bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–10–05
fifty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.
  2. The molecular mechanisms of mitochondrial dynamics and mitophagy and their complex association with cancer drug resistance.
  3. Impacts of sarcopenia and resistance exercise training on mitochondrial quality control proteins.
  4. Mitigating effects of resveratrol on cold exposed-induced cardiac mitochondrial dysfunction and lipid metabolic disorder in broilers.
  5. The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
  6. Zn2 + alleviates ischemia/reperfusion injury in H9c2 cells by modulating mitochondrial biogenesis and dynamics via MCU.
  7. Three-dimensional human mucopolysaccharidosis IVA chondrocyte culture reveals significant impairments in the lysosomal-mitochondrial crosstalk.
  8. Research on the molecular mechanism of intervertebral disc degeneration caused by mitochondrial dysfunction.
  9. Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.
  10. Double-edged mitophagy: balancing inflammation and resolution in lung disease.
  11. Hederagenin exerts anti-tumor effects in pancreatic cancer by impairing DRP1 mediated-mitophagy via VDAC1-HK2-PINK1/PARKIN pathway.
  12. Astragalus polysaccharide enhances OGT-mediated O-GlcNAcylation to stabilize PINK1 to induce mitophagy in D-galactose treated C2C12 myoblasts.
  13. Polystyrene nanoplastics induce cognitive dysfunction and dendritic spine deterioration via excessive mitochondrial fission.
  14. ASIC1a Induces Excessive Mitophagy and PANoptosis of Chondrocyte by the Inhibition of SIRT3 Mitochondrial Translocation.
  15. BNIP3L/NIX-mediated mitophagy: Future directions in Alzheimer's disease.
  16. Changpu Yujin Tang mitigates tourette syndrome by enhancing mitophagy and suppressing NLRP3 inflammasome-mediated pyroptosis.
  17. Dynamin-Related Protein 1 and the NLRP3 Inflammasome in Parkinson's Disease: Mechanistic Insights and Therapeutic Opportunities.
  18. Exploring the connection between the Mitochondrial DNA and the Circadian Rhythm: Insights into Mitochondrial Biogenesis and its Dynamics.
  19. Activin A protects against lipopolysaccharide/TNF-α induced damage of dopaminergic neurons both in vivo and in vitro by regulating mitochondrial fusion.
  20. Dual activation of PPARα/γ by bezafibrate triggers PINK1/Parkin-Mediated mitophagy to enhance lenvatinib sensitivity in hepatocellular carcinoma.
  21. TET2 Deficiency Exacerbates Podocyte Injury and Mitophagy Disorder in Diabetic Nephropathy by Regulating M5C Methylation of Bcas3.
  22. Cross-regulatory mechanisms linking ferroptosis, epigenetics, and circadian rhythm to mitochondrial quality control in diabetic cardiomyopathy.
  23. Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
  24. Intratracheal Instillation of Silver Nanoparticles to Rats Induces Mitochondrial Fission and Aortic Damage: Protective Effect of Sodium Selenite.
  25. Study on the molecular mechanism of KPNA2 regulation of myocardial ischemia/delayed reperfusion injury through mitophagy.
  26. The synthetic cannabinoid THJ-2201 modulates mitochondrial activity and enhances mitochondrial recruitment to newly-forming neurites during neurodifferentiation of NG108-15 cells.
  27. Interconnectivity of mitochondrial protein biogenesis and quality control.
  28. Therapeutic Approaches Involving Mitochondria in the Treatment of Acute Kidney Injury.
  29. Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.
  30. Bone marrow mesenchymal stem cell-derived exosomes attenuate hepatic stellate cell activation through miR-223-3p-mediated mitophagy.
  31. Dehydrocostus lactone induces apoptosis and mitophagy in gastric cancer cells through the ROS-mediated mitochondrial pathway.
  32. Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway.
  33. Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review).
  34. TRAP1 inhibits KANSL3 acetylation to alleviate mitochondrial dysfunction by promoting mitophagy in cardiomyocytes under diabetic conditions.
  35. Rethinking post-sepsis syndrome: linking cellular dysfunction to the clinical picture.
  36. Cyclic mechanical stretching enhances mitophagy and oxidative stress resistance in adipose-derived stem cells via the Piezo1/ATP axis to accelerate wound healing.
  37. RSV-Induced Glutaric Acid Modulates Neuronal Mitochondrial Heterogeneity via the Lung-Brain Axis.
  38. AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease.
  39. FoxO1/PINK1/Parkin-dependent mitophagy mediates the chondroprotective effect of Guzhi Zengsheng Zhitong decoction in osteoarthritis.
  40. Licochalcone D Alleviates Radiation-Induced Intestinal Injury via SIRT3-Dependent Mitophagy: A Natural Phytochemical Strategy for Radioprotection.
  41. Propylparaben disrupts early embryonic development by causing oxidative stress-induced organelle dysfunction and actin zipper abnormality.
  42. ATP1B4 as a candidate upstream regulator of muscle atrophy in diabetic sarcopenia via PI3K/AKT/mTOR-mediated autophagy.
  43. HDAC3 mediates retinal endothelial cell metabolic reprogramming and angiogenesis.
  44. Bone remodeling stimulated by Wnt-mediated mitophagy regulated extracellular vesicles in subchondral bone contributes to osteoarthritis development.
  45. Mn-MIL-100@AKG alleviates intervertebral disc degeneration by regulating mitophagy.
  46. The healing power of natural gifts: How the natural herbaceous plants targeting mitophagy can reverse diabetic complications.
  47. CREB3L4 upregulates SIRT4 expression to increase GABA/glutamate ratio and mitochondrial homeostasis for epilepsy suppression.
  48. Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.
  49. Methionine sulfoxide reductase A deficiency impairs zebrafish heart regeneration via inhibiting Prohibitin 2-Pink1-mediated mitophagy.
  50. Illuminating Mitochondrial Dynamics: Ultrahigh Labeling Stability Probe for Long-Term SIM Super-Resolution Imaging of Mitochondria.
  51. Mitochondrial adaptations from heat acclimation - A narrative review.
  52. BRD-K20733377 inhibits ferroptosis and alleviates intervertebral disc degeneration via the STAT3/NFKB1 axis: a multiapproach study.
  53. MFN2-a multifaceted guardian against Parkinson's pathophysiology: mitochondria, ferroptosis, inflammation and oxidative stress.
  54. Arabidopsis Dynamin-Related Protein 1a is important for cell plate fusion with parent cell plasma membrane in cytokinesis during pollen mitosis I.
  1. Cell Biochem Funct. 2025 Oct;43(10): e70125
    A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.
    Hailun He, Xin Zhang, Lidan Xiong, Xiao Qin.
      FUN14 domain-containing 1 (FUNDC1), an outer mitochondrial membrane protein, has emerged as a critical regulator of mitochondrial quality control and cellular homeostasis. Initially identified as a mitophagy receptor, FUNDC1 orchestrates hypoxia-induced mitophagy through phosphorylation-dependent interactions with LC3. Recent studies reveal its multifaceted roles in mitochondrial dynamics (fission/fusion), mitochondria-associated endoplasmic reticulum membranes (MAMs), and metabolic regulation, mediated by posttranslational modifications (phosphorylation, ubiquitination, acetylation). FUNDC1 dysfunction is implicated in cardiovascular diseases, neurodegeneration, cancer, and dermatological pathologies. It modulates oxidative stress primarily through impaired clearance of ROS-generating mitochondria via disrupted mitophagy, while also influencing apoptosis, pyroptosis, and inflammation via crosstalk with Bcl-2 family proteins, MOMP, mPTP, and cGAS-STING pathways. This review synthesizes FUNDC1's molecular mechanisms, highlighting its dual role as a protector (clearing damaged mitochondria) and potentiator of injury (excessive mitophagy). We also discuss therapeutic targeting of FUNDC1-dependent pathways in mitochondrial disorders.
    Keywords:  FUNDC1; MAMs; metabolic diseases; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1002/cbf.70125
  2. J Transl Med. 2025 Oct 02. 23(1): 1047
    The molecular mechanisms of mitochondrial dynamics and mitophagy and their complex association with cancer drug resistance.
    Zhuo Zhao, Yuru Ren, Meijie Yuan, Guobin Liu, Jian Sun.
      The development of drug resistance by cancer cells is among the main reasons for cancer treatment failure, greatly limiting the efficacy of chemotherapy, targeted therapy, and immunotherapy. Mitochondria, as the core organelles of cellular energy metabolism, play a key role in the cellular stress response. The dynamic changes in mitochondria, including fusion, fission, and mitophagy, not only regulate cellular energy metabolism and biosynthesis but also affect cell survival and death. Through mitochondrial fusion, fission, and mitophagy, a sufficient number of effective mitochondria are ensured to supply cellular energy, thereby increasing the tolerance of tumor cells to chemotherapeutic drugs and generating drug resistance. Recently, the role of mitochondrial dynamics and mitophagy in cancer drug resistance has gradually gained attention, but their complex structure and function and multiple roles in tumor biology pose challenges for the clinical application of cancer treatment strategies based on it. Therefore, targeting mitochondrial dynamics and mitophagy for cancer drug resistance has attracted increasing attention for various cancer types. In this study, we provide insights into the molecular mechanisms of mitochondrial fusion, fission, and mitophagy and summarize their complex associations with cancer drug resistance through a systematic review of the latest literature.
    Keywords:  Cancer drug resistance; Mitochondrial fission; Mitochondrial fusion; Mitophagy
    DOI:  https://doi.org/10.1186/s12967-025-07078-x
  3. J Frailty Aging. 2025 Oct 01. pii: S2260-1341(25)00083-0. [Epub ahead of print]14(6): 100090
    Impacts of sarcopenia and resistance exercise training on mitochondrial quality control proteins.
    Catherine B Springer-Sapp, Olayinka O Ogbara, Odessa Addison, Sarah Kuzmiak-Glancy, Steven J Prior.
       BACKGROUND: The progression of sarcopenia with aging may be related to mitochondrial dysfunction due in part to altered mitochondrial dynamics (fusion, fission, mitophagy, and biogenesis). Previous work has identified altered expression of proteins associated with these processes in with aging, but whether further changes occur in sarcopenia remains unclear.
    OBJECTIVES: The purpose of this study was to assess protein expression of markers of mitochondrial fusion (Mfn2, Opa1), fission (Drp1, Fis1), mitophagy (Parkin), biogenesis (PGC-1α), and content (Complex IV: CIV) in sarcopenic and non-sarcopenic older adults. We also determined whether resistance training affected skeletal muscle mitochondrial content and expression of mitochondrial quality control proteins in sarcopenic older adults.
    DESIGN: Longitudinal exercise training study, with cross-sectional baseline comparison.
    SETTING AND PARTICIPANTS: Ten older adults with mild-moderate sarcopenia, plus ten non-sarcopenic, matched older adults from Maryland, USA.
    INTERVENTION: Twelve-week resistance training.
    MEASUREMENTS: Strength, sarcopenic index (ALM/BMI: appendicular lean mass divided by body mass index), body composition, and mitochondrial morphology and protein expression in vastus lateralis muscle.
    RESULTS: No differences in protein expression were observed between sarcopenic and non-sarcopenic participants at baseline; however, ALM/BMI was inversely related to CIV expression (r = -0.55, P = 0.013) across all subjects. Similarly, lean body mass and ALM correlated inversely with expression of the fusion protein Opa1-S (r = -0.55 - -0.51, P ≤ 0.022). Resistance training increased strength in sarcopenic older adults by 13 % (P = 0.02), but this group's expression of mitochondrial quality control proteins was mostly unaltered.
    CONCLUSIONS: The presence of sarcopenia identified by ALM/BMI was not associated with changes in protein expression that are consistent with impaired mitochondrial dynamics beyond those changes that might occur with aging alone. While short-term resistance training increased strength in older adults with sarcopenia, this was not accompanied by changes in protein expression, with the possible exception of fusion protein Mfn2.
    Keywords:  Age; Fission; Fusion; Mitophagy; Muscle health
    DOI:  https://doi.org/10.1016/j.tjfa.2025.100090
  4. J Nutr Biochem. 2025 Sep 26. pii: S0955-2863(25)00295-5. [Epub ahead of print] 110133
    Mitigating effects of resveratrol on cold exposed-induced cardiac mitochondrial dysfunction and lipid metabolic disorder in broilers.
    Haidong Wei, Deyang Miao, Haochen Li, Hongyu Wang, Qiang Xue, Yuanyuan Liu, Yanju Bi, Jianhong Li.
      Cold climate is a severe challenge to the sustainability of global poultry production, as it impairs the health and growth performance. Resveratrol (RES) is a natural polyphenol and has antioxidative and anti-inflammatory activities. To investigate whether RES alleviates cardiac substance metabolism disorder caused by cold exposure (CE) via regulating mitochondrial quality control. 28-day-old broilers were subjected to CE at 8±1°C for 14 days and fed the diets with 0, 250, 500, and 750 mg RES/kg feed, respectively. CE reduced body weight, and caused mitochondrial structure abnormalities and lipid droplet formation in the heart. CE elevated reactive oxygen species level, reduced mRNA and protein expression of AMPK and genes related to antioxidative function (Nrf2, HO-1, SOD1, SOD2, CAT, and GPx), mitochondrial biogenesis (Nrf1 and PGC-1α), mitochondrial dynamics (MFF, MFN1, MFN2, and OPA1), and lipolysis (PPARα, CPT1, and ACO2), promoted mRNA and protein expression of dynamin-related protein 1 and genes associated with mitophagy (PINK1, Parkin, ATG5, LC3Ⅱ/Ⅰ, p62, and Beclin1) and lipogenesis (SREBP1, FAS, ACC, and PPARγ), increased the concentrations of triglyceride, total cholesterol and LDLC, and reduced free fatty acids and HDLC concentrations in serum. RES reduced CE-caused oxidative stress and improved mitochondrial health, improving lipid metabolism by regulating the AMPK/PGC-1α/PPAR pathway in broiler heart. Therefore, this study suggests that dietary supplementation with RES, especially a 500 mg/kg dosage, could relieve CE-induced heart injury and dysfunction associated with lipid metabolism disorder by improving the Nrf2/HO-1 pathway-modulated antioxidative defense function and balancing the AMPK signaling-regulated mitochondrial quality control system in broilers.
