characteristics of CSCs, the metabolic reprogramming for OXPHOS and glycolytic flexibility, molecular regulators of mitochondrial function, mitochondrial dynamics in stemness pathways and how the TME regulates these processes. We also review novel diagnostic techniques and therapies that target mitochondrial vulnerabilities to eliminate CSCs and provide better clinical outcomes.
    Keywords:  CSCs; OxPhos; drug resistance; metabolic plasticity; mitochondrial bioenergetics; mitochondrial dynamics; therapeutic resistance; tumor relapse
    DOI:  https://doi.org/10.3389/fmolb.2026.1741800
  38. J Ethnopharmacol. 2026 Mar 12. pii: S0378-8741(26)00376-4. [Epub ahead of print]364 121525
    Quercetin enhances skin flap survival via SIRT1-regulated mitophagy promotion and pyroptosis inhibition.
    An Wang, Sihan Chen, Jialong Yang, Jiapeng Deng, Weilong Song, Panshen Xu, Hebin Pan, Kai Chen, Zhigang Bian, Wenpin Cai, Dingsheng Lin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Flap necrosis remains a prevalent and challenging complication in reconstructive surgery. Quercetin (QUE), a primary bioactive flavonoid found in the traditional Chinese medicine Sophora japonica L. (Huai Hua), is renowned for its abilities to clear heat, cool the blood, and resolve toxicity. Although QUE exhibits a broad spectrum of pharmacological activities, its specific role in flap survival remains unclear.
    AIM OF THE STUDY: The purpose of this study was to assess QUE's effectiveness in increasing skin flap survival and to clarify underlying mechanisms.
    MATERIALS AND METHODS: Use bioinformatics to identify the key mechanisms involved in the IRI process. On the dorsal surface of Sprague-Dawley rats, a modified McFarlane flap model was created. The rats were administered control, positive control, QUE-L (50 mg/kg/d), QUE-H (100 mg/kg/d), and QUE-I (QUE + EX527) groups. Flap survival area, blood perfusion, histopathological changes, oxidative stress markers, LDH release, and the expression of proteins related to inflammation, pyroptosis, and mitophagy were evaluated. In vitro experiments were performed in HUVECs subjected to OGD/R, and SIRT1 was further silenced by siRNA to verify the involvement of SIRT1-related signaling pathways.
    RESULTS: The bioinformatics analysis indicates that mitophagy and pyroptosis are the key pathways regulating the survival of the skin flap. QUE treatment significantly improved flap survival and blood perfusion. It attenuated oxidative stress, reduced neutrophil infiltration, and downregulated pro-inflammatory cytokines. In vivo experiments showed that QUE suppressed NF-κB/NLRP3-mediated pyroptosis by activating SIRT1. Concurrently, QUE activated the SIRT1/PINK1/Parkin pathway to enhance mitophagy. In vitro, QUE exerted similar regulatory effects on pyroptosis- and mitophagy-related proteins in OGD/R-treated HUVECs, whereas SIRT1 knockdown partially abolished these effects, further confirming the essential role of SIRT1 in mediating the protective effects of QUE. These protective effects were also partially reversed by EX527 in vivo.
    CONCLUSION: QUE promotes skin flap survival by mitigating pyroptosis via the SIRT1/NF-κB/NLRP3 pathway, while concurrently enhancing mitophagy through the SIRT1/PINK1/Parkin axis, thereby offering a novel therapeutic candidate for preventing flap necrosis.
    Keywords:  Ischemia-reperfusion injury; Mitophagy; Pyroptosis; Quercetin; ROS; Skin flap
    DOI:  https://doi.org/10.1016/j.jep.2026.121525
  39. Kidney Blood Press Res. 2026 Mar 17. 1-18
    Nobiletin from Xiaoyu Xiezhuo Decoction: Restoring Mitochondrial Dynamics and Alleviating Renal Ischemia-Reperfusion Injury via M1 Macrophage Modulation.
    Yuan Yuan, Jing Huang, Yinchao Zhou, Zhibo Weng, Yiru Weng, Zhouzhou Dong.
       INTRODUCTION: There have been reports that the traditional Chinese medicine formula Xiaoyu Xiezhuo Decoction (XYXZD) protects against kidney damage. Its possible mechanisms in renal ischemia-reperfusion damage (IRI) are yet unknown, though. Investigating XYXZD's function and possible therapeutic effects on renal IRI is the goal of this investigation.
    METHODS: Liquid chromatography-mass spectrometry and network pharmacology were applied to identify key target genes associated with XYXZD and renal IRI. Molecular docking was employed to forecast the binding affinity of bioactive compounds to these targets. The effects of nobiletin (NOB) on macrophage polarization, inflammatory cytokine production, mitochondrial function, and oxidative stress were evaluated. The impact of NOB on HK-2 mitochondrial dynamics through M1 macrophage polarization was evaluated via the Cell Counting Kit-8 assay, enzyme-linked immunosorbent assay, western blotting, and transmission electron microscopy.
    RESULTS: Network pharmacology analysis identified matrix metalloproteinase-9 (MMP9) and poly(ADP-ribose) polymerase 1 (PARP1) as key regulatory factors linking macrophage polarization and mitochondrial function. Molecular docking revealed a strong binding affinity between NOB and MMP9. NOB reduced M1 macrophage polarization, along with the downregulation of pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-6 (IL-6). In HK-2 cells, NOB mitigated mitochondrial dysfunction by modulating M1 macrophage polarization, reducing reactive oxygen species (ROS) production, and restoring mitochondrial dynamics.
    CONCLUSION: By preventing M1 macrophage polarization, lowering inflammation, and reestablishing mitochondrial homeostasis in renal tubular epithelial cells, this study showed that NOB has renoprotective benefits. These results provided fresh perspectives on NOB's potential as a treatment for renal IRI.
    DOI:  https://doi.org/10.1159/000551502
  40. Anatol J Cardiol. 2026 Mar 17.
    Study of the Mechanism by Which Shenfu Injection Regulates Cardiomyocyte Hypertrophy Based on Dopamine Receptor D2-Mediated Mitochondrial Fission.
    Yuhan Zhang, Su Zhang, Tonghui Li, Xiaoyue Yang, Xiaoli Wang, Yuzhou Ye, Chen Sun.