    Keywords:  broiler heart; cold exposure; lipid metabolism; mitochondrial quality control; oxidative stress
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.110133
  5. Sci Adv. 2025 Oct 03. 11(40): eadw7376
    The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
    Valentina Cianfanelli, Monica Nanni, Samantha Corrà, Sofia Mauri, David Sumpton, Sergio Lilla, Rossella De Cegli, Matteo Bordi, Giacomo Milletti, Caterina Ferraina, Arnaldur Hall, Michele Petraroia, Valentina Clausi, Ezio Giorda, Marco Scarsella, Alessandra Barbiera, Giulia Cadeddu, Marco Colasanti, Tiziana Persichini, Kenji Maeda, Apolinar Maya-Mendoza, Jiri Bartek, Chiara Di Malta, Franco Locatelli, Sara Zanivan, Shehab Ismail, Elena Ziviani, Francesco Cecconi.
      Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.
    DOI:  https://doi.org/10.1126/sciadv.adw7376
  6. J Trace Elem Med Biol. 2025 Sep 26. pii: S0946-672X(25)00182-8. [Epub ahead of print]92 127769
    Zn2 + alleviates ischemia/reperfusion injury in H9c2 cells by modulating mitochondrial biogenesis and dynamics via MCU.
    Bingyu Wang, Bohan Xing, Luyao Huang, Xiaoyi Li, Xiyun Bian, Jinkun Xi.
       BACKGROUND: Zinc is an essential nutrient implicated in cardiovascular health. This study investigates whether Zn2+ protects H9c2 cells by regulating mitochondrial biogenesis, dynamics, and calcium homeostasis via the mitochondrial calcium uniporter (MCU).
    METHODS: The I/R model were established using simulated ischemia and reoxygenation as previous reported, and cells were then treated with MCU siRNA. Biochemical kits, inductively coupled plasma mass spectrometry (ICP-MS), RT-qPCR, and transmission electron microscopy were used to assess the effects of Zn2+ on cell viability, cytotoxicity, Zn2+ and ATP content, NAD⁺/NADH ratio, mtDNA copy number, and mitochondrial morphological changes following myocardial I/R. Confocal microscopy and fluorescence microscopy were used to observe the fluorescence changes of Zn2+, mitochondrial membrane potential, protein expression, and mitochondrial Ca2+. The effects of Zn2+ on protein expression levels were evaluated using molecular docking and Western blot analysis.
    RESULTS: Compared to the Control group, the I/R group exhibited decreased cell viability, and increased cytotoxicity. Intracellular and mitochondrial Zn2+ levels were reduced, accompanied by mitochondrial dysfunction and an increase in mitochondrial Ca2+ content. The expression levels of mitochondrial biosynthesis proteins SIRT1, PGC-1α, NRF1, and TFAM, mitochondrial fusion proteins OPA1, MFN1, and MFN2, as well as MCUb gene and protein expression were downregulated. Conversely, the expression of mitochondrial fission proteins DRP1 and FIS1, along with MCU, MICU1, and MICU2 proteins, was upregulated. Exogenous Zn2+ treatment reversed these alterations. MCU silencing by siRNA further enhanced the protection effects of Zn2+.
    CONCLUSIONS: I/R induced damage in H9c2 cells and mitochondrial dysfunction. Zn2+ protected H9c2 cells against I/R injury by regulating mitochondrial biogenesis, mitochondrial dynamics, and Ca2+ homeostasis via the MCU, with this protective effect potentially associated with the entire MCU complex.
    Keywords:  MCU; Mitochondrial biogenesis; Mitochondrial dynamics; Myocardial ischemia/reperfusion injury; Zinc ion
    DOI:  https://doi.org/10.1016/j.jtemb.2025.127769
  7. Sci Rep. 2025 Oct 01. 15(1): 34140
    Three-dimensional human mucopolysaccharidosis IVA chondrocyte culture reveals significant impairments in the lysosomal-mitochondrial crosstalk.
    Andrés Felipe Leal, Sampurna Saikia, Shaukat A Khan, Shunji Tomatsu.
      Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase enzyme. MPS IVA patients suffer from skeletal dysplasia due to the abnormal function of chondrocytes. Given the interactions of lysosomes with various intracellular organelles, it is not surprising that lysosomal dysfunction can lead to improper functioning of lysosome-interacting organelles such as mitochondria. Mitochondrial alterations have been evaluated in several LSDs; nevertheless, they have not been fully addressed in MPS IVA. In this study, we assessed the mitochondrial alterations in MPS IVA chondrocytes using a three-dimensional culture approach. Our findings revealed that MPS IVA chondrocytes exhibited an increased mitochondrial-triggered apoptosis profile, mitochondrial depolarization, and heightened oxidative stress. Additionally, the proteins associated with mitophagy, PINK1/Parkin, were significantly reduced in MPS IVA chondrocytes, whereas LC3-II and p62 were elevated. Our assessment of mitochondrial dynamics revealed increased levels of Drp1 and Fis1 along with decreased levels of Opa1. Regarding biogenesis, the mitochondrial regulators TFAM and PGC-α were upregulated in MPS IVA chondrocytes. Finally, MPS IVA chondrocytes showed a metabolic shift from mitochondrial respiration towards a glycolytic profile. Collectively, these data indicate that alterations in mitochondrial homeostasis may play a critical role in the pathogenesis of MPS IVA.
    DOI:  https://doi.org/10.1038/s41598-025-04871-y
  8. Tissue Cell. 2025 Sep 25. pii: S0040-8166(25)00437-9. [Epub ahead of print]98 103155
    Research on the molecular mechanism of intervertebral disc degeneration caused by mitochondrial dysfunction.
    Pandeng Hao, Yuheng He, Feilong Li, Yingjin Luo, Chao Song, Zongchao Liu, Zhijiang Fu.
      Intervertebral Disc Degeneration (IVDD) is the primary pathological basis of chronic low back pain, typically characterized by degeneration of the nucleus pulposus (NP), fissures in the annulus fibrosus (AF), and calcification of the cartilage endplates. These changes ultimately lead to nerve compression and loss of spinal function. Current treatment approaches are primarily symptomatic and cannot reverse disease progression. Therefore, a detailed understanding of the molecular mechanisms of IVDD and the exploration of targeted therapeutic strategies are of considerable clinical importance.Growing evidence indicates that mitochondrial dysfunction is a key factor in the pathogenesis of IVDD. Aberrations such as excessive production of reactive oxygen species (ROS), imbalance in mitochondrial dynamics, impaired mitophagy, and abnormal metabolic reprogramming converge to disrupt cellular activities, accelerate programmed cell death, and drive the breakdown of the extracellular matrix (ECM). This article comprehensively summarizes the role of mitochondrial damage in IVDD, with a focus on oxidative stress, dysregulated autophagy, and excessive mitochondrial fission. Furthermore, it evaluates emerging preclinical strategies aimed at restoring mitochondrial quality.From the perspective of bioenergetic dysfunction, this review proposes that interventions targeting the mitochondrial quality control network may establish a novel therapeutic paradigm for IVDD, thereby laying a theoretical foundation for translational and multidisciplinary research.
    Keywords:  Intervertebral disc degeneration; Mitochondrial autophagy; Mitochondrial dysfunction; Mitochondrial fission; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tice.2025.103155
  9. Front Cell Dev Biol. 2025 ;13 1646072
    Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.
    Qingzhi Ran, Chen Gao, Chunrong Xiang, Xuanhui He, Yongkang Zhang, Yin Zhang, Hengwen Chen.
      Mitochondrial fission process 1 (MTFP1) has emerged as a central regulator of mitochondrial dynamics, playing indispensable roles in maintaining organellar integrity, bioenergetic homeostasis, and stress adaptation - particularly in high-energy-demand tissues such as cardiac and skeletal muscle. Mounting evidence implicates MTFP1 dysfunction in the pathogenesis of diverse diseases including cardiovascular disorders, myopathies, and cancer. Beyond its canonical role in mediating mitochondrial fusion-fission balance, recent studies have unveiled MTFP1's multifaceted involvement in calcium signaling modulation, ROS metabolism, and mitochondria-ER communication networks, substantially expanding its functional repertoire in cellular physiology. The protein's pleiotropic effects stem from its ability to integrate metabolic status with organelle dynamics and quality control mechanisms. Particularly noteworthy is MTFP1's cell-type-specific regulation of the ROS-calcium axis, which appears critical for its differential impacts in disease states. These discoveries position MTFP1 as both a mechanistic linchpin connecting mitochondrial dynamics to cellular homeostasis and a promising but challenging therapeutic target requiring precise contextual modulation. Current research frontiers focus on elucidating tissue-specific regulatory mechanisms of MTFP1 activity, developing microenvironment-sensitive targeting strategies, and exploring its potential as a biomarker for mitochondrial dysfunction-related pathologies. This evolving understanding of MTFP1's integrative functions opens new avenues for developing precision therapies targeting mitochondrial dynamics in energy-metabolism-linked diseases.
    Keywords:  Mitochondria; Tumor; autophagy; cardiovascular disease; drug Targets; inflammation; mitochondrial fission process 1 protein
    DOI:  https://doi.org/10.3389/fcell.2025.1646072
  10. Clin Sci (Lond). 2025 Sep 30. pii: CS20256705. [Epub ahead of print]139(19):
    Double-edged mitophagy: balancing inflammation and resolution in lung disease.
    Sijia Tian, Yingyi Zhang, Chuanchuan Liu, Huajing Zhang, Qianying Lu, Yanmei Zhao, Haojun Fan.
      Inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and asthma, are driven by mitochondrial dysfunction and aberrant immune responses, yet the regulatory role of mitophagy-a selective autophagy eliminating damaged mitochondria-remains poorly defined. This review synthesizes evidence from in vivo and in vitro studies to dissect the molecular interplay between mitophagy and inflammation. Key fundings reveal that mitophagy exerts context-dependent effects: Protective mitophagy (via PTEN-induced putative kinase 1 [PINK1]-Parkin or FUN14 domain-containing protein 1 [FUNDC1] pathways) clears mitochondrial reactive oxygen species (mtROS)/mitochondrial DNA (mtDNA), suppressing NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and pyroptosis, but excessive mitophagy exacerbates mitochondrial fragmentation and necroptosis. Notably, bidirectional cross-talk exists, and therapeutic strategies-genetic and pharmacological-could restore mitophagy flux, attenuating inflammation in preclinical models. However, challenges persist in targeting tissue-specific mitophagy (such as alveolar and bronchial epithelia). This work underscores mitophagy as a double-edged sword in lung inflammation and proposes precision interventions to balance mitochondrial quality control, offering novel avenues for inflammatory lung diseases.
    Keywords:  inflammation; lung diseases; mitophagy; mtROS; therapeutic targeting
    DOI:  https://doi.org/10.1042/CS20256705
  11. Toxicol Appl Pharmacol. 2025 Sep 30. pii: S0041-008X(25)00362-X. [Epub ahead of print] 117586
    Hederagenin exerts anti-tumor effects in pancreatic cancer by impairing DRP1 mediated-mitophagy via VDAC1-HK2-PINK1/PARKIN pathway.
    Fang Su, Jianhua Yu, Shenhao Xu, Huanjun Tong, Jiandong Li, Fangfang Tao, Baochun Lu.
      Pancreatic cancer (PC) is widely regarded as the deadliest form of malignancy with a notably bleak prognosis. Although survival rates have shown gradual improvements, the pace of advancement remains slower when compared to other forms of cancer. Mitophagy suppression has surfaced as a novel approach for cancer treatment. Hederagenin (HDG), a triterpenoid extracted from the Hedera helix, has been identified as a potent inhibitor of mitophagy in PC. HDG has demonstrated the capacity to suppress the growth of BXPC-3 and PANC-1 cells in vitro, while also showing efficacy in diminishing tumor expansion in vivo. Furthermore, HDG promoted the opening of mitochondrial permeability transition pores, and enhance the accumulation of ROS. In addition, HDG led to a disruption in autophagic flux and an increase in autophagosomes within PC cells. Western blot analysis suggested that HDG hindered the fusion of lysosomes and autophagosomes by downregulating the expression of SNAP29, LAMP1, and Rab7. HDG also altered mitochondrial morphology in PC cells by suppressing the expression of dynamin-related protein 1 (DRP1), a crucial element in mitochondrial division machinery. This inhibition subsequently triggered voltage-dependent anion-selective channel protein 1 (VDAC1) oligomerization, mitochondrial hexokinase 2 (HK2) dissociation, and downregulation of the PINK1/PARKIN pathway, ultimately inhibiting the proliferation of PC cells in vitro. Moreover, the anti-mitophagy impact of HDG was reversed by DRP1 overexpression, while DRP1 knockdown produced the opposite results. These findings collectively suggest that HDG exerts anti-tumor activity by inhibiting mitophagy in PC cells. The underlying mechanism may involve the suppression of the DRP1-VDAC1-HK2-PINK1/PARKIN signaling pathway.
    Keywords:  DRP1; Hederagenin; Mitophagy; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.taap.2025.117586
  12. Int Immunopharmacol. 2025 Oct 01. pii: S1567-5769(25)01608-X. [Epub ahead of print]166 115617
    Astragalus polysaccharide enhances OGT-mediated O-GlcNAcylation to stabilize PINK1 to induce mitophagy in D-galactose treated C2C12 myoblasts.
    Deqing Chen, Zijin Qiu, Yongxin Wu, Yingxiao Zhang, Huanhuan Huang, Hailing Yang, Qian Xiao.
       BACKGROUND: Astragalus polysaccharide (APS) has been shown to alleviate muscle atrophy. This study investigated the effects and underlying mechanisms of APS on D-galactose (D-gal)-induced mitochondrial autophagy in C2C12 myoblasts.
    METHODS: Cell viability in C2C12 myoblasts was assessed using the CCK-8 assay. To further elucidate the role of APS, we evaluated skeletal muscle cell diameter and mitochondrial autophagy in C2C12 myoblasts, with and without O-GlcNAc transferase (OGT). Immunofluorescence staining for myosin heavy chain (MyHC) and western blot analysis were employed. Co-immunoprecipitation (Co-IP) experiments and immunofluorescence staining were conducted to examine the interaction between OGT and PTEN-induced putative kinase 1 (PINK1). In vivo, male C57BL/6 J mice were treated with D-gal to induce sarcopenia, and APS was administered to assess its effects on muscle function and mitochondrial health.
    RESULTS: APS promoted mitophagy in vitro by inducing O-GlcNAcylation through OGT. Knockdown of OGT significantly weakened the protective effects of APS. OGT modifies PINK1 with O-GlcNAcylation through the S425 site. In vivo, APS treatment significantly improved grip strength and muscle mass in D-gal-induced sarcopenia mice. Histological analysis showed increased cross-sectional area of gastrocnemius muscle fibers, and Western blot analysis revealed enhanced expression of LC3II, PINK1, and Parkin in muscle tissues.
    CONCLUSION: Collectively, APS promotes OGT-mediated O-GlcNAcylation to stabilize PINK1, thereby facilitating mitophagy in D-gal-treated C2C12 myoblasts in vitro. In vivo, APS improves muscle function and mitochondrial health in a mouse model of sarcopenia. These findings suggest that APS could serve as a potential therapeutic agent for muscle atrophy and related conditions.
    Keywords:  APS; Mitophagy; O-GlcNAcylation; OGT; PINK1
    DOI:  https://doi.org/10.1016/j.intimp.2025.115617
  13. Ecotoxicol Environ Saf. 2025 Oct 01. pii: S0147-6513(25)01478-2. [Epub ahead of print]304 119133
    Polystyrene nanoplastics induce cognitive dysfunction and dendritic spine deterioration via excessive mitochondrial fission.
    Hongxiang Yu, Lingting Jin, Yunjia Zi, Jing Lu, Yuming Long, Ran Xiong, Bei Zhang.
      Our research addresses the critical issue of polystyrene nanoplastics (PS-NPs) exposure and their neurotoxic effects, highlighting a significant environmental health concern. We proved that PS-NPs could breach the blood-brain barrier (BBB) and accumulate in murine brains, emphasizing the need for further investigation into their impact on human health. Using both in vivo models with Thy1-GFP-M transgenic mice and in vitro models with primary hippocampal neurons, we explored the effects of PS-NPs on cognitive function and neuroplasticity. Our results revealed that PS-NPs lead to cognitive impairment, evidenced by impaired performance in behavioral tests. Additionally, PS-NPs caused a significant reduction in dendritic spine density and altered the morphology of spines in hippocampal CA1 neurons. We explored the underlying mechanisms, finding that PS-NPs induced mitochondrial dysfunction, characterized by decreased membrane potential, reduced ATP production, and excessive mitochondrial fission. This mitochondrial disruption was associated with excessive mitophagy. Importantly, Mitochondrial Division Inhibitor-1 (Mdivi-1) treatment alleviated the neurotoxic effect, stabilized mitochondrial function, maintained dendritic spine density, and reversed the cognitive impairment induced by the PS-NPs. Overall, our study highlights the significant neurotoxic potential of PS-NPs and suggests that targeting mitochondrial fission can be a viable therapeutic strategy. This work underscores the urgent need to understand the neurological consequences of NPs exposure and develop strategies to counteract their health risks.
    Keywords:  Dendritic Spine Deterioration; Mitochondrial Fission; Mitophagy; Neurotoxicity; Polystyrene Nanoplastics (PS-NPs)
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119133
  14. Theranostics. 2025 ;15(18): 9623-9642
    ASIC1a Induces Excessive Mitophagy and PANoptosis of Chondrocyte by the Inhibition of SIRT3 Mitochondrial Translocation.
    Zhuoyan Zai, Xuewen Qian, Yayun Xu, Huifang Lv, Mengjia Hao, Yueming Tao, Lixin Rui, Xiaoyue Zhang, Xiaoqing Peng, Yihao Zhang, Feihu Chen.
      Rationale: The death of chondrocytes triggered by extracellular acidification represents a critical factor in the degradation of cartilage tissue and bone, thereby exacerbating the progression of rheumatoid arthritis (RA). Our previous research demonstrated that acid-sensing ion channel 1a (ASIC1a) serves as a key acid sensor mediating the destruction of articular cartilage in RA, which is closely associated with mitochondrial damage of chondrocytes. However, its regulatory mechanism remains unclear. Methods: Cartilage samples from RA patients and collagen-induced arthritis (CIA) rat models were examined to determine the levels of mitophagy and PANoptosis. In parallel, primary rat articular chondrocytes were cultured and subjected to either ASIC1a activation or silencing. Mitochondrial function, mitophagy, and PANoptotic markers were evaluated using immunoblotting, immunofluorescence, and transmission electron microscopy. Additionally, the subcellular distribution of SIRT3 to clarify its role in maintaining mitochondrial homeostasis. Results: We observed a significant increase in the levels of mitophagy and PANoptosis within the cartilage tissue of both RA patients and collagen-induced arthritis (CIA) rat models. Activation of ASIC1a by extracellular acidification triggered mitophagy, ultimately resulting in PANoptosis of chondrocytes. The loss of ASIC1a protected chondrocytes from PANoptosis, thereby alleviating disease progression in CIA rats. Mechanistically, we demonstrated that the transport of SIRT3 from cytoplasm to mitochondria was inhibited upon ASIC1a activation. ASIC1a upregulated calcineurin (CaN) expression, which competitively bound to HSP70, disrupting the SIRT3-HSP70 complex and thereby impairing SIRT3 mitochondrial translocation. The reduced levels of SIRT3 in mitochondria induced mitochondrial dysfunction and excessive mitophagy in primary rat articular chondrocytes, ultimately leading to PANoptosis of chondrocytes. Restoration of SIRT3 improved mitochondrial dysfunction and inhibited excessive mitophagy in the process of ASIC1a-induced PANoptosis of chondrocytes. Conclusion: Our study demonstrated that ASIC1a induces the destruction of articular cartilage through the disruption of the equilibrium between mitochondrial quality control and cell fate. This suggests that ASIC1a is a promising therapeutic target to improve the clinical treatment of RA.
    Keywords:  ASIC1a; PANoptosis; SIRT3; mitophagy; oxidative stress
    DOI:  https://doi.org/10.7150/thno.116712
  15. Brain Res. 2025 Sep 27. pii: S0006-8993(25)00533-5. [Epub ahead of print]1867 149970
    BNIP3L/NIX-mediated mitophagy: Future directions in Alzheimer's disease.
    Violina Kakoty, Khang Wen Goh, Prashant Kesharwani, Young Tag Ko.
      BCL2-interacting protein 3 like (BNIP3L) /Nip3-like protein X (NIX) is a mitochondrial outer membrane protein possessing mitophagic and pro-apoptotic properties. Mitochondrial dysfunction and subsequent mitophagy impairment are some of the early triggers for Alzheimer's Disease (AD), which is a progressive neurodegenerative condition affecting memory, thinking, and behavior. AD is associated with mitochondrial protein impairment and mitophagy failure. A recent study showed downregulation in BNIP3L expression in response to stress hormone release during Alzheimer's, and pretreatment with a BNIP3L enhancer of a corticosterone-exposed mouse upregulated mitophagy. This research proved that BNIP3L stimulation can be an effective therapeutic strategy against Alzheimer's. However, BNIP3L-mediated mitophagy studies focused on Alzheimer's have been relatively scarce, and expanding knowledge on its regulatory proteins will help lay a smoother road ahead for future Alzheimer's research. In this review, we aim to summarize all the recent findings of the downstream proteins of BNIP3L, which play an indispensable role in inducing BNIP3L-mediated mitophagy effects. The review also explicates the significance of healthy mitochondria and normally functioning mitophagy in Alzheimer's. Finally, the review states the implications of BNIP3L in other diseases, like cardiovascular conditions and cancer, underscoring the immense potential of this wonder protein.
    Keywords:  Alzheimer’s Disease; BCL2-interacting protein 3-like/Nip3-like protein X; Downstream proteins; Mitophagy
    DOI:  https://doi.org/10.1016/j.brainres.2025.149970
  16. Immunobiology. 2025 Sep 22. pii: S0171-2985(25)00252-9. [Epub ahead of print]230(6): 153118
    Changpu Yujin Tang mitigates tourette syndrome by enhancing mitophagy and suppressing NLRP3 inflammasome-mediated pyroptosis.
    Shuang Huang, Liwei Huang, Mengxue Li, Mingyang Sun, Kexin Sun, Xing Wei, Bing Jiang, Yuezhen He, Fuchun Xue, Lv Gao, Manqi Lu, Jing Shang, Zhenggang Shi.
       BACKGROUND: Changpu Yujin Tang (CPYJT) is an effective Chinese herbal compound for treating Tourette syndrome (TS). However, its precise molecular mechanisms remain to be fully elucidated.
    METHODS: 105 SD rats were randomly divided into the Control (n = 15) and the TS (n = 90) groups. The TS group was induced by intraperitoneal injection of 3,3'-iminodipropionitrile. After successful modeling, the TS group was further divided into 6 subgroups (n = 15 in each group): the Model group, the Tiapride group, the CPYJT group, the Rapamycin (RAPA) group, the 3-methyladenine (3-MA) group, and the CPYJT +3-MA group, and were treated with the corresponding drugs for 4 weeks.
    RESULTS: Compared with the Control group, rats in the Model group showed increased stereotyped and motor behaviors, damage to striatal neuronal cells and mitochondrial ultrastructure, decreased PINK1/Parkin-mediated mitophagy, and activation of NLRP3 inflammasome. CPYJT reduced stereotyped and motor behaviors, attenuated neuronal cell damage, and repaired mitochondrial pathology in the TS rats. Furthermore, both CPYJT and RAPA enhanced PINK1/Parkin-mediated mitophagy, eliminated ROS accumulation, and inhibited NLRP3 inflammasome activation. Notably, CPYJT counteracted 3-MA's inhibitory effect on PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation and pyroptosis.
    CONCLUSION: CPYJT inhibits NLRP3 inflammasome activation and reduces pyroptosis by enhancing PINK1/Parkin-mediated mitophagy and attenuating ROS accumulation, which in turn ameliorates TS.
    Keywords:  Changpu Yujin Tang; NLRP3 inflammasome; PINK1/Parkin-mediated mitophagy; Pyroptosis; Tourette syndrome
    DOI:  https://doi.org/10.1016/j.imbio.2025.153118
  17. Curr Mol Med. 2025 Sep 26.
    Dynamin-Related Protein 1 and the NLRP3 Inflammasome in Parkinson's Disease: Mechanistic Insights and Therapeutic Opportunities.
    Chethan Konasuru Someshwar, Kamsagara Linganna Krishna.
       INTRODUCTION: Parkinson's disease (PD) is characterized by the progressive destruction of the dopaminergic cells in the substantia nigra region. The incidence of PD continues to rise, with over 8.5 million people affected in 2019 and projections indicating it could reach over 17 million by 2040 compared with levels observed since 1980. This review examines the mechanistic role of Dynamin-Related Protein 1 (Drp1) and Nod-Like Receptor Family Pyrin Domain-Containing 3 (NLRP3) inflammasome in the development and pathogenesis of PD.
    METHODS: The information was collected from databases such as PubMed, Embase, Google Scholar, Web of Science, and Elsevier database.
    RESULTS: There is a potential for Drp1 and NLRP3 pathways to serve as therapeutic targets in PD. Drp1 inhibitors, such as Mdivi-1, aid in mediating mitochondrial homeostasis, and NLRP3 inhibitors prevent inflammation. Natural compounds that modulate such pathways include resveratrol and curcumin, and preclinical models demonstrate multi-target neuroprotection via direct antioxidant and anti-inflammatory properties.
    DISCUSSION: The intricate relationship among oxidative stress, mitochondrial dynamics and inflammation indicates that a combination drug therapy approach is more likely to be effective compared to a single-agent strategy. In a subsequent phase, there is a need for improved formulation and enhancement of natural compounds to maximize their bioavailability and efficacy, particularly in terms of selective Drp1 and NLRP3 inhibitors.
    CONCLUSION: The Drp1-NLRP3 axis is one of the essential mechanistic connections between mitochondrial dynamics and neuroinflammation in PD. Focusing on this axis could offer novel therapeutic options, and advancing these approaches could pave the way for therapies that not only alleviate symptoms but also slow or halt the progression of the disease.
    Keywords:  Drp1; NLRP3; Parkinson’s disease; mitochondrial dynamics; neuroinflammation; oxidative stress.
    DOI:  https://doi.org/10.2174/0115665240397746250915001750
  18. Mol Biol Rep. 2025 Sep 30. 52(1): 971
    Exploring the connection between the Mitochondrial DNA and the Circadian Rhythm: Insights into Mitochondrial Biogenesis and its Dynamics.
    Sowmya Anand, Piyush Jagdish Balgote, Jayanthi Sivaraman.