       BACKGROUND: Shenfu Injection (SFI) has been widely utilized in the treatment of cardiovascular diseases in China for over 3 decades. In recent years, the therapeutic role of SFI in cardiovascular diseases has garnered significant attention. This study aims to elucidate the effects and possible mechanism of SFI using in vitro experiments and network pharmacology analysis.
    METHODS: Hypertrophy was induced by Angiotensin II (Ang II) treatment of HL-1 and isoprenaline (ISO) treatment of AC16. First, cell viability was detected upon different concentrations of SFI to screen the safe dosage of SFI. The effect of SFI on cell functions was evaluated by cell size, atrial natriuretic peptide/brain type natriuretic peptide (ANP/BNP) levels, mitochondrial morphology, and Ser616/Ser579 or Ser637/Ser600 levels. The potential targets of SFI against cardiomyocyte hypertrophy were predicted by network pharmacology, and then experimentally validated by qRT-PCR.
    RESULTS: Shenfu Injection treatment significantly reduced cell size, ANP expression, BNP expression, and mitochondrial injury compared to Ang and ISO groups (P < .001). Western blot analysis showed that SFI decreased the expression of Dynamin-related protein 1 (Drp1) phosphorylation at Ser616/Ser579 and increased the expression of Drp1 phosphorylation at Ser637/Ser600 in Ang- and ISO-induced cells. Network pharmacology analysis and cell experiments showed SFI decreased dopamine receptor D2 (DRD2) and increased protein kinase A levels in induced cardiomyocytes.
    CONCLUSION: In summary, the findings demonstrate that SFI may alleviate cardiomyocyte hypertrophy by targeting DRD2 and inhibiting mitochondrial fission. #Yuhan Zhang and Su Zhang contributed equally to this work.
    DOI:  https://doi.org/10.14744/AnatolJCardiol.2026.5425
  41. Poult Sci. 2026 Mar 13. pii: S0032-5791(26)00413-X. [Epub ahead of print]105(6): 106786
    Effect of yeast selenium on autophagy and PINK1/Parkin expression in Diquat-induced chicken liver and kidney cells.
    Yangshan Jin, Xiangyuan Cheng, Yachao Tan, Jie Luo, Ben Liu, Mingcan Wang, Yiping Wang.
      (Objective) This study aims to explore the effect of yeast selenium on alleviating autophagy and PINK1/Parkin expression in chicken liver and kidney cells induced by diquat. (Method) A total of 120 180-day-old Kangle Yellow chickens were randomly divided into 4 groups (5 replicates per group, 6 chickens per replicate): control group (A, basal diet + 15 mg/kg 0.9% normal saline), Diquat group (B, basal diet + 15 mg/kg diquat), Diquat + Se group (C, basal diet + 0.5 mg/kg yeast selenium + 15 mg/kg diquat), and selenium group (D, basal diet + 0.5 mg/kg yeast selenium + 15 mg/kg 0.9% normal saline). After a one-week adaptive feeding period, the experiment was conducted, and liver and kidney tissues were collected at the end. Immunohistochemistry, Western blotting, and real-time fluorescence quantitative PCR techniques were used to detect the mRNA and protein expression levels of LC3B, PINK1, and Parkin. (Result) The results showed that diquat significantly increased the mRNA and protein expression levels of LC3B, PINK1, and Parkin in chicken liver and kidney tissues (P < 0.05). The Diquat + Se group significantly reduced this trend, and there was no significant difference between the selenium group and the control group. Immunohistochemical results indicated that yeast selenium alleviated the overexpression and distribution of LC3B, PINK1, and Parkin in chicken liver and kidney induced by diquat. (Conclusion) Therefore, yeast selenium can alleviate diquat-induced autophagy in chicken liver and kidney cells, and the mechanism may be related to the PINK1/Parkin mitochondrial autophagy pathway.
    Keywords:  Chicken; Diquat; Mitophagy; PINK1/Parkin; Yeast selenium
    DOI:  https://doi.org/10.1016/j.psj.2026.106786
  42. Front Immunol. 2026 ;17 1630969
    Ironing out COPD: ferroptosis-driven immune dysregulation, metabolic rewiring, and precision therapeutic opportunities.
    Feng-Xian Ni, Hui-Hui Chen, Ze-Bo Jiang, Dong-Hui Huang.
      Chronic obstructive pulmonary disease (COPD) is a global health crisis driven by oxidative stress and immune dysregulation. Emerging evidence positions ferroptosis-an iron-dependent cell death driven by iron-catalyzed peroxidation of esterified polyunsaturated fatty acids (PUFAs) in membrane phospholipids-as a pivotal mediator of COPD pathogenesis. This review synthesizes cutting-edge insights into how cigarette smoke (CS) induces mitochondrial fission (via dynamin-related protein 1 (DRP1) phosphorylation) to exacerbate ferroptosis, potentially by enhancing lipid droplet (LD)-mitochondria contact sites and promoting lipid peroxidation in airway epithelial cells. This review further elucidates the complex and context-dependent role of nuclear factor erythroid 2-related factor 2 (Nrf2). While Nrf2 signaling is often suppressed globally in COPD lungs, its dysfunction in macrophages may paradoxically promote ferritinophagy-mediated iron retention through nuclear receptor coactivator 4 (NCOA4), overwhelming ferroprotein (FPN)-mediated iron export and unintentionally fueling ferroptosis. Clinically, plasma malondialdehyde (MDA)-a byproduct of lipid peroxidation-serving as a biomarker of oxidative stress severity, with elevated levels correlating with accelerated lung function decline in COPD patients. Therapeutically, promising targeted strategies are highlighted, such as inhaled exosomes loaded with liproxstatin-1, which can selectively inhibit pulmonary ferroptosis without inducing system immunosuppression. By bridging molecular mechanisms to therapeutic innovation, this review outlines a roadmap for precision medicine in COPD, focusing on the ferroptosis-immune axis to disrupt the self-perpetuating cycle of inflammation and tissue damage.
    Keywords:  COPD; ferroptosis; immune-metabolic crosstalk; lipid peroxidation; mitochondrial dynamics; precision inhalation therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1630969
  43. Free Radic Biol Med. 2026 Mar 13. pii: S0891-5849(26)00226-1. [Epub ahead of print]249 453-468
    Extracellular vesicle-mediated transcellular mitophagy as a modulatory target for moderate hyperoxia-induced alveolar developmental arrest in bronchopulmonary dysplasia.
    Yifan Sun, Tengfei Wang, Yun Yang, Rui Wang, Bowen Zhu, Jinya Wang, Gaoli Liang, Wei Peng, Na Zhang, Xirong Guo, Xingyun Wang.
      Oxygen therapy is required for the survival of premature infants with respiratory distress, yet hyperoxia exposure is a major contributor to alveolar developmental arrest in bronchopulmonary dysplasia (BPD). Despite the recognized role of fibroblasts in lung development, their functional contributions to the alveolar niche under hyperoxia remain poorly defined. Here, we profiled the involvement of fibroblasts using a BPD model induced by moderate hyperoxia (60% oxygen). Single-cell RNA sequencing (scRNA-seq) revealed that fibroblasts transitioned toward a disease-associated phenotype and exhibited enhanced communication with type II alveolar epithelial cells (AEC IIs) under moderate hyperoxia. Furthermore, activated fibroblasts increased the susceptibility of AEC IIs to hyperoxia via extracellular vesicles (EVs). These EVs were enriched with mitochondrial components, particularly the outer mitochondrial membrane (OMM) protein VDAC1. OMM-enriched EVs inhibited BNIP3-dependent mitophagy initiation in AEC IIs via VDAC1-GCN2 complex formation, leading to autophagic flux blockade and mitochondrial dysfunction. Inhibition of fibroblast-derived EV release using GW4869 or administration of human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs attenuated hyperoxia-induced AEC II dysfunction and alveolar structural impairment. Taken together, our findings identify a fibroblast-epithelial communication mechanism that impairs mitochondrial homeostasis and leads to alveolar developmental arrest, highlighting a promising therapeutic target for BPD.
    Keywords:  Alveolar developmental arrest; Fibroblast-derived extracellular vesicles; Mitochondrial transfer; Mitophagy; Outer mitochondrial membrane
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.035
  44. Zhonghua Xue Ye Xue Za Zhi. 2026 Feb 14. 47(2): 130-138
    [A preliminary study on the role of platelet mitochondria in the proliferation and metabolism of multiple myeloma cells].
    L Y Zhang, Y H Xiang, Y Y Li, J Zhang.
      Objective: To analyze platelet (PLT) characteristics and mitochondrial features in patients with multiple myeloma (MM) , and to investigate the impact of PLT mitochondrial respiration on MM cell proliferation, metabolism, and mitochondrial dynamics. Methods: Peripheral blood was collected from healthy volunteers and newly diagnosed MM (NDMM) patients at Sichuan Provincial People's Hospital between January 2020 and December 2023, and PLTs were isolated. PLT activation and mitochondrial reactive oxygen species (ROS) levels were assessed by scanning and transmission electron microscopy and flow cytometry. Serum levels of PLT-related factors were measured by enzyme-linked immunosorbent assay (ELISA) . MM cell lines (RPMI 8226 and U266) were co-cultured with untreated PLTs from healthy volunteers or with PLTs pretreated with rotenone or oligomycin. MM cell proliferation was assessed by the CCK-8 assay. mRNA expression of metabolism- and mitochondrial dynamics-related genes in MM cells was quantified by real-time quantitative PCR (qPCR) . Drp1 and phosphorylated Drp1 were analyzed by Western blot. Results: Compared with healthy volunteers, MM patients showed increased expression of the PLT activation marker CD41/CD61 [ (2.10 ± 1.15) % vs (0.22 ± 0.19) % , P=0.048], decreased CD42b expression [ (52.80 ± 8.73) % vs (74.58 ± 5.11) % , P=0.020], and elevated mitochondrial ROS levels in PLTs (150.50 ± 17.79 vs 62.45 ± 21.34, P=0.001) . Serum factor analysis showed reduced levels of interleukin-34 (IL-34) and platelet factor 4 (PF4) and increased levels of basic fibroblast growth factor (bFGF) , insulin-like growth factor 1 (IGF-1) , IL-6, P-selectin, platelet-derived growth factor (PDGF) , and transforming growth factor β1 (TGF-β1) in MM patients (all P<0.05) , whereas vascular endothelial growth factor (VEGF) levels did not differ significantly (P=0.086) . In vitro co-culture experiments showed that co-culture with PLTs for 48 h promoted MM cell proliferation, whereas PLTs pretreated with rotenone or oligomycin lost this pro-proliferative effect (all P<0.001) . qPCR showed that co-culture increased mRNA expression of the metabolism-related genes citrate synthase (CS) and lactate dehydrogenase A (LDHA) and the mitochondrial dynamics related genes dynamin-1-like protein (DNM1L) and mitochondrial fission 1 (FIS1) in MM cells (all P<0.05) . Pretreatment with the Drp1 inhibitor Mdivi-1 inhibited DNM1L mRNA expression in MM cells (0.75 ± 0.16 vs 1.00 ± 0.09, P=0.002) ; this inhibition was reversed by subsequent co-culture with PLTs (1.02 ± 0.13 vs 0.75 ± 0.16, P=0.007) . Western blot analysis showed that co-culture with PLTs increased p-Drp1 (Ser616) protein levels in U266 cells (P<0.05) . Conclusion: In vitro experiments suggest that PLTs and their mitochondrial respiratory function may be involved in regulating MM cell proliferation, metabolic reprogramming, and mitochondrial dynamics. However, their relevance and applicability in vivo and in clinical practice require further validation in additional preclinical and clinical studies.
    Keywords:  Metabolic reprogramming; Mitochondrial dynamics; Mitochondrial respiration; Multiple myeloma; Platelets
    DOI:  https://doi.org/10.3760/cma.j.cn121090-20250616-00278
  45. Sci Rep. 2026 Mar 20.
    Thioredoxin protects against diabetic hearing loss by regulating TOMM22 mediated mitochondrial autophagy in hair cells and inhibiting microglial M1 polarization.
    Shiwen Zhong, Meng Xu, Quanxiang Wang, Sifan Wang, Xiang Li, Yan Guo, Hui Kong.
      
    Keywords:  Diabetic hearing loss; Microglial polarization; Mitochondrial autophagy; Thioredoxin
    DOI:  https://doi.org/10.1038/s41598-026-44909-3
  46. Exp Eye Res. 2026 Mar 16. pii: S0014-4835(26)00132-6. [Epub ahead of print] 110976
    Nrf2 attenuates epithelial-mesenchymal transition of lens epithelial cells in fibrotic cataract via PINK1-mediated mitophagy.