      Mitochondrial DNA (mtDNA), inherited exclusively from the mother, encodes genes essential for mitochondrial function, including oxidative phosphorylation (OXPHOS), which generates ATP, the cell's primary energy currency. Circadian rhythm is a crucial biological system that refers to the innate biological clock, whose core is in the suprachiasmatic nucleus (SCN) of the brain. This nucleus regulates various physiological processes, such as sleep-wake cycles, hormone secretion, cellular repair, energy homeostasis, and metabolism, on a roughly 24-hour cycle. Peripheral clocks exist in various tissues, including cells sensitive to external stimuli, and are linked to the circadian rhythm due to mitochondria's role in cellular energy metabolism. Core clock genes like Bmal1 and Clock influence mitochondrial biogenesis, oxidative phosphorylation, and mitophagy, while mitochondrial dysfunction disrupts circadian rhythms, leading to metabolic imbalance and disease progression. Emerging research suggests a bidirectional connection between circadian regulation and mitochondrial dynamics. This review focuses on the complex interplay between the circadian rhythm and mitochondrial processes, as regulated by various cellular proteins, transcription factors, ions, receptors, channels, and the mitochondrial genetic machinery, to understand the harmonious coordination between energy metabolism and timing mechanisms needed to optimize cellular processes and maintain physiological balance. The study of this relationship provides new insights into aging, neurodegenerative disorders, and metabolic diseases, potentially guiding future interventions focusing on chronotherapy and mitochondrial targeting.
    Keywords:  BMAL1; Circadian rhythm; Mitochondrial DNA (mtDNA); Mitochondrial biogenesis; PGC1-α; SIRT
    DOI:  https://doi.org/10.1007/s11033-025-11010-3
  19. Neuroscience. 2025 Sep 26. pii: S0306-4522(25)00973-X. [Epub ahead of print]
    Activin A protects against lipopolysaccharide/TNF-α induced damage of dopaminergic neurons both in vivo and in vitro by regulating mitochondrial fusion.
    Yue Zhang, Shuxiang Tian, Mingguang Niu, Han Yang, Lulu Liu, Yuyang Kang, Yanyan Yin.
      There is increasing evidence that the pathogenesis of Parkinson's disease (PD) is closely related to mitochondrial dysfunction and iron deposition. Activin A (Act A) is a homodimeric cytokine from the TGF-β superfamily and has neuroprotective effects in various neurological diseases. However, the specific mechanisms by which Act A exerts a neuronal protective effect in PD remain unclear. In this study, we selected lipopolysaccharide (LPS) -induced PD model mice to investigate the mechanism of protective effects of Act A on neurons, focusing on its effects on the expression of mitochondrial dynamics and ferroptosis related proteins. Meanwhile, the human neuroblastoma cell line SH-SY5Y was selected in vitro to detect mitochondrial membrane potential and reactive oxygen species (ROS) levels to clarify the potential molecular mechanism of Act A in PD. The results of the study showed that Act A attenuated dopaminergic neuron damage in the LPS-induced PD model mice, possibly through regulating mitochondrial dynamics, inhibiting ferroptosis, and reducing ROS. Additionally, mitochondrial fusion inhibitor (MFI8) increased the intracellular ROS levels, while Act A attenuated MFI8-mediated ROS elevation. In conclusion, our results suggest that Act A is involved in the onset and development of PD and may exert neuronal protective effects by regulating mitochondrial fusion.
    Keywords:  Activin A; Dopaminergic neurons; Mitochondrial dynamics; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.09.043
  20. Biochem Pharmacol. 2025 Sep 26. pii: S0006-2952(25)00632-X. [Epub ahead of print]242(Pt 3): 117367
    Dual activation of PPARα/γ by bezafibrate triggers PINK1/Parkin-Mediated mitophagy to enhance lenvatinib sensitivity in hepatocellular carcinoma.
    Jian Wang, Lu Chen, Li Jiang, Yuteng Wang, Wenqian Xue, Xinyan Cai, Hui Li, Tianxiao Wang.
      Lenvatinib resistance, driven by metabolic adaptation and angiogenic escape, poses a major challenge in hepatocellular carcinoma (HCC) therapy. This study explores bezafibrate, a clinically approved Peroxisome Proliferator-Activated Receptor Alpha or Gamma (PPARα/γ) dual agonist, to enhance lenvatinib sensitivity by inducing PTEN-Induced Putative Kinase 1(PINK1)/ Parkin-mediated mitophagy. Using SNU-739/HepG2 cells, we investigated bezafibrate's anti-tumor efficacy alone and in combination with lenvatinib. The results demonstrated that bezafibrate alone exhibits anti-tumor efficacy in HCC and enhances the anti-HCC efficacy of lenvatinib. It was observed that bezafibrate activated PPARα, increasing fatty acid oxidation (FAO) via Carnitine Palmitoyltransferase IA (CPT1A)/ Acyl-CoA Oxidase 1(ACOX1) upregulation, leading to elevated ROS and reduced mitochondrial membrane potential (ΔΨm). It also activated PPARγ, which bound to PINK1 with high affinity (ΔG = -64.6 kcal/mol). Dual PPARα/γ activation by bezafibrate enhanced Parkin recruitment and promoted mitophagic cell death, characterized by reduced p62 and Translocase of Outer Mitochondrial Membrane 20 (TOM20), increased LC3-II, decreased ATP, and elevated Annexin V-positive cells. This approach demonstrated efficacy, inducing PINK1/Parklin-mediated mitophagy and reducing VEGF-A/C and EGFR in vitro, and decreasing tumor volume and weight in a syngeneic H22 mouse model compared to lenvatinib alone, without significant toxicity. In conclusion, bezafibrate, through PPARα/γ-mediated PINK1/Parkin activation and angiogenic suppression, complements lenvatinib's therapeutic effects in HCC, providing a rationale for clinical evaluation to address treatment resistance.
    Keywords:  Bezafibrate; Hepatocellular Carcinoma (HCC); Lenvatinib; Mitophagy; PPARα/γ
    DOI:  https://doi.org/10.1016/j.bcp.2025.117367
  21. FASEB J. 2025 Oct 15. 39(19): e70966
    TET2 Deficiency Exacerbates Podocyte Injury and Mitophagy Disorder in Diabetic Nephropathy by Regulating M5C Methylation of Bcas3.
    Xiao-Han Ma, Zi-Yun Hu, Yu-Kai Wang, Yu Ma, Guang-Peng Liu, Xue-Qi Liu.
      Recent evidence highlights the critical role of 5-methylcytidine (m5C) as an epigenetic modification in the pathogenesis of various diseases. However, its regulatory mechanisms in diabetic nephropathy (DN) remain poorly understood. In this study, we observed a marked increase in m5C levels in the kidneys of type 2 diabetic (db/db) mice and in high glucose (HG)-stimulated podocytes, which was linked to reduced expression of the m5C demethylase ten-eleven translocation 2 (TET2). Moreover, renal biopsy samples from patients with DN exhibited decreased TET2 expression, correlating with impaired renal function. Gain-of-function assays revealed that TET2 overexpression in HG-induced podocytes enhanced mitophagy and ameliorated podocyte injury both in vitro and in vivo. Therapeutically, systemic delivery of AAV-TET2 in db/db mice reduced albuminuria, improved renal histopathology, and restored mitophagy. Mechanistically, TET2 regulated mitophagy by modulating the m5C methylation of Breast Carcinoma Amplified Sequence 3 (Bcas3). Furthermore, Bcas3 overexpression promoted mitophagy and attenuated podocyte damage under HG conditions. In conclusion, TET2-mediated m5C modification contributes to podocyte injury in DN, and targeting m5C via TET2 presents a promising therapeutic strategy for DN.
    Keywords:  Bcas3; TET2; diabetic nephropathy; m5C; mitophagy; podocytes
    DOI:  https://doi.org/10.1096/fj.202500946R
  22. J Adv Res. 2025 Sep 30. pii: S2090-1232(25)00750-7. [Epub ahead of print]
    Cross-regulatory mechanisms linking ferroptosis, epigenetics, and circadian rhythm to mitochondrial quality control in diabetic cardiomyopathy.
    Xinxin Liu, Yingqi Ma, Xuefeng Wang, Xiaowen Zhang, Chen Shen, Youzhu Su, Xing Chang, Hao Zhou, Jian-Ping Liu.
      Diabetic cardiomyopathy (DCM) is a distinct cardiac disorder that develops independently of coronary artery disease and hypertension. Mitochondrial dysfunction is widely recognized as a hallmark pathological feature of DCM. Effective mitochondrial quality control (MQC) is critical for preserving cardiomyocyte metabolism and contractile performance, and its disruption substantially contributes to both disease initiation and progression. We synthesize current evidence on disruptions of MQC in diabetic cardiomyopathy. The spectrum covers imbalanced fission-fusion dynamics, attenuated mitochondrial biogenesis, compromised mitophagy, disturbed Ca2+ homeostasis, heightened ferroptotic vulnerability, loss of proteostasis, and epigenetic dysregulation. We emphasize the intricate cross-talk among these processes, which collectively exacerbate mitochondrial deterioration and myocardial injury. Building on these mechanistic insights, we also summarize recent therapeutic advances targeting MQC, such as natural compounds, antidiabetic agents, and non-pharmacological approaches. These interventions show promise in modulating mitochondrial signaling and restoring homeostasis. Nevertheless, substantial barriers remain for clinical translation, including the limitations of existing experimental models, the low quality of supporting evidence, and pronounced inter-individual variability. Future research should focus on developing integrated, multi-target therapeutic strategies, particularly those addressing the regulatory roles of non-coding RNAs, epigenetic modifications, and post-translational protein regulation. Advancing these areas will be essential for establishing precise and effective MQC-targeted therapies in both preclinical and clinical contexts.
    Keywords:  Circadian rhythm; Diabetic cardiomyopathy; Epigenetic regulation; Ferroptosis; Mitochondrial quality control; Pharmacological intervention
    DOI:  https://doi.org/10.1016/j.jare.2025.09.046
  23. Nat Commun. 2025 Sep 30. 16(1): 8685
    Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
    Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.
      Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-63813-4
  24. Int J Nanomedicine. 2025 ;20 11685-11696
    Intratracheal Instillation of Silver Nanoparticles to Rats Induces Mitochondrial Fission and Aortic Damage: Protective Effect of Sodium Selenite.
    Shan He, P Andy Li, Jing He, Zhizhong Wang, Xuexing Liang, Zhehao He, Shaobin Jia, Wanrui Ma.
       Purpose: This study aims to investigate the influence of AgNPs intratracheal instillation on mitochondrial fission in aortic endothelial cells of rats and to explore the therapeutic effects of sodium selenite (Se).
    Animals and Methods: Male Sprague Dawley rats were divided into four groups (n=8): Control group (A), AgNPs exposure group (B), Se treated group (C), and Se+ AgNPs treated group (D). Rats in groups B and D received one dose of intratracheal instillation of AgNPs, while groups A and C received the same volume of 0.9% NaCl intratracheally. Rats in groups C and D were also intraperitoneally injected with sodium selenite for 7 days immediately after the AgNPs exposure. Morphological changes of the aorta were assessed using hematoxylin and eosin (HE) staining and electron microscopy. Masson's Trichrome Staining assayed collagen deposition in the aorta. Reactive oxygen species (ROS) generation, caspase-3 activity, and mitochondrial fission markers were analyzed.
    Results: Exposure to AgNPs increased collagen deposition and caused ultrastructural damage to endothelial cells in the aorta, including reduction of cytosolic contents, dissolution of mitochondrial cristae, and swollen mitochondria. Levels of ROS and cleaved caspase-3 increased moderately in AgNPs group (p<0.05 vs Control). Mitochondrial fission markers Dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1) in the aortic tissue homogenate of the AgNPs group nearly doubled the values of those in Control group (p<0.05 vs Control). Se alleviated AgNPs-induced ultrastructure changes and this effect was associated with suppressed ROS accumulation, inhibited caspase-3 activation, and attenuated mitochondrial fission.
    Conclusion: This study demonstrates that AgNPs induced oxidative stress, caspase 3 activation, and mitochondrial fission are linked to the morphological alterations of the aortic endothelial cells; and these adverse effects resulted from AgNPs can be alleviated by sodium selenite, suggesting that selenite could be used as a protective agent against AgNPs toxicity.
    Keywords:  aorta; endothelial cells; mitochondrial fission; reactive oxygen species; selenium; silver nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S524020
  25. Cell Signal. 2025 Oct 01. pii: S0898-6568(25)00572-8. [Epub ahead of print] 112157
    Study on the molecular mechanism of KPNA2 regulation of myocardial ischemia/delayed reperfusion injury through mitophagy.
    Ende Tao, Zhe Tao, Fudon Wang, Songjie Bai, Songqing Lai, Xiaogui Li, Yang Bai, Chengtao Peng, Li Wan.
      This study investigates the role of Karyopherin Subunit Alpha 2 (KPNA2) in myocardial ischemia/delayed reperfusion (I/dR) injury and its underlying molecular mechanisms. Using SD rat I/dR models and cell hypoxia/reoxygenation (H/R) models, we found that KPNA2 expression was significantly upregulated following I/dR treatment, leading to mitophagy dysfunction and myocardial cell damage. Mechanistic studies revealed that the transcription factor Paired box 6 (PAX6) promotes KPNA2 expression by binding to its promoter, while KPNA2 protein directly interacts with Phosphate Cytidylyltransferase 1 Alpha (PCYT1A). This KPNA2-PCYT1A interaction significantly inhibited mitophagy activity, as evidenced by the downregulation of key mitophagy molecules such as PINK1 and Parkin, along with a decreased LC3-II/LC3-I ratio and accumulation of p62 protein. In animal experiments, PAX6 inhibition downregulated KPNA2/PCYT1A expression, restored mitophagy function, alleviated myocardial injury, and improved cardiac function. This study, for the first time, elucidates a novel mechanism by which the PAX6-KPNA2-PCYT1A signaling axis regulates mitophagy in myocardial I/dR injury, providing potential targets for clinical treatment.
    Keywords:  Cell apoptosis; KPNA2; Mitophagy; Myocardial ischemia/delayed reperfusion injury; Oxidative stress; PAX6; PCYT1A
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112157
  26. Arch Toxicol. 2025 Oct 04.
    The synthetic cannabinoid THJ-2201 modulates mitochondrial activity and enhances mitochondrial recruitment to newly-forming neurites during neurodifferentiation of NG108-15 cells.