    Lijun Wang, Xin Hu, Bo Zhao, Yang Huang, Yao Zhang, Jianhao Bai, Wanru Zhou, Haiying Jin.
      Oxidative stress plays a critical role in lens fibrosis, and nuclear factor erthroid 2-related factor 2 (Nrf2) is a key antioxidant transcription factor. This study investigates the specific role and underlying mechanism of Nrf2 in fibrotic cataract using in vitro and in vivo models. An in vitro model of fibrotic cataract was established by treating lens epithelial cells (LECs) with TGF-β2 (10 ng/mL). We found that oxidative stress participated in epithelial-mesenchymal transition (EMT) in LECs, concomitant with reduced Nrf2 expression. Moreover, Nrf2 overexpression alleviated oxidative stress, suppressed cell migration, and inhibited EMT. The anterior capsule injury method was utilized to establish a murine model of anterior subcapsular cataract (ASC). In the ASC model, LECs displayed increased oxidative stress and reduced Nrf2 expression. Consistently, Nfe2l2-knockout mice exhibited exacerbated lens fibrosis and higher oxidative stress levels compared to wild-type controls. The mechanism of Nrf2 in lens fibrosis was then investigated by RNA sequencing and validated in LECs in vitro. Our data revealed that Nrf2 promoted PINK1-mediated mitophagy, through which it attenuated oxidative stress and suppressed EMT in LECs. To elucidate how Nrf2 regulates PINK1, the Nrf2 binding sites in the promoter region of PINK1 were predicted using the JASPAR database and subsequently confirmed by both chromatin immunoprecipitation and electrophoretic mobility shift assay. We found that Nrf2 directly binds to the PINK1 promoter to drive its transcription. Collectively, our study suggests that Nrf2 activation mitigates lens fibrosis by promoting PINK1-dependent mitophagy, identifying the Nrf2-PINK1 axis as a potential therapeutic target.
    Keywords:  Epithelial-mesenchymal transition; Fibrotic cataract; Lens epithelial cells; Mitophagy; Nrf2; Oxidative stress
    DOI:  https://doi.org/10.1016/j.exer.2026.110976
  47. J Physiol Biochem. 2026 Mar 17. pii: 26. [Epub ahead of print]82(1):
    Aerobic exercise improve physical endurance and muscle function by ameliorating oxidative stress and modulating mitochondrial dynamics in aged skeletal muscle.
    Fengting Zheng, Jiawei Zhou, Yangfan Cao, LuYi Lin, Wenxin Wang, Liang Zhang, Wei Li, Ting Li, Lifeng Wang.
      
    Keywords:  Aerobic exercise; Aging; Mitochondria; Oxidative stress; Skeletal muscle
    DOI:  https://doi.org/10.1007/s13105-026-01146-6
  48. Nat Commun. 2026 Mar 16.
    DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.
    Yanhao Lai, Rebecca Z Fan, Harry J Brown, Said S Salehe, Ethan K Tieu, Kim Tieu.
      Neuroinflammation is a major pathogenic mechanism underlying neurodegenerative diseases. Understanding how neuroinflammation is regulated is critical to therapeutic development. Here, we report that dynaminrelated protein 1 (DRP1), well-recognized for its role in mitochondrial fission, also functions as a transcription factor that regulates neuroinflammation. Using multiple inflammatory models, we demonstrate that upon stimulation with pro-inflammatory lipopolysaccharides (LPS), DRP1 translocates from the cytosol to the nucleus, where it binds to the promoter region of Rela (encoding NF-κB p65) to activate its gene products and other downstream inflammatory cytokines. Our data further reveal a significant role of the proinflammatory lipocalin-2 in the brain. In combination, this study identifies a previously unrecognized function of DRP1 in mediating neuroinflammation via the NF-κB-lipocalin-2 axis and highlights DRP1-mediated pathways as potential therapeutic targets for neurodegenerative and other inflammation-related diseases.
    DOI:  https://doi.org/10.1038/s41467-026-70780-x
  49. Nat Commun. 2026 Mar 14.
    MFF budding from mitochondria regulates melanosome size and maturation.
    Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.
      Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70572-3
  50. Front Pharmacol. 2026 ;17 1723748
    Current perspectives on circadian regulation of mitochondrial dynamics in mood disorders and perioperative stress.
    Florencia Verbal, Nicole Rubilar, Ana M Marileo, Humberto Fierro, Oscar Guillermo Ramirez-Molina, Araceli Pinto-Leon, Gonzalo E Yevénes, Jorge Fuentealba, Jessica Panes-Fernández.
      Mitochondria act as a central integrative hub for oxidative phosphorylation, calcium homeostasis and metabolic signaling, reflecting their evolutionary origin from an α-proteobacterial endosymbiont. Although nearly 90% of their ancestral genes have been transferred to the nuclear genome, their role extends far beyond energy production. Emerging evidence positions mitochondria as active modulators of stress responses, which we term the "Mito-Mood Hypothesis." This framework proposes that mitochondrial dynamics actively regulate gene expression and signaling, thereby shaping vulnerability to mood disorders such as depression, dysthymia, and seasonal affective disorder. Consistent with this view, patients with major depressive disorders show altered expression of nuclear-encoded mitochondrial genes, linking bioenergetics directly to psychiatric risk. We further discuss how oxidative phosphorylation (OXPHOS) modulates neurotransmitter cycles and how mitohormesis-adaptive responses to mild mitochondrial stress-can enhance resilience and cognition. Beyond psychiatry, mitochondrial vulnerability manifests in clinical settings: patients with mitochondrial diseases face elevated anesthetic risk, where agents such as propofol or volatile anesthetics may precipitate life-threatening metabolic crises. Collectively, these insights underscore mitochondria as central regulators of human health and highlight novel therapeutic opportunities bridging mood disorders and perioperative medicine.
    Keywords:  circadian cycle; mitochondria; mitochondrial dynamics; mood disorders; neurotransmission; oxidative phosphorylation; perioperative stress
    DOI:  https://doi.org/10.3389/fphar.2026.1723748
  51. Cell Death Dis. 2026 Mar 21.
    Oncogenic GPRIN1 sustains proliferation and mitochondrial homeostasis via dual‑layer CDK1-PI3K/Akt signalling in gallbladder cancer.