    Rui Filipe Malheiro, Ana Catarina Costa, Helena Carmo, Félix Carvalho, João Pedro Silva.
      Synthetic cannabinoids (SCs) have been increasingly associated with neurodevelopmental impairment; however, the underlying mechanisms remain poorly understood. In particular, the impact of SCs on mitochondria during neurodifferentiation remains largely unexplored, despite the central role of these organelles in this process. Building upon our previous findings that THJ-2201, a widely used SC, enhances neurite outgrowth in NG108-15 neuroblastoma-glioma cells at biologically relevant concentrations (1 pM-1 μM), we investigated whether this SC influences mitochondrial function, morphology, and dynamics during neurodifferentiation. THJ-2201 exposure caused a 30-40% reduction in intracellular ATP levels in a CB1-dependent manner, along with a 20-30% decrease in TMRE retention during NG108-15 neurodifferentiation. Cells treated with 1 μM THJ-2201 failed to sustain the expected increase in VDAC levels (an indirect marker of mitochondrial mass) during regular differentiation. Concurrently, THJ-2201 elevated PGC-1α levels, a key regulator of mitochondrial biogenesis, by disrupting its translocation to the nucleus. Expression of both fusion (Opa1, Mfn1, and Mfn2) and fission (Drp1 and Fis1) markers exhibited a less pronounced increase between 24 and 72 h in THJ-2201-treated cells. Mitochondrial morphology exhibited alterations in mean area, perimeter, branching, and circularity in the soma after 72 h exposure. Additionally, THJ-2201 reduced mitochondrial mobility in neurites without affecting their average speed or run length and led to a mitochondrial accumulation within neurites, as indicated by decreased Miro1 expression. Overall, these findings suggest that THJ-2201-induced mitochondrial remodelling and redistribution may transiently enhance local energy supply for neurite outgrowth, but at the expense of somatic mitochondrial function, resulting in an overall bioenergetic imbalance.
    Keywords:  Mitochondrial fusion and fission; Mitochondrial mobility; Mitochondrial morphology; Neurodevelopment; New psychoactive substances; Substances of abuse
    DOI:  https://doi.org/10.1007/s00204-025-04217-7
  27. Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00222-1. [Epub ahead of print]
    Interconnectivity of mitochondrial protein biogenesis and quality control.
    Abi S Ghifari, Carmela Vazquez-Calvo, Andreas Carlström, Martin Ott.
      Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.
    Keywords:  mitochondria; proteases; protein import; proteolysis; proteostasis; translation
    DOI:  https://doi.org/10.1016/j.tibs.2025.09.004
  28. Semin Nephrol. 2025 Sep 29. pii: S0270-9295(25)00154-8. [Epub ahead of print] 151676
    Therapeutic Approaches Involving Mitochondria in the Treatment of Acute Kidney Injury.
    Prisha S Patel, Navjot S Pabla, Amandeep Bajwa.
      Acute kidney injury (AKI) continues to pose a significant clinical burden, characterized by high morbidity and mortality rates. Emerging evidence has established mitochondrial dysfunction as a central driver in the pathogenesis of AKI, encompassing deficits in bioenergetics, excessive production of reactive oxygen species, and disruption of mitochondrial dynamics. Therapeutic interventions targeting mitochondrial pathways-most notably peptide-based agents such as SS-31-have demonstrated promising results in preclinical models. Recent discoveries have identified phospholipid scramblase 3 (PLSCR3) as an essential mediator of SS-31's mitochondrial protective effects, positioning it as a novel therapeutic target. This review synthesizes current mitochondrial-directed approaches for AKI, with a particular emphasis on the mechanistic role of PLSCR3 in maintaining mitochondrial homeostasis and injury responses. Despite encouraging data, mitochondrial therapies face several translational hurdles, including limited bioavailability, challenges in establishing effective dosing regimens, incomplete mechanistic understanding, and variability in efficacy across different experimental models. Moreover, concerns regarding cost, accessibility, and long-term safety remain unresolved, contributing to inconsistent outcomes in clinical trials. Herein we evaluate the emerging role of PLSCR3 as a potentially druggable mitochondrial target, supported by recent genetic, biochemical, and in vivo evidence, and discuss translational strategies that may bridge the gap between experimental promise and clinical application. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
    Keywords:  SS-31 (Elamipretide); acute kidney injury; cardiolipin; mitochondria-targeted antioxidants; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; phospholipid scramblase 3 (PLSCR3); reactive oxygen species
    DOI:  https://doi.org/10.1016/j.semnephrol.2025.151676
  29. Front Cell Neurosci. 2025 ;19 1635775
    Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.
    Kota Aoshima, Yuya Takagi, Michinori Funato, Yoshiki Kuse, Shinsuke Nakamura, Masamitsu Shimazawa.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone's therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.
    Keywords:  Leber’s hereditary optic neuropathy; in vitro disease modeling; mitochondrial disease; mitophagy; retinal organoid
    DOI:  https://doi.org/10.3389/fncel.2025.1635775
  30. BMC Med Genomics. 2025 Oct 03. 18(1): 148
    Bone marrow mesenchymal stem cell-derived exosomes attenuate hepatic stellate cell activation through miR-223-3p-mediated mitophagy.
    Lijie Ma, Weidong Weng, Jie Chen, Hongdi Wu, Jiajia Liang, Fengbin Lu.
       BACKGROUND: Liver fibrosis is a common pathological process in chronic liver diseases and effective treatments are lacking. The activation of hepatic stellate cells (HSCs) is a critical step in the development of liver fibrosis. Our previous research confirmed that bone marrow mesenchymal stem cell-derived exosomes (BMSC-exosomes) could regulate the level of miR-223-3p to alleviate intrahepatic inflammation, but whether they contribute to the protection of the liver against fibrosis remains unknown.
    METHODS: In this study, the antifibrotic function of BMSC-exosomes was validated through cell experiments. JS-1 cells (murine HSC line) were used as activated cells to simulate liver fibrosis. TGF-β is a stimulating factor for JS-1 cell activation. BMSC-exosomes were isolated via ultracentrifugation.
    RESULTS: Our results demonstrated that BMSC-exosomes internalized by JS-1 cells attenuated TGF-β-induced HSC activation and promoted HSC apoptosis. Moreover, BMSC-exosomes significantly reversed the upregulation of miR-223-3p levels and mitophagy induced by TGF-β. Luciferase activity reporter analysis further verified that hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) was a downstream target of miR-223-3p. By transfecting a miR-223-3p inhibitor, we found that downregulating miR-223-3p could increase the expression level of HMGCS1 and alleviate mitophagy, thereby reducing TGF-β-induced HSC activation and promoting HSC apoptosis.
    CONCLUSIONS: These results suggest that BMSC-exosomes may have antifibrotic effects. The mechanism may be related to regulating miR-223-3p in HSCs to target HMGCS1 and mitophagy.
    Keywords:  BMSC-exosomes; HMGCS1; Liver fibrosis; MicroRNA-223-3p; Mitophagy
    DOI:  https://doi.org/10.1186/s12920-025-02228-y
  31. Naunyn Schmiedebergs Arch Pharmacol. 2025 Oct 03.
    Dehydrocostus lactone induces apoptosis and mitophagy in gastric cancer cells through the ROS-mediated mitochondrial pathway.
    Qiuxiong Chen, Ying Li, Junjie Mu, Qian Ming, Chaohong Zhu, Ziyue He, Mengyue Ma, Xiaoqin Long, Hui Wu, Baoli Qiu, Lihe Zhang, Xian Yang, Xue Zhang.
      Dehydrocostus lactone (Dehy) is a sesquiterpenoid compound extracted from the dried roots of Aucklandia lappa Decne, a plant in the Compositae family, and has been shown to have significant efficacy in anti-tumor and gastrointestinal diseases. However, the anti-cancer molecular mechanisms of Dehy in gastric cancer (GC) are unclear, and further in-depth studies are needed to elucidate its potential molecular pathways and therapeutic capabilities. This study systematically studied the anti-GC effect of Dehy and its molecular mechanism by integrating network pharmacology (NP) prediction and in vitro experimental verification strategies. The effects of the compound on proliferation, apoptosis, and expression of mitophagy marker proteins in GC cells were evaluated by CCK-8 assay, plate cloning assay, flow cytometry, and Western blotting techniques. NP analysis revealed its potential targets and key signaling pathways, which were further verified by experiments such as mitochondrial membrane potential detection and reactive oxygen species (ROS) level determination. The results showed that Dehy significantly inhibited the proliferation of GC cells and caused changes in cell morphology. Its mechanism of action involves promoting the accumulation of intracellular ROS, thereby activating mitochondria-dependent apoptosis pathways and mitophagy processes. Notably, ROS is a therapeutic target for Dehy, and the mitochondrial pathway is its key mechanism of action in this context. The results confirm that Dehy is a potential drug for the treatment of GC.
    Keywords:  Dehydrocostus lactone; Gastric cancer; Mitochondrial pathway; Mitophagy; Network pharmacology; ROS
    DOI:  https://doi.org/10.1007/s00210-025-04645-3
  32. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2502841122
    Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway.
    Qi-Qiang Guo, Shan-Shan Wang, Xiao-You Jiang, Xiao-Chen Xie, Yu Zou, Jing-Wei Liu, Yang Guo, Yu-Han Li, Xi-Yan Liu, Shuang Hao, Xin-Yue Zhang, Xiao-Xu Wu, Song-Ming Lu, Hong-De Xu, Wen-Dong Guo, Yan-Ling Feng, Chuan-Gui Wang, Sheng-Ping Zhang, Jia-Bin Li, Chen Liu, Xiao-Yu Song, Toren Finkel, Liu Cao.
      The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2-/- mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia-reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.
    Keywords:  ATM; CHK2; PINK1; mitophagy; mtROS
    DOI:  https://doi.org/10.1073/pnas.2502841122
  33. Int J Mol Med. 2025 Dec;pii: 215. [Epub ahead of print]56(6):
    Mitochondrial dysfunction in perimenopausal mood disorders: From hormonal shifts to neuroenergetic failure (Review).
    Yang Yu, Han Yapeng, Zelin Liu, Lei Fang, Jianuo Li, Yifeng Luan, Wenzhong Li, Huifang Cong, Xiuhong Wu.
      Perimenopause represents a key transition from a reproductive to non‑reproductive state in women, characterized by physiological and psychological changes. Mood disturbances during this period, such as depression, anxiety and cognitive decline, are increasingly understood as complex neuroendocrine and metabolic disorders. Mitochondrial homeostasis carries out a key role in the pathophysiology of these affective symptoms. Disruptions in mitochondrial biogenesis, mitophagy and calcium regulation contribute to synaptic dysfunction and neuroimmune changes. These mitochondrial alterations interact with inflammatory pathways and hormonal signals, exacerbating neuropsychiatric symptoms. A more comprehensive understanding of the molecular mechanisms of mitochondrial dysfunction in menopausal mood disorders unveils potential therapeutic strategies, including mitochondria‑targeted antioxidants, hormone replacement therapy, and lifestyle interventions designed to restore mitochondrial integrity and cerebral bioenergetic function.
    Keywords:  estrogen deficiency; mitochondrial dysfunction; mood disorders; perimenopause
    DOI:  https://doi.org/10.3892/ijmm.2025.5656
  34. Cell Commun Signal. 2025 Oct 02. 23(1): 414
    TRAP1 inhibits KANSL3 acetylation to alleviate mitochondrial dysfunction by promoting mitophagy in cardiomyocytes under diabetic conditions.
    Xiaoyu Zhang, Shiyao Cheng, Wenxin Li, Xintian Xu, Xiaojing Huang, Zhichong Chen, Qinglang Li, Wanjing Huang, Lingxiao Zhang, Mao Ouyang.
      
    Keywords:  Acetylation; Diabetic cardiomyopathy; Mitochondrial dysfunction; Mitophagy; TRAP1
    DOI:  https://doi.org/10.1186/s12964-025-02402-w
  35. Crit Care. 2025 Oct 02. 29(1): 418
    Rethinking post-sepsis syndrome: linking cellular dysfunction to the clinical picture.
    Gabriel-Petre Gorecki, Andrei Bodor, Marius-Bogdan Novac, Dan-Gabriel Costea, Daniel-Ovidiu Costea, Andreea-Cristina Costea, Cătălin-Nicolae Grasa, Dana-Rodica Tomescu.
      Post-sepsis syndrome (PSS) encompasses a range of long-term complications, including immune dysregulation, chronic inflammation, and neuromuscular impairment, that persist beyond the resolution of the acute septic episode. While these clinical phenotypes are increasingly recognized, the underlying molecular mechanisms remain incompletely defined. Mitochondrial dysfunction, particularly in the form of persistent mitochondrial senescence, is emerging as a potential unifying factor driving multiple PSS trajectories. Accumulating evidence suggests that damaged mitochondria not only lose their bioenergetic capacity but also actively contribute to chronic immune and inflammatory signalling. Based on this, we propose a dual-intervention strategy ("mitochondrial flush") which involves the coordinated elimination of senescent mitochondria and stimulation of mitochondrial biogenesis. The regenerative component, supported by established preclinical research on Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α) activation, represents a partially developed therapeutic arm, while the selective clearance of dysfunctional mitochondria remains an area of active investigation. This concept raises important questions regarding regenerative capacity, therapeutic timing, and cellular resilience following critical illness. We further propose a working definition of PSS as a state of persistent mitochondrial dysfunction, possibly driven by ongoing oxidative stress, which may underlie a broader range of clinical phenotypes than currently recognized. A deeper understanding of mitochondrial quality control may offer a new therapeutic framework for reversing the chronic physiological decline observed in sepsis survivors.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dysfunction; Mitochondrial flush; Mitochondrial senescence; Mitochondrial-targeted dual therapy; Mitophagy; Oxidative stress; Post-sepsis clinical phenotypes; Post-sepsis syndrome; Sepsis
    DOI:  https://doi.org/10.1186/s13054-025-05491-8
  36. Theranostics. 2025 ;15(18): 9862-9884
    Cyclic mechanical stretching enhances mitophagy and oxidative stress resistance in adipose-derived stem cells via the Piezo1/ATP axis to accelerate wound healing.