    Chang Xu, Zijun Gong, Xiaojian Ni, Lingxi Nan, Wentao Sun, Houbao Liu, Xuanming Luo, Min Li.
      Novel therapeutic targets are urgently needed for the aggressive malignancy gallbladder cancer (GBC). G-protein regulated inducer of neurite outgrowth 1 (GPRIN1) is a candidate oncogene, but its function in GBC and its connection to mitochondrial dysregulation remain unknown. In this study, we analyzed clinical samples and demonstrated that GPRIN1 is significantly upregulated in GBC tissues, where its high expression correlates with advanced clinical stage and poor patient prognosis. Functional assays revealed that GPRIN1 is essential for GBC progression, driving cell cycle advancement and maintaining mitochondrial homeostasis. By integrating proteomic and molecular analyses, our study delineates a bimodal and hierarchical regulatory program commanded by GPRIN1 to ensure the robust activation of CDK1. In the nucleus, GPRIN1 functions as a transcriptional co-activator, scaffolding and stabilizing E2F1 to drive CDK1 expression. In parallel, it functions at a post-translational level to directly promote CDK1 activation by physically steering the kinase away from its inhibitor, MYT1, and toward its activator, Cdc25C. This dual-pronged regulation culminates in hyperactivated CDK1, which in turn unleashes a PI3K-Akt signaling cascade to couple relentless cell proliferation with the necessary mitochondrial support. Importantly, genetic or pharmacological disruption of this GPRIN1-CDK1-PI3K/Akt axis completely abrogated tumorigenesis in vitro and in vivo. Taken together, these results reveal GPRIN1 as a master regulator whose dual transcriptional and post-translational control of CDK1 integrates cell cycle progression with mitochondrial homeostasis, suggesting that targeting GPRIN1 may represent a highly specific therapeutic strategy in this lethal malignancy.
    DOI:  https://doi.org/10.1038/s41419-026-08550-2
  52. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70256
    IL-15 Links Muscle-Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy.
    Yin Li, Jialing Rao, Weiyan Lai, Yuxiang Sun, Hongchun Lin, Jun Zhang, Zengchun Ye, Zhaoyong Hu, Hui Peng.
       OBJECTIVES: High glucose induces mitochondrial dysfunction in podocytes, contributing to the development of diabetic nephropathy (DN). There is increasing evidence that muscles play a protective role by secreting myokines into the kidneys. Here, we investigated how skeletal muscle influences podocyte health via muscle-kidney crosstalk.
    METHODS: To increase myokine release, we overexpressed PGC-1α specifically in skeletal muscle (mPGC-1α) and crossed these mice with db/m mice to generate diabetic mPGC-1α:db/db mice. In parallel, db/db mice were treated intraperitoneally with recombinant murine interleukin-15 (IL-15). Mechanistic studies were performed using isolated primary podocytes and cultured podocyte cell lines.
    RESULTS: Compared with db/db controls, mPGC-1α:db/db mice exhibited reduced urinary albumin excretion (p < 0.001), mesangial matrix expansion (p < 0.001), glomerular basement membrane thickening (p < 0.001) and urinary podocin excretion (p < 0.001), along with increased podocyte number (p < 0.001). Podocytes from mPGC-1α:db/db mice showed higher expression of Nephrin and COX IV (p < 0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (p < 0.05). Skeletal muscle from mPGC-1α:db/db mice displayed elevated IL-15 mRNA (p < 0.05) and protein (p < 0.01) levels, accompanied by increased plasma IL-15 concentrations (p < 0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, p < 0.05), ATP-coupled respiration (p < 0.05) and maximal respiration (p < 0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (p < 0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (p < 0.05).
    CONCLUSIONS: Skeletal muscle-derived IL-15 mediates renal protection by maintaining mitochondrial fusion in podocytes during DN progression. Targeting this pathway may offer a therapeutic strategy to preserve kidney function and slow progression to end-stage renal disease.
    Keywords:  diabetic nephropathy; interleukin‐15; mitochondria; optic atrophy 1; podocyte
    DOI:  https://doi.org/10.1002/jcsm.70256
  53. J Orthop Translat. 2026 Jan;56 101036
    Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression.
    Chang Yang, Jin Ke, Qiongdong Xu, Wei Dong, Wenqian Yu, Yan Wang, Jiawei Wang.
       Objective: Emerging evidence has shown that inflammatory synovial macrophage and anabolism-impaired chondrocytes play essential roles in osteoarthritis (OA). The present work aims at uncovering the pathogenic mechanism of how the damage-associated molecular patterns (DAMPs) released from inflammatory synovial macrophage promote extracellular matrix (ECM) degradation of chondrocytes and developing feasible strategies to counter its detrimental effects.
    Methods: We identified pyroptosis of synovial macrophages in the synovium of OA human and mouse. The effect and mechanism of mitochondrial DNA (mtDNA) released from pyroptotic synovial macrophage in ECM degradation of chondrocytes and cartilage degeneration was further explored in cellular and animal models. Finally, the ameliorative effect of folic acid-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles in OA was elucidated by in vivo experiments.
    Results: Mitochondrial dysfunction in synovial macrophages leads to the release of mtDNA into the cytoplasm, which promotes macrophage pyroptosis, thereby facilitating extracellular release of mtDNA and creating an inflammatory microenvironment unfavorable to cartilage in OA. DDIT3 deficiency inhibits mtROS production by enhancing PINK1/Parkin-dependent mitophagy, which constraining the mtDNA release into the cytoplasm. The decreased cytosolic mtDNA, in turn, dampens macrophage pyroptosis. In vivo, DDIT3 deficiency significantly alleviates synovial inflammation and cartilage degeneration in OA progression, and targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles mimics the protective effects of DDIT3 deficiency against OA progression.
    Conclusions: Our findings identified the pathological role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA, and demonstrated the efficacy of using folic acid-modified PLGA nanoparticles as a delivery for OA treatment.
    The translational potential of this article: This study highlights the pivotal role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA. Targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles might serve as a potential therapeutic target for alleviating cartilage degeneration in OA.
    Keywords:  Cartilage degeneration; DDIT3; Osteoarthritis; Pyroptotic macrophages; mtDNA release
    DOI:  https://doi.org/10.1016/j.jot.2025.101036
  54. iScience. 2026 Mar 20. 29(3): 115068
    Lipid overload triggers PERK-ALCAT1-mediated mitophagy failure in hepatocytes.
    Wenli Zhao, Yangguang Bao, Lei Liu, Yixin Gu, Xuran Liu, Óscar Monroig, Tingting Zhu, Peng Sun, Douglas R Tocher, Qicun Zhou, Min Jin.
      Mitochondria-associated endoplasmic reticulum membranes (MAMs), contact sites between the endoplasmic reticulum (ER) and mitochondria, are critical for calcium signaling and lipid metabolism. However, how MAMs contribute to mitochondrial dysfunction in lipid overload-induced fatty liver remains unclear. Here, using teleost fish as a model, we showed that high-fat diets promoted the aggregation of PERK and ALCAT1 at MAMs, causing mitochondrial calcium overload and membrane depolarization, and impairing PINK1/Parkin-dependent mitophagy. Acetylation of PERK at lysine 388 facilitated its binding to ALCAT1, while activation of SIRT1 by resveratrol induced site-specific deacetylation of PERK, disrupted PERK-ALCAT1 interaction, and restored mitophagy and mitochondrial integrity. These findings revealed a conserved SIRT1-PERK-ALCAT1 signaling axis linking ER stress to mitophagy failure and identified a potential nutritional intervention to alleviate lipid-induced hepatic injury. This mechanism is conserved across species and offers a basis for controlling metabolic dysfunction-associated steatotic liver disease (MASLD) in teleosts and potentially other vertebrate systems.
    Keywords:  Lipid; Metabolic flux analysis; Molecular network
    DOI:  https://doi.org/10.1016/j.isci.2026.115068
  55. CNS Neurol Disord Drug Targets. 2026 Mar 11.
    Precision Neurodegeneration: Integrating Molecular Mechanisms, Biomarkers, and Targeted Therapeutics.
    Guizhen Lyu, Dongbing Li.
      Neurodegenerative diseases (NDDs) such as Alzheimer's, Parkinson's and related tauopathies are converging pathologies driven by protein misfolding, maladaptive microglial responses, epigenetic dysregulation and metabolic failure. Here we synthesize recent mechanistic advances that are already reshaping precision diagnostics and therapeutics. Cryo-EM has resolved distinct tau and α-synuclein strains, which correlate with discrete clinical phenotypes, enabling the development of conformation-selective PET tracers and the use of plasma p-tau217/NfL ratios to classify patients within the A/T/N framework with >90% accuracy relative to CSF or amyloid-PET. Single-cell transcriptomics have delineated disease-associated microglia (DAM) and NLRP3 inflammasome activation as therapeutic nodes; small-molecule TREM2 agonists and CSF1R modulators are entering phase II trials, while TSPO-PET and plasma GFAP provide pharmacodynamic read-outs. Epigenetic enhancer-promoter rewiring and DNA methylation clocks are emerging as reversible drivers of synaptic failure. CRISPR-dCas9-based epigenetic editors or brain-penetrant HDAC/HDAC6 inhibitors restore memory in transgenic mice, with first-in-human safety studies currently being planned. Metabolic interventions-including ketone esters, time-restricted feeding, and medium-chain triglycerides- restore mitochondrial quality control via PINK1-Parkin-mediated mitophagy, and synergize with immunotherapy to reduce amyloid and tau pathology in parallel. Integration of blood-based A/T/N algorithms with patient-specific genetics now enables adaptive platform trials that assign individuals to anti-amyloid, anti-tau, microglial, or metabolic arms based on real-time biomarker profiles. We conclude that mechanistically informed, multi-modal precision medicine is no longer aspirational for NDDs but is being operationalized in ongoing clinical pipelines.
    Keywords:  Proteinopathies; blood biomarkers; epigenetic therapy; microglial reprogramming; mitophagy enhancers; precision medicine.
    DOI:  https://doi.org/10.2174/0118715273435428251202075956
  56. Life Sci. 2026 Mar 16. pii: S0024-3205(26)00135-9. [Epub ahead of print] 124326
    Decoding the mitochondrial metabolic engine for tumor metastasis and clinical therapeutic opportunities.
    Zixin Ye, Pai Zeng, Yujie Kang, Wenbin Liu, Hongde Li, Xiangjian Luo.
      Mitochondrial metabolic reprogramming, a recognized cancer hallmark, plays a pivotal role in malignant progression. These organelles serve as the cell's metabolic hubs, coordinating essential processes including OXPHOS, the TCA cycle, and FAO. This review delineates the significant alterations and functions of mitochondrial reprogramming in tumor metastasis, encompassing mechanisms such as energy restructuring and EMT promotion. Furthermore, mitochondrial dynamics exert profound effects on mitochondrial morphology and function, thereby reprogramming cellular metabolism to facilitate tumor metastasis. This review also explores the substantial mitochondrial metabolic changes within the TME and their interplay in optimizing energy utilization, forming the pre-metastatic niche, and sculpting an immunosuppressive milieu. Finally, it provides a critical evaluation of current and emerging therapeutic strategies targeting mitochondrial metabolism, including their use in combination regimens and the application of novel nano-delivery platforms.
    Keywords:  Metastasis; Mitochondrial dynamics; Mitochondrial metabolism reprogramming; TME; Targeted therapy
    DOI:  https://doi.org/10.1016/j.lfs.2026.124326
  57. Cell Mol Life Sci. 2026 Mar 16.
    Identification of alterations of immunometabolism associated with Pompe disease.
    Helena Costa-Verdera, Marco Gargaro, Umut Cagin, Giorgia Manni, Giulia Scalisi, Philippe Veron, Estevão Carlos Silva Barcelos, Benedetta Pieroni, Giulia Mencarelli, Doriana Ricciuti, Ivan Nemazanyy, Peggy Sanatine, Laetitia van Wittenberghe, Pascal Laforêt, David-Alexandre Gross, Giuseppe Ronzitti, Francesca Fallarino, Federico Mingozzi.