    Yujie Xiao, Zhijun Shi, Yixuan Yuan, Danna Yao, Rongqin Feng, Yue Zhang, Deli Zhao, Hao Zhang, Panpan Sun, Yang Liu, Yan Li, Xuefeng Shen, Zhantong Wang, Dahai Hu, Hao Guan, Hongtao Wang.
      Adipose-derived stem cells (ADSCs) hold significant potential in regenerative medicine, yet their therapeutic efficacy is often limited by low survival rates in the presence of oxidative stress. While mechanical cues regulate cytoskeletal dynamics, their roles in modulating cellular metabolism and mitochondrial adaptation remain unexplored. This study aimed to elucidate how physiological-range cyclic mechanical stretching (CMS) enhances ADSCs resistance to oxidative stress through the Piezo1/ATP signaling axis, thereby establishing an innovative strategy for developing antioxidant-functionalized stem cell therapies. Methods: To examine the impact of CMS on oxidative stress resistance, ADSCs were exposed to CMS (8% strain, 0.5 Hz, 24 h) using the Flexcell FX-6000 system. Oxidative stress models employed H₂O₂ (200 μM), with apoptosis, mitochondrial function, and metabolic flux analyzed in vitro. A murine full-thickness wound model was used to assess in vivo survival and regenerative outcomes. Results: CMS activated Piezo1 channels, resulting in enhanced ATP synthesis and remodeling of the tricarboxylic acid cycle. This improved the effectiveness of mitochondrial oxidative phosphorylation. Mechanically preconditioned ADSCs exhibited reduced apoptosis, ​enhanced oxidation resistance, stabilized mitochondrial membrane potential, and upregulated mitophagy. In vivo, these cells demonstrated superior healing capacity and accelerated wound closure. Conclusion: CMS orchestrated the Piezo1/ATP-driven metabolic-mitochondrial axis to enhance ADSCs oxidative stress resistance by coupling metabolic reprogramming with mitophagy activation. This mechanometabolic interaction identifies mechanical signaling as a direct regulator of cellular bioenergetics, offering a translatable strategy to engineer antioxidant-functionalized stem cells for regenerative therapies.
    Keywords:  Piezo1; adipose-derived stem cells; cyclic mechanical stretch; mitophagy; oxidative stress
    DOI:  https://doi.org/10.7150/thno.118364
  37. J Med Virol. 2025 Oct;97(10): e70625
    RSV-Induced Glutaric Acid Modulates Neuronal Mitochondrial Heterogeneity via the Lung-Brain Axis.
    Taorui Du, Ousman Bajinka, Amie N Joof, Yurong Tan, Ling Chu.
      The study was designed to explore how glutaric acid induced by respiratory syncytial virus (RSV) infection affects nerve cell mitochondrial heteroplasmy. An RSV infection animal model was established, and lung tissues were collected after 7 days for metabolomic analysis. Then, a neuroinflammatory cell model was constructed with lipopolysaccharide (LPS). The CCK8 assay detected proliferation, the DCFH-DA probe assessed reactive oxygen species (ROS) levels, and ELISA measured IL-1, IL-4, IL-6, and IFN-γ levels in HT-22 cells. RT-qPCR detected Drp1 and Mfn2 expression levels to study the mechanism of glutaric acid-exacerbated neuroinflammation. Immunofluorescence and RT-qPCR detected the effects of glutaric acid on neuron biomarkers in the lung (PGP9.5) and brain (NeuN). Bioinformatics screened glutaric acid-interacting proteins, and the enzymatic activities of NAD-dependent malate dehydrogenase (NAD-ME) were validated at cellular and animal levels. High-performance liquid chromatography (HPLC) detected glutaric acid content in blood and brain tissues. After glutaric acid treatment, Drp1 protein expression increased, Mfn2 decreased, and ROS, IL-1, and IL-6 cytokine levels rose significantly. Glutaric acid affects the central nervous system by disrupting the lung neural network, causing mitochondrial homeostasis dysregulation. Its interaction with NAD-ME accelerates mitochondrial imbalance. Glutaric acid induced by RSV infection aggravates neuroinflammation by affecting nerve cell mitochondrial homeostasis via the lung-brain axis. These findings offer new insights into RSV-induced neuroinflammation and potential targets for neuroprotective strategies.
    Keywords:  glutaric acid; lung−brain axis; mitochondrial heterogeneity; respiratory syncytial virus
    DOI:  https://doi.org/10.1002/jmv.70625
  38. Neuropharmacology. 2025 Sep 26. pii: S0028-3908(25)00408-3. [Epub ahead of print]281 110700
    AMPK activation mitigates α-synuclein pathology and dopaminergic degeneration in cellular and mouse models of Parkinson's disease.
    Yoonha Kim, Jong Sam Lee, Sumin Son, Seobin Park, Hyungkeun Oh, Yoon Kyung Choi, Dong-Eun Kim.
      Parkinson's disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and pathological accumulation of p-α-Synuclein (p-α-Syn). AMP-activated protein kinase (AMPK) has emerged as a regulator of cellular energy homeostasis, yet its role in PD pathology remains unclear. Here, we examined the effects of AMPK activation in SH-SY5Y neuroblastoma cells and in an MPTP-induced PD mouse model. In both undifferentiated and retinoic acid-differentiated SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA), pharmacological AMPK activation with AICAR reduced reactive oxygen species (ROS) production and p-α-Syn aggregation. These effects were associated with enhanced mitophagy, increased lysosomal degradation, and stimulation of mitochondrial biogenesis, collectively restoring mitochondrial integrity and improving dopaminergic features. In vivo, AICAR treatment attenuated nigrostriatal dopaminergic degeneration in MPTP-exposed mice, reduced p-α-Syn accumulation, and preserved tyrosine hydroxylase expression. Moreover, systemic cytokine analysis revealed that AMPK activation suppressed IL-6-mediated inflammation, while modulating IL-1β levels in a context-dependent manner. These results demonstrate that AMPK activation mitigates α-synuclein pathology, preserves mitochondrial function, and protects dopaminergic neurons in both cellular and animal PD models. Our findings support AMPK as a potential therapeutic target for disease modification in PD.
    Keywords:  AMP-Activated protein kinase; Mitochondrial homeostasis; Oxidative stress; Parkinson's disease; p-α-Syn
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110700
  39. Phytomedicine. 2025 Sep 26. pii: S0944-7113(25)00960-2. [Epub ahead of print]148 157322
    FoxO1/PINK1/Parkin-dependent mitophagy mediates the chondroprotective effect of Guzhi Zengsheng Zhitong decoction in osteoarthritis.
    Lu Bocheng, Chen Yongfu, Cai Junjie, Li Ziqi, Guo Lina, Qu Tingli, Tang Li, Zheng Qian.
       OBJECTIVE: Guzhi Zengsheng Zhitong Decoction (GZZD) is a classic traditional Chinese medicine (TCM) prescription for treating knee osteoarthritis (OA), and has been widely used in clinical practice in China. Given that Forkhead box protein O 1 (FoxO1) has been identified as a potential therapeutic target for OA treatment, this study investigates the chondroprotective effects of GZZD through FoxO1-mediated mitochondrial regulation, bridging traditional medicine with contemporary molecular insights.
    METHODS: The therapeutic effects of GZZD on OA and its chondroprotective mechanisms were evaluated both in vivo and in vitro. A rat model of knee OA was established by intra-articular injection of monosodium iodoacetate (MIA), while an in vitro OA model was induced by IL-1β stimulation in chondrocytes. Histological staining, immunohistochemistry, and Western blot analyses were performed to assess cartilage protection. Serum ingredients of GZZD were identified using LC-MS/MS, and the core pathways involved in GZZD-mediated chondroprotection were explored through transcriptomics and network pharmacology. Key protein expression was examined, and molecular biology techniques were applied to validate the role of FoxO1 and its downstream pathways in regulating chondrocyte autophagy, apoptosis, and mitochondrial dysfunction. Additionally, molecular docking and molecular dynamics simulations were conducted to analyze interactions between bioactive compounds and FoxO1.
    RESULTS: GZZD significantly ameliorated MIA-induced knee joint damage, reduced cartilage degradation and subchondral bone destruction, and decreased OARSI scores. Treatment with GZZD markedly decreased serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while enhancing protective autophagy in chondrocytes. Furthermore, GZZD inhibited chondrocyte apoptosis and mitochondrial dysfunction, accompanied by the upregulation of the cartilage matrix protein COL2A1 and the anti-apoptotic protein BCL2, along with downregulation of catabolic factors (MMP13, IL-1β). Mechanistically, GZZD activated the FoxO1/PINK1/Parkin pathway, restoring mitochondrial homeostasis and mitigating mitochondrial-dependent apoptosis, ultimately protecting chondrocytes from OA-related damage.
    CONCLUSION: For the first time, this study demonstrates that the traditional Chinese medicine formula GZZD alleviates osteoarthritis by activating the FoxO1/PINK1/Parkin pathway, thereby restoring mitochondrial function and protecting chondrocytes from injury. These findings not only establish GZZD as a promising complementary therapy for OA but also provide a scientific foundation for developing FoxO1-targeted therapeutics.
    Keywords:  Chondroprotection; FoxO1; Guzhi Zengsheng Zhitong Decoction; Mitophagy; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.phymed.2025.157322
  40. J Agric Food Chem. 2025 Oct 01.
    Licochalcone D Alleviates Radiation-Induced Intestinal Injury via SIRT3-Dependent Mitophagy: A Natural Phytochemical Strategy for Radioprotection.
    Jiaxin Zhang, Shengjie Ma, Zhen Wang, Pai Wang, Heshi Liu, Quan Wang.
      Oxidative stress, a key mechanism in radiation-induced intestinal injury (RIII), is triggered by ionizing radiation. Licochalcone D (LCD), a bioactive compound derived from licorice, exhibits potent antioxidant properties, yet its role and mechanism in RIII remain unclear. In this study, in vitro experiments revealed that the pretreatment of intestinal epithelial cells with LCD significantly enhanced cell viability, reduced radiation-induced DNA breaks, and suppressed reactive oxygen species (ROS) accumulation. In vivo, LCD administration mitigated radiation-induced body weight loss, preserved intestinal crypt integrity, and attenuated villous damage in irradiated mice. Mechanistically, LCD stabilizes SIRT3 protein to activate mitophagy, thereby eliminating radiation-generated ROS and subsequently alleviating DNA damage and preventing cell apoptosis. These findings broaden the potential applications of LCD in protecting against RIII and establish the SIRT3-mitophagy axis as a novel pharmacological target for preventing radiation-induced intestinal damage.
    Keywords:  Licochalcone D; SIRT3; mitophagy; radiation-induced intestinal injury
    DOI:  https://doi.org/10.1021/acs.jafc.5c05399
  41. Toxicol Appl Pharmacol. 2025 Sep 27. pii: S0041-008X(25)00357-6. [Epub ahead of print] 117581
    Propylparaben disrupts early embryonic development by causing oxidative stress-induced organelle dysfunction and actin zipper abnormality.
    Zhen-Nan Pan, Li-Li Zhuang, Hui-Shan Zhao, Shu-Yuan Yin, Min Chu, Xiao-Yan Liu, Hong-Chu Bao.
      Propylparaben (PrPB) is a commonly used preservative in personal care products and food items, but studies have shown that it can disrupt various physiological processes, especially in the reproductive system. Our previous research revealed the toxic effects of PrPB on mouse oocyte maturation. However, knowledge about the toxicity of PrPB in early embryos remains limited. In the present study, we demonstrated that in vitro exposure to 600 μM PrPB increased ROS levels, inducing autophagy, mitophagy and ER stress, ultimately leading to embryonic arrest at the 4-cell stage. PrPB exposure promoted autophagy through the induction of DNA damage, reflected by enhanced lysosome, LC3 and γH2A.X fluorescence signals. PrPB exposure enhanced mitophagy, as indicated by increased colocalization of mitochondria with LAMP1 and Parkin. PrPB exposure also caused ER stress, as indicated by disordered ER distribution and abnormal Ca2+ homeostasis. In addition, 600 μM PrPB exposure disrupted the formation of the actin zipper by interfering with the localization of ZO1 and E-cadherin, further affecting blastocyst formation. Although 300 μM PrPB exposure did not affect the embryo development rate, a decreased TE cell number was observed, indicating poor blastocyst quality. Taken together, the results of our study demonstrate that high-dose PrPB exposure causes oxidative stress-induced organelle dysfunction and abnormal actin zipper formation, whereas low-dose PrPB exposure affects early lineage specification.
    Keywords:  Actin zipper; Autophagy; Early embryonic development; Endoplasmic Reticulum (ER) stress; Mitophagy; Propylparaben
    DOI:  https://doi.org/10.1016/j.taap.2025.117581
  42. Int J Biochem Cell Biol. 2025 Sep 27. pii: S1357-2725(25)00137-2. [Epub ahead of print]189 106869
    ATP1B4 as a candidate upstream regulator of muscle atrophy in diabetic sarcopenia via PI3K/AKT/mTOR-mediated autophagy.
    Tingting Duan, Shumin Jia, Dan Zhou, Liqun Zhao.
       OBJECTIVE: This study aimed to elucidate the regulatory role of the muscle-specific gene ATP1B4 in skeletal muscle metabolism and mitophagy in diabetic sarcopenia (DS) rats.
    METHODS: Differentially expressed genes were screened from the GEO dataset GSE7014, and ATP1B4 was identified as a candidate gene associated with DS. A DS rat model was established via high-fat diet feeding and streptozotocin injection. ATP1B4 expression was modulated through lentiviral overexpression or knockdown. Additionally, PI3K/AKT/mTOR pathway activators (SC79, leucine) and inhibitors (LY294002, MK-2206) were administered. Protein expression of ATP1B4, phosphorylated PI3K/AKT/mTOR components, and autophagy markers (LC3-II, DRP1, ATG9, MFN2) was assessed via Western blotting, immunohistochemistry, and immunofluorescence. Skeletal muscle function and structure were evaluated using behavioral tests (treadmill and inclined plane) and histopathological staining (H&E, Masson, PAS).
    RESULTS: Bioinformatic analysis of the GSE7014 dataset identified ATP1B4 as a skeletal muscle-related differentially expressed gene enriched in extracellular matrix and metabolic pathways. In DS rats, ATP1B4 expression was upregulated, coinciding with suppression of PI3K/AKT/mTOR signaling and activation of mitophagy markers (LC3-II, DRP1, ATG9). Overexpression of ATP1B4 exacerbated hyperglycemia, muscle atrophy, collagen accumulation, and glycogen deposition, while knockdown reversed these effects. Activation of the PI3K/AKT/mTOR pathway improved muscle function and histological architecture, normalized autophagy, and reduced pathological features. However, co-overexpression of ATP1B4 eliminated the protective effects of pathway activation. Conversely, dual intervention with ATP1B4 knockdown and PI3K activation restored skeletal muscle integrity and autophagy flux. Importantly, ATP1B4 expression remained unchanged following pathway modulation, supporting its unidirectional upstream regulatory role in DS.
    CONCLUSION: ATP1B4 may aggravate diabetic sarcopenia by acting as an upstream suppressor of the PI3K/AKT/mTOR pathway.
    Keywords:  ATP1B4; Autophagy; Diabetic sarcopenia; Gastrocnemius muscle; PI3K/AKT/mTOR; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biocel.2025.106869
  43. Acta Pharmacol Sin. 2025 Sep 29.
    HDAC3 mediates retinal endothelial cell metabolic reprogramming and angiogenesis.
    Christian D Mitchell, Carol A Morris, Melissa Wild, Ashlynn Cunningham, Piyanan Chuesiang, Aya A Mohammed, Bolni Marius Nagalo, Nancy J Rusch, Abdelrahman Y Fouda, Esraa Shosha.
      Pathological retinal neovascularization (NV) contributes to vision loss in diabetic retinopathy (DR) and retinopathy of prematurity, which are the leading causes of blindness in working-age adults and children, respectively. Retinal hypoxia is a key driver of pathological neovascularization that results in uncontrolled vessel sprouting and the formation of immature and leaky blood vessels. Anti-vascular endothelial growth factor and laser therapies are the standard of care to mitigate vision loss, but their limited effectiveness underlies the need to identify new therapeutic targets. The goal of the current study was to define the role of the enzyme histone deacetylase 3 (HDAC3) in the pathogenesis of experimental NV. Pathological neovascularization was induced by subjecting C57BL/6 J mouse pups to oxygen-induced retinopathy (OIR). Retinal tissues were analyzed by Western blotting and immunofluorescent labeling was conducted on mouse retinal flatmounts and human retinal sections from patients with DR. In vitro studies used cultured bovine retinal endothelial cells (REC) subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R). Cells were treated with the HDAC3 inhibitor, RGFP966, the mitochondrial fission inhibitor, Mdivi-1 or DMSO as a control. Endpoints included assays of cell migration, untargeted proteomic analysis, Seahorse analysis of glycolysis, and mitochondrial morphology using MitoTracker dye. Using the methods described above, we found that HDAC3 expression was increased in retinal vessels of OIR mice and human DR retinal samples. HDAC3 also was upregulated in REC following OGD/R. Treatment with RGFP966 (2, 8 μM) attenuated OGD/R-induced angiogenesis as determined by cell migration. In confirmation, siRNA-mediated HDAC3 knockdown attenuated REC migration whereas HDAC3 overexpression increased it. OGD/R induced a strong upregulation of the rate-limiting glycolysis enzyme, hexokinase 2 (HK2), as determined by untargeted proteomic analysis, which correlated with increased glycolysis and mitochondrial fission. Treatment with RGFP966 or Mdivi-1 (5 μM), blocked HK2 upregulation, suppressed glycolytic flux, and reduced mitochondrial fission. Our findings indicate that HDAC3 plays a crucial role in pathological neovascularization by driving endothelial cell metabolic reprogramming toward glycolysis via the induction of mitochondrial fission and HK2 signaling. Targeting HDAC3 or its downstream metabolic pathways may offer a promising therapeutic strategy for mitigating pathological NV. Retinal endothelial cells (REC) respond to oxygen glucose deprivation/reperfusion (OGD/R) injury by increasing the expression of HDAC3 which, in turn, upregulates hexokinase 2 (HK2) and mitochondrial fission. These then go on to metabolically reprogram the REC toward a more glycolytic phenotype and promote the process of pathological angiogenesis of the retina. Inhibiting HDAC3 by RGFP966 protects against the OGD/R-induced metabolic changes. In a similar fashion, the inhibition of mitochondrial fission with Mdivi-1 mitigates the glycolytic shift and HK2 expression. These findings suggest a working model in which HDAC3-induced mitochondrial fission upregulates HK2, induces glycolysis and promotes REC pathological angiogenesis.
    Keywords:  HDAC3; HK2; endothelial cells; glycolysis; mitochondrial fission; retinal angiogenesis
    DOI:  https://doi.org/10.1038/s41401-025-01642-3
  44. Theranostics. 2025 ;15(18): 10007-10027
    Bone remodeling stimulated by Wnt-mediated mitophagy regulated extracellular vesicles in subchondral bone contributes to osteoarthritis development.
    Yuyuan Gu, Qirong Zhou, Shihao Sheng, Huijian Yang, Dan Huang, Qin Zhang, Hao Zhang, Zijian Cao, Yuanwei Zhang, Zuhao Li, Yingying Jiang, Xiao Chen, Yingying Jing, Chenglong Wang, Hongbo Tan, Ke Xu, Jiacan Su.
      Rationale: Osteoarthritis (OA) is increasingly understood as a disease involving not only cartilage degeneration but also pathological subchondral bone remodeling. The contribution of osteoblast (OB) heterogeneity and their secreted extracellular vesicles (EVs) to this process remains poorly characterized. This study aims to investigate how EVs from distinct OB subtypes modulate subchondral bone remodeling and contribute to OA progression. Methods: OB subtypes representing endothelial (EnOBs), stromal (StOBs), and mineralizing (MinOBs) stages were generated by time-controlled osteogenic induction of BMSCs. EVs were isolated from each OB subtype and characterized by TEM, Western blot, DLS, and miRNA profiling. Functional assays included osteogenic induction, angiogenesis, and cartilage degradation analyses in vitro. RNA-seq and qRT-PCR were used to identify relevant signaling pathways and miRNAs. In vivo effects of EVs were tested in a DMM-induced OA mouse model using intravenous injections, followed by histology, micro-CT, and immunostaining. Results: EVs derived from different OB subtypes exhibited distinct pro-osteogenic, pro-angiogenic, and cartilage-degrading effects. MinOB-derived EVs significantly enhanced osteogenic differentiation and mineralization, correlated with enrichment of calcium phosphate content and specific pro-osteogenic miRNAs. These EVs also carried amorphous calcium phosphate and mitochondrial content, linked to activated mitophagy. Wnt signaling dynamically regulated mitophagy and EV composition, particularly in MinOBs. In vivo, tail vein administration of OB-derived EVs exacerbated subchondral bone sclerosis and cartilage degradation in a time-dependent manner, with MinOB-EVs inducing the most pronounced pathological changes. Conclusions: OB-derived EVs exhibit subtype-dependent regulatory functions in subchondral bone remodeling, mediated by distinct miRNA profiles and mineral cargo shaped by Wnt-regulated mitophagy. These EVs actively participate in OA progression, and their effects vary with disease stage and route of administration. Targeting specific OB subtypes or modulating Wnt-mitophagy signaling may offer novel therapeutic strategies for stage-specific OA intervention.
    Keywords:  extracellular vesicles; mitophagy; osteoarthritis; osteoblast; subchondral bone
    DOI:  https://doi.org/10.7150/thno.111724
  45. Mater Today Bio. 2025 Dec;35 102252
    Mn-MIL-100@AKG alleviates intervertebral disc degeneration by regulating mitophagy.
    Xianglong Chen, Haiyang Gao, Anran Zhang, Pengzhi Shi, Yuhang Chen, Zhangrong Cheng, Wang Wu, Wenbo Wu, Yukun Zhang.
      Currently, the therapy of intervertebral disc degeneration (IDD) mostly focuses on basic molecular causes. Research on the alterations of metabolites in the intervertebral disc prior to and following intervertebral disc degeneration (IDD) remains inadequate, with even less therapeutic options available for metabolites. In contrast to traditional investigations of molecular mechanisms, it has been shown that a reciprocal relationship exists between the nutritional metabolism of the intervertebral disc and the molecular mechanisms of degeneration. Impaired energy metabolism in deteriorated nucleus pulposus cells exacerbates numerous degenerative phenotypes within the cells. This work investigated the metabolic alterations in the intervertebral disc after the creation of inflammatory degeneration models and illustrated the therapeutic benefits of α-ketoglutarate (AKG) on degenerated nucleus pulposus cells. This study introduces the first demonstration of a metal-organic framework (MOF)-based delivery system (Mn-MIL-100@AKG) for α-ketoglutarate (AKG) aimed at treating intervertebral disc degeneration (IDD), revealing a unique mode of mitophagy control through the HIF-1α-BNIP3-LC3B axis. Our study elucidated the critical function of autophagy regulation via the HIF-1α-BNIP3-LC3B axis in mitigating NPC degeneration and established a MOF-based AKG drug delivery system, offering a novel approach for the treatment of IDD.
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102252
  46. J Ethnopharmacol. 2025 Oct 01. pii: S0378-8741(25)01368-6. [Epub ahead of print] 120676
    The healing power of natural gifts: How the natural herbaceous plants targeting mitophagy can reverse diabetic complications.
    Xinxin Ma, Bing Jiang, Shengfang Wan, Zhaohui Wei.
       ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes is a chronic metabolic disorder characterized by a variety of etiological factors that progressively damage various tissues and organs due to prolonged metabolic dysregulation and elevated blood glucose levels. This condition poses significant risks to both physical and mental health. Natural botanical therapeutics are characterized by their "multi-component, multi-target, and multi-pathway" properties, and their safety profiles have been well established, particularly due to their relatively low hepatotoxic and nephrotoxic effects. Consequently, there is a growing preference among researchers for these agents.
    AIM OF THE REVIEW: The current review aims to conduct a comprehensive analysis of the ethnopharmacological applications of natural herbaceous plants to mitophagy within the context of diabetic complications.
    METHODS: An investigation into natural herbal remedies for diabetic complications was conducted, with a particular emphasis on the regulation of mitophagy. This study utilized traditional medical texts and ethnomedicinal literature as primary sources. Furthermore, relevant information related to ethnobotany, phytochemistry, and pharmacology is obtained from online databases, including PubMed and the China National Knowledge Infrastructure (CNKI), among others. "Diabetic complications", "mitophagy", "natural botanical drugs", "traditional Chinese medicine compounds", "single herbs extracts", and "active metabolites" were used as keywords when searching the databases. Consequently, pertinent articles published in recent years were collected and analyzed.
    RESULT: The integration of herbal plants into managing diabetic complications offers several notable advantages, which can be examined from two primary perspectives. Firstly, the molecular mechanisms that regulate mitophagy are influenced by various signaling pathways, including, but not limited to PINK1/Parkin, PI3K/Akt/mTOR, and AMPK/ULK1. Consequently, pharmacological agents targeting a single pathway may encounter challenges in effectively engaging multiple biological processes. Furthermore, an expanding body of research suggests that numerous herbal plants and their bioactive constituents can modulate various biological targets. These compounds appear to interact with several critical targets associated with mitophagy during diabetic complications, such as PINK1, Parkin, LC3B, Beclin1, p62, ATG5, and Drp1. Secondly, herbal plants and their bioactive compounds have exhibited a favorable safety profile, particularly in terms of diminished hepatotoxicity and nephrotoxicity when compared to conventional Western pharmacotherapy. For example, various compound formulations, including Huangqi Danshen decoction, Ginseng Dingzhi decoction, Shexiang Baoxin pill, Tangzhiqing decoction, and Jianpi Xingqi Huoxue decoction, have been utilized in China for centuries, demonstrating promising clinical efficacy. Recently, an increasing number of researchers have sought to isolate active constituents from these clinically effective compound formulations using diverse chemical methodologies. This endeavor is driven by the necessity to address challenges related to complex ingredient compositions and intricate processing methods. The isolated active compounds have been utilized in cellular and animal studies to elucidate the molecular mechanisms that underlie the efficacy of these formulations.
    CONCLUSIONS: Numerous traditional compound formulations from China have emerged as promising candidates for the development of pharmacological agents aimed at addressing diabetic complications. Notably, several of these formulations, which focus on the regulation of mitophagy, are currently the subject of extensive research by an increasing number of scholars.
    Keywords:  Diabetic complications; active metabolites; mitophagy; natural botanical drugs; single herbs extracts; traditional Chinese medicine compounds
    DOI:  https://doi.org/10.1016/j.jep.2025.120676
  47. Epilepsy Res. 2025 Sep 25. pii: S0920-1211(25)00169-X. [Epub ahead of print]218 107668
    CREB3L4 upregulates SIRT4 expression to increase GABA/glutamate ratio and mitochondrial homeostasis for epilepsy suppression.
    Haoyu Liu, Qiannan Song, Jiayi Jin, Hong Chen.
       BACKGROUND: cAMP response element-binding protein 3-like transcription factor 4 (CREB3L4) serves as an important transcriptional regulatory factor and plays a crucial role in neurological diseases, however, its specific mechanism in epilepsy pathogenesis remains unclear. This study aims to investigate the role of the CREB3L4-Sirtuin 4 (SIRT4) regulatory axis in epilepsy pathogenesis and its effects on γ-aminobutyric acid GABA/glutamate balance and mitochondrial function.
    METHODS: A classical epilepsy animal model was established, and quantitative real-time PCR, Western blot, and immunofluorescence staining techniques were employed to detect the expression changes of CREB3L4 and SIRT4 in the epilepsy model. CREB3L4 expression levels were modulated through lentivirus-mediated gene overexpression and RNA interference techniques to observe their effects on epileptic behavioral manifestations. ELISA was used to detect GABA and glutamate contents in brain tissues, and the GABA/glutamate ratio was calculated.
    RESULTS: CREB3L4 expression was downregulated 3.2-fold in the epilepsy model (1.026 ± 0.051-0.325 ± 0.028, p < 0.001), with 1.8-fold decreased GABA/glutamate ratio (1.065 ± 0.063-0.581 ± 0.046, p < 0.001). CREB3L4 overexpression upregulated SIRT4 mRNA 3.5-fold (0.185 ± 0.051-0.643 ± 0.039, p < 0.01) and reduced seizure frequency 2.0-fold (67.6 ± 3.1-34.4 ± 2.4 seizures, p < 0.001) and severity 2.2-fold (4.3 ± 0.3-2.0 ± 0.3 grade, p < 0.001). Conversely, CREB3L4 silencing exacerbated epilepsy progression, increasing seizure frequency 1.4-fold (58.7 ± 2.7-79.3 ± 4.2 seizures, p < 0.001) and severity 1.3-fold (3.7 ± 0.3-4.7 ± 0.2 grade, p < 0.001), with 2.2-fold decreased GABA/glutamate ratio (0.639 ± 0.051-0.288 ± 0.041, p < 0.001). Mechanistic studies demonstrated that CREB3L4 overexpression improved mitochondrial function through SIRT4 upregulation, thereby maintaining mitochondrial homeostasis. Meanwhile, activation of the CREB3L4-SIRT4 axis effectively increased brain tissue GABA content, improved the GABA/glutamate ratio, and restored neurotransmitter balance. Rescue experiments demonstrated that SIRT4 silencing (3.1-fold knockdown) significantly attenuated CREB3L4's neuroprotective effects, increasing seizure severity 1.6-fold (3.0 ± 0.5-4.8 ± 0.2 grade, p < 0.01), frequency 1.7-fold (43.2 ± 3.1-74.7 ± 4.2 seizures, p < 0.001), and reducing GABA/glutamate ratio 1.6-fold (1.81 ± 0.05-1.12 ± 0.05, p < 0.001), confirming SIRT4 as the key downstream mediator.
    CONCLUSION: This study elucidates the important role of the CREB3L4-SIRT4 regulatory axis in epilepsy pathogenesis, revealing the molecular mechanism by which CREB3L4 transcriptionally activates SIRT4, subsequently regulates GABA/glutamate balance and maintains mitochondrial homeostasis, ultimately suppressing seizures and associated pathophysiological damage.
    Keywords:  CREB3L4; Epilepsy; GABA/glutamate ratio; Mitochondrial homeostasis; SIRT4
    DOI:  https://doi.org/10.1016/j.eplepsyres.2025.107668
  48. J Med Chem. 2025 Oct 01.
    Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.
    Zhongli Xu, Dmitry Pokushalov, Md Kabir, Youngeun Lee, Mrittika Chattopadhyay, Edmund C Jenkins, Cessarina Choo, H Ümit Kaniskan, Doris Germain, Jian Jin.
      Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound 9 (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound 9 induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound 9 therefore add to the expanding arsenal of imipridones to target ClpP in cancer.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c01315
  49. Free Radic Biol Med. 2025 Sep 27. pii: S0891-5849(25)01008-1. [Epub ahead of print]
    Methionine sulfoxide reductase A deficiency impairs zebrafish heart regeneration via inhibiting Prohibitin 2-Pink1-mediated mitophagy.
    Huicong Li, Xin Yang, Jiayi Li, Yan Zhao, Jieling Liang, Yanmei Liu, Fen Du, Hong Yu, Ruilin Zhang.
      Ischemic heart disease is among the cardiovascular diseases with the highest mortality rates worldwide. Redox homeostasis is critical for a wide range of biological processes, including cardiac injury and repair. Methionine sulfoxide reductase A (MSRA) has been reported as a protective factor for cardiomyocytes both in vivo and in vitro, however, the underlying mechanisms are not fully understood. Here we demonstrated that Msra deficiency in zebrafish results in heart regeneration failure after larval ventricle ablation. Using a proximity labelling assay we identified prohibitin 2a (Phb2a), an ortholog of human PHB2, as a potential substrate of Msra. We further revealed that Pink1-mediated mitophagy is inhibited, thereby impairing heart regeneration in Msra-deficient zebrafish. Moreover, mitophagy is also impeded in Msra-KO HL-1 mouse cardiomyocytes under oxidative stress. Blocking the oxidation of PHB2 by substituting its essential methionine with valine rescues Msra-KO cardiomyocytes from oxidative stress. Taken together, our findings shed light on the role that methionine redox homeostasis plays in the regulation of mitophagy in ischemic heart disease and provide a foundation for the identification of novel therapeutic targets.
    Keywords:  heart regeneration; methionine sulfoxide reductase A; mitophagy; prohibitin 2; redox homeostasis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.051
  50. ACS Cent Sci. 2025 Sep 24. 11(9): 1700-1714
    Illuminating Mitochondrial Dynamics: Ultrahigh Labeling Stability Probe for Long-Term SIM Super-Resolution Imaging of Mitochondria.
    Xiangpeng Lin, Xuelei Pang, Yue Huang, Xinxin Duan, Yunfei Wei, Ning Jing, Meng Zhang, Yu-Hui Zhang.
      Delineating intricate mitochondrial dynamic changes over extended time scales through combined fluorescent probes and super-resolution microscopy is pivotal for deciphering the pathogenesis of mitochondrial-related diseases. However, a major challenge lies in the scarcity of probes that simultaneously exhibit robust labeling stability, exceptional photostability, and minimal cytotoxicity. Herein, rational design and screening yielded a novel covalent mitochondrial probe, HZ Mito Red. Due to its exceptional covalent labeling efficiency, HZ Mito Red exhibits superior mitochondrial labeling stability, with a 10-fold improvement compared to Mito Tracker Red (MTR). Furthermore, it exhibits remarkable photostability, retaining over 80% fluorescence after 300 SIM images, and negligible phototoxicity, preserving mitochondrial integrity even after 400 SIM images of continuous imaging. These advantageous properties facilitated the pioneering of high signal-to-noise, long-term dynamic SIM super-resolution imaging of mitochondria during ferroptosis, apoptosis, and autophagy, achieving unprecedented detailed delineation of mitochondrial morphology. Additionally, engineered for multichannel mitochondrial imaging, HZ Mito Deep Red mirrors the exceptional labeling stability of HZ Mito Red, achieving near-phototoxicity-free dynamic tracking with 60% fluorescence retention after 300 SIM images. Significantly, both HZ Mito Red and HZ Mito Deep Red are compatible with cell immunofluorescence staining. This study provides a robust and versatile tool for the in-depth analysis of mitochondrial dynamics in disease states.
    DOI:  https://doi.org/10.1021/acscentsci.5c00695
  51. J Therm Biol. 2025 Sep 27. pii: S0306-4565(25)00240-2. [Epub ahead of print]133 104283
    Mitochondrial adaptations from heat acclimation - A narrative review.
    Marcos S Keefe, Danielle E Levitt, Heather L Vellers, Courteney L Benjamin, Yasuki Sekiguchi.
      In recent decades, global temperature and humidity levels have surged. These increases in temperature and humidity are associated with higher risk of heat-related illnesses and impaired exercise performance, thereby prompting investigation into physiological responses to heat stress. Preconditioning strategies, including heat acclimation/acclimatization (HA), elicit physiological adaptations to enhance response to future heat exposures. Within HA research, an area of growing interest is examination of subcellular adaptations that contribute to whole-body acclimation, such as changes to/within mitochondria. External heat stress alters molecular pathways involved in mitochondrial biogenesis and bioenergetic function, but the relationship between these alterations and whole-body HA adaptations remains relatively unknown. Therefore, this review provides a detailed examination of the impact of HA on mitochondria across cell models, rodent models, and humans, linking these changes to exercise performance. Based on the current evidence, we propose a HA protocol aimed at promoting mitochondrial adaptations while maximizing traditional HA benefits. Lastly, we identify key areas for future research to further explore and enhance our understanding of mitochondrial responses to HA.
    Keywords:  Heat acclimation; Heat stress; Mitochondria; Mitochondrial biogenesis; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.jtherbio.2025.104283
  52. Stem Cell Res Ther. 2025 Sep 29. 16(1): 531
    BRD-K20733377 inhibits ferroptosis and alleviates intervertebral disc degeneration via the STAT3/NFKB1 axis: a multiapproach study.
    Hua Sun, Xuan You, Zhaoyu Li, Zhengguang Li, Benkui Hua, Chen Liu, Yongbo Zhang, Huofeng Wu, Shuangjia Zai, Liang Zhang.
       INTRODUCTION: Intervertebral disc degeneration (IVDD) is one of the main causes of low back pain. Existing literature has confirmed the occurrence of ferroptosis in IVDD. With the widespread application of artificial intelligence (AI), an increasing number of compounds have been screened for their potential to alleviate IVDD. BRD-K20733377 is one such compound with anti-aging properties. Preliminary experiments have shown that BRD-K20733377 can significantly inhibit cellular ferroptosis. However, research on the potential therapeutic targets and mechanisms of BRD-K20733377 in IVDD remains limited.
    OBJECTIVE: This study aims to explore the main targets and potential mechanisms of BRD-K20733377 in the treatment of IVDD.
    METHODS: Network pharmacology, bioinformatics, machine learning algorithms, molecular docking, molecular dynamics, and Mendelian randomization were used to comprehensively analyze the effects, potential targets, and mechanisms of BRD-K20733377 in IVDD. Rat nucleus pulposus-derived mesenchymal stem cells (NPMSCs) were selected for in vitro experiments. Cell viability was measured by CCK-8 and flow cytometry, while antioxidant defense, lipid peroxidation, and iron metabolism were explored using JC-1, Reactive Oxygen Species (ROS), FerroOrange dye, Lipid peroxides, Malondialdehyde (MDA), and Mitochondrial transmission electron microscopy. The expression levels of ferroptosis-related proteins were detected by Western blot and immunofluorescence. In the rat IVDD model, the effects of BRD-K20733377 on pain threshold, pain behavior, and its therapeutic efficacy were evaluated.
    RESULTS: Predictive results identified 30 genes related to ferroptosis in BRD-K20733377 and IVDD, revealing that the potential mechanism of BRD-K20733377 in treating IVDD is closely associated with ferroptosis. In addition, functional enrichment analysis indicated that these genes are involved in multiple signaling pathways. Machine learning algorithms further identified the core targets STAT3 and NFKB1, and Mendelian randomization validated their direct causal relationship with IVDD. In vitro experiments confirmed that BRD-K20733377 inhibited IVDD by reducing intracellular Fe²⁺ levels and lipid peroxidation, thus regulating ferroptosis. Theoretically, BRD-K20733377 may inhibit NPMSCs ferroptosis via STAT3/NFKB1 axis. Ferroptosis-related proteins and immunofluorescence results further supported this mechanism. In vivo experiments showed that BRD-K20733377 significantly improved the behavior of SD rats, reduced pain scores, and alleviated IVDD.
    CONCLUSION: BRD-K20733377 inhibits ferroptosis through the STAT3/NFKB1 axis, thereby alleviating IVDD. This provides a new perspective for the study of IVDD and could serve as a potential therapeutictarget for IVDD.
    Keywords:  Ferroptosis; Intervertebral disc degeneration; Mendelian randomization; Molecular dynamics; Network pharmacology
    DOI:  https://doi.org/10.1186/s13287-025-04662-2
  53. Front Aging Neurosci. 2025 ;17 1611958
    MFN2-a multifaceted guardian against Parkinson's pathophysiology: mitochondria, ferroptosis, inflammation and oxidative stress.
    Yan Cheng, Hongjiang Zhai, Yong Liu, Yunzhou Yang, Bo Fang, Mingxiang Song, Xiuqin Wang, Ping Zhong.
       Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and its exact pathogenesis remains unclear. This study aims to comprehensively explore the role of MFN2 in PD based on in vivo and in vitro models for multidimensional understanding.
    Methods: In vivo, C57BL/6 J male mice were administered MPTP and probenecid by intraperitoneal injection to establish PD models. Lentivirus carrying MFN2 was microinjected into the bilateral striatum of specific groups of mice. The motor and cognitive functions of the mice were evaluated using the rotarod test and the open field test. In vitro, SH-SY5Y cells were treated with MPP+ to establish cell-based PD models. Transfection of plasmids was used to achieve overexpression or knockdown of MFN2. Subsequently, a series of experiments such as qRT-PCR, Western blot, CCK-8, flow cytometry and ELISA were used to verify the potential mechanism of MFN2.
    Results: In PD models, the expressions of DHODH, MFN1, MFN2, GPX4, and FSP1 were significantly down-regulated, and their motor coordination, self-cognitive behavior, and exploration ability were decreased. Concurrently, inflammatory and oxidative stress responses were enhanced, cell viability was weakened, apoptosis was increased, and mitochondrial abnormalities were observed. Overexpression of MFN2 improved the motor, cognitive and neurological damage in mice, enhanced cell viability, inhibited apoptosis, reduced the levels of inflammatory and oxidative stress factors, and up-regulated the expressions of DHODH, MFN1, GPX4 and FSP1. Mitochondrial morphological observation showed that MFN2 overexpression alleviated mitochondrial abnormalities.
    Conclusion