      
    Keywords:  Autophagy; Enzyme replacement therapy; Immunogenicity; Immunometabolism; Mitophagy; T cells
    DOI:  https://doi.org/10.1007/s00018-026-06135-y
  58. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2529914123
    SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial integrity is central to energy homeostasis, particularly in brown adipose tissue where dynamic remodeling fuels thermogenesis. Two major proteostatic systems, the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy, have been shown to intersect in vitro, but their physiological coordination in metabolically active tissues remains unclear. Here, we demonstrate that ERAD and autophagy act in synergy to safeguard mitochondrial integrity in brown adipocytes. Using various adipocyte-specific knockout (KO) mouse models and high-resolution ultrastructural 2D and 3D imaging, we show that simultaneous deletion of Sel1L and Atg7 (double KO, DKO) causes striking mitochondrial abnormalities under room temperature, absent in single KO or Sel1L-Ire1a double knockout mice. DKO adipocytes accumulate hyperfused megamitochondria extensively penetrated by ER tubules, accompanied by ER expansion, excessive ER-mitochondrial contacts, and impaired thermogenesis. These findings reveal that SEL1L-HRD1 ERAD and autophagy cooperate, rather than act redundantly, to maintain mitochondrial integrity in brown fat, uncovering a previously unrecognized mitochondrial surveillance mechanism based on ERAD-autophagy crosstalk.
    Keywords:  3D FIB-SEM; ER–mitochondrial contacts; brown adipocytes; megamitochondria; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2529914123
  59. J Adv Res. 2026 Mar 16. pii: S2090-1232(26)00250-X. [Epub ahead of print]
    A Rsv@HMnO2-HA nanozyme for AKI therapy via targeting inflammatory storm and activating SIRT1/PGC-1α to restore mitochondrial homeostasis.
    Jiaxin Su, Lingcheng Wu, Huiru Zhu, Haoru Wang, Xiaoya He, Bing Liang, Jinhua Cai.
       INTRODUCTION: Acute kidney injury (AKI) is a devastating global health burden. Its pathogenesis, particularly in ischemia/reperfusion (I/R) injury, centers on a vicious cycle between a reactive oxygen species (ROS)-driven inflammatory storm and severe mitochondrial dysfunction in renal tubular cells. While activation of the SIRT1/PGC-1α pathway is a promising therapeutic target for mitochondrial recovery, its potent agonist resveratrol (Rsv) suffers from poor bioavailability, and monotherapy fails to address the concomitant inflammatory pathology.
    OBJECTIVE: This study aimed to develop a kidney-targeted theranostic nanoplatform that synergistically breaks this pathological cycle. We hypothesized that a nanoplatform co-delivering Rsv and a ROS-scavenging component could concurrently suppress inflammation via direct ROS elimination and restore mitochondrial homeostasis via SIRT1/PGC-1α activation, with integrated magnetic resonance imaging (MRI) capability for monitoring.
    METHODS: We engineered a theranostic nanoplatform designated Rsv@HMnO2-HA (HMRH NPs). The platform was constructed by loading Rsv into hollow mesoporous manganese dioxide (HMnO2) nanozymes, followed by surface coating with hyaluronic acid (HA) for active targeting to CD44 receptors over expressed on injured renal tubules. The system's physicochemical properties were thoroughly characterized. Its therapeutic efficacy and theranostic performance were systematically evaluated in a well-established murine model of renal I/R-induced AKI, using a combination of biochemical assays, histological analysis, molecular biology techniques, and in vivo MRI.
    RESULTS: HMRH NPs successfully accumulated in injured kidneys and disassembled in situ. The HMnO2 shell effectively scavenged excess ROS, attenuating the inflammatory response. The co-released Rsv activated the SIRT1/PGC-1α pathway, restored mitochondrial biogenesis, and improved cellular energy homeostasis. The released Mn2+ ions enabled clear T1-weighted MRI contrast, allowing real-time visualization of renal targeting and therapeutic progression.
    CONCLUSION: The results conclusively demonstrate that the HMRH NPs successfully implements a synergistic two-pronged therapeutic strategy. By co-delivering a ROS-scavenger and a mitochondrial-regenerative agent directly to the site of injury, the platform effectively disrupts the critical pathological crosstalk between inflammation and mitochondrial damage in AKI. This work presents a holistic, targeted, and image-guided nanomedicine strategy, offering a promising approach for the effective treatment and monitoring of AKI.
    Keywords:  Acute kidney injury; Hollow mesoporous manganese dioxide; Inflammatory storm; Mitochondrial homeostasis; Nanoplatform; Theranostics
    DOI:  https://doi.org/10.1016/j.jare.2026.03.029
  60. Free Radic Biol Med. 2026 Mar 17. pii: S0891-5849(26)00235-2. [Epub ahead of print]
    Corrigendum to "Melatonin improves spermatogenesis and alleviates oxidative stress in cryopreserved testicular tissue through suppression of the ROS/PINK1-Parkin mitophagy axis" [Free Radic. Biol. Med. 248 (2026) 238-254].
    Menghui Ma, Yanqing Li, Jintao Guo, Linyan Lv, Zhenhan Xu, Peigen Chen, Haicheng Chen, Junxian He, Wenlong Su, Haitao Zeng, Cong Fang, Xiaoyan Liang, Guihua Liu.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.044
  61. Prev Nutr Food Sci. 2026 Feb;pii: pnf.2025.231. [Epub ahead of print]31(1):
    Purslane (Portulaca oleracea L.) Extract Attenuates Obesity-Induced Inflammation and Enhances Mitochondrial Biogenesis via the miR-221/222 and AMPK/SIRT1 Axis in Rats.
    Gayoung Kim, Jungeun Kim, Mak-Soon Lee, Jumi Lee, Minji Kim, Miae Doo, Yangha Kim.
      Purslane (Portulaca oleracea L.) exhibits anti-inflammatory and antioxidant properties, but its role in regulating adipose tissue inflammatory microRNAs and mitochondrial biogenesis in skeletal muscle under high-fat diet (HFD) conditions remains unclear. This study aimed to evaluate the effects of purslane extract (PE) on HFD-induced inflammation and mitochondrial biogenesis, focusing on regulation of the miR-221/222 cluster in white adipose tissue (WAT) and the AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) axis in skeletal muscle. Male Sprague-Dawley rats were divided into four groups: normal chow diet, HFD, HFD+0.2% PE, and HFD+0.4% PE for 12 weeks. PE supplementation significantly reduced body weight gain, improved serum and hepatic lipid profiles, and decreased circulating inflammatory cytokines (P<0.05). In WAT, PE reduced expression of pro-inflammatory cytokines and M1 macrophage markers while increasing expression of a M2 marker. Additionally, PE inhibited phospho-nuclear factor-kappa B levels and suppressed miR-221/222 expression in WAT. In skeletal muscle, PE enhanced the expression of genes related to mitochondrial biogenesis and restored mitochondrial content. Furthermore, PE increased AMPK, total SIRT, and SIRT1 activities, supporting its role in improving mitochondrial function in skeletal muscle. These findings suggest that the beneficial effects of PE against HFD-induced obesity are mediated, at least in part, by suppression of the WAT miR-221/222 cluster and activation of the AMPK/SIRT1 axis in skeletal muscle, thereby alleviating inflammation and enhancing mitochondrial biogenesis.
    Keywords:  Portulaca; inflammation; microRNAs; mitochondria; obesity
    DOI:  https://doi.org/10.3746/pnf.2025.231
  62. Hepatology. 2026 Mar 16.
    Hepatic STEAP4 promotes liver regeneration by regulating lysosomal iron homeostasis and membrane integrity in acetaminophen-induced liver injury.
    Peng Cao, Mengwei Niu, Hualong Zhu, Chen Zhang, Hao Zhu, Hangfei Xu, Wanqing Liu, Hong-Min Ni, Wen-Xing Ding.
       BACKGROUND: Understanding the mechanisms behind liver repair in acetaminophen (APAP)-induced liver injury (AILI) is crucial for developing effective treatments. Six-transmembrane epithelial antigen of the prostate 4 (STEAP4) is a metalloreductase involved in iron regulation. The roles of STEAP4 and endolysosomal iron in liver regeneration in AILI remain unclear.
    METHODS: Alb Cre- Steap4flox/flox and liver-specific STEAP4 knockout (Alb Cre+ Steap4flox/flox, L-STEAP4 KO) mice were given APAP for different periods. Deferiprone (DFP) was administered with or after APAP. Biochemical and histological analyses were performed to examine iron homeostasis and liver injury.
    RESULTS: STEAP4 expression decreased in human AILI livers. APAP treatment lowered hepatic STEAP4 expression in mice. L-STEAP4 KO mice showed similar hepatocyte death and serum ALT levels between 6-24 hours but experienced delayed liver recovery at 48 hours after APAP compared to wild-type mice. Loss of STEAP4 led to iron buildup in endolysosomes, lysosomal membrane damage and the release of cathepsin B following APAP treatment, which was correlated with lower hepatic mTOR activity, impaired mitophagy, and reduced hepatocyte proliferation 48 hours after APAP. DFP restored mitochondrial and lysosomal functions, providing protection against AILI. Overexpressing STEAP4 or TFEB (a key regulator of lysosomal biogenesis) or posttreatment with DFP repaired lysosomal membranes and inhibited AILI in both wild-type and L-STEAP4 KO mice.
    CONCLUSIONS: STEAP4 is not essential during the early injury phase but plays a critical role in liver regeneration by maintaining lysosomal iron homeostasis and function after APAP overdose. Targeting STEAP4-mediated endolysosomal iron overload may open new therapeutic avenues for AILI.
    Keywords:  DILI; ferroptosis; hepatotoxicity; lysosome; mitophagy
    DOI:  https://doi.org/10.1097/HEP.0000000000001718
  63. Biochemistry (Mosc). 2026 Feb;91(2): 253-273
    Mitochondria "Shackled" by Mutant Huntingtin: Analysis of Morphological Alterations and Disruptions of Intracellular Transport.
    Vyacheslav I Pasko, Aleksandra S Churkina, Lilia D Belikova, Anton S Shakhov, Svetlana V Lavrushkina, Anton V Burakov, Alexandra N Bogomazova, Maria A Lagarkova, Irina B Alieva.
      Mitochondria are semi-autonomous, multifunctional organelles that supply cells with energy. They are highly dynamic structures, capable of moving, fusing, dividing, and forming branched networks. The number, density, and complexity of mitochondrial network are unique to each cell type and reflect cellular demands for ATP and other mitochondria-dependent metabolites. Mitochondrial dysfunction is a hallmark of many neurodegenerative diseases; however, the relationships between neurodegeneration and mitochondrial morphogenesis, intracellular localization, and dynamics remain incompletely understood. Interpretation and comparison of published data are complicated by the diversity of analytical approaches used to study mitochondrial behavior. In this research, we investigated the effects of a pathogenic mutation in the huntingtin protein (HTT), which causes Huntington's disease (HD), on mitochondrial morphology and motility, with particular emphasis on associated disruptions in the cytoskeletal organization. We performed a systematic evaluation of automated mitochondrial analysis tools and selected MiNA, TrackMate, and JACoP as the optimal platforms for quantitative assessment of the effects of mutant HTT (mHTT) on the mitochondrial morphology, motility, and interaction with cytoskeletal components and identification of specific disruptions directly related to HD pathogenesis. Our analysis revealed that mitochondria in mHTT-expressing cells are significantly shorter, more branched, and less motile than in control cells. Moreover, their interactions with microtubules and vimentin intermediate filaments are markedly altered. Together, these findings establish a link between HD and specific defects in the mitochondrial network, thus contributing to understanding cellular mechanisms of HD development, and suggest that mHTT disrupts the interaction of mitochondria with cytoskeletal components responsible for their movement and distribution in the cell, thereby negatively affecting mitochondrial motility and morphology.
    Keywords:  Huntington’s disease; huntingtin; mitochondrial dynamics; neurodegenerative diseases
    DOI:  https://doi.org/10.1134/S0006297925602850
  64. Acta Neuropathol Commun. 2026 Mar 19.
    LncRNA-HLX-2-7/HLX axis-dependent metabolic reprogramming drives cancer progression in group 3 medulloblastoma.
    Keisuke Katsushima, Yohei Sanada, David A Scott, Stacie Stapleton, George Jallo, Charles G Eberhart, Ranjan J Perera.
      
    Keywords:   Lnc-HLX-2-7/HLX ; Medulloblastoma; Metabolism; Mitochondrial biogenesis; Oxidative phosphorylation
    DOI:  https://doi.org/10.1186/s40478-026-02266-2
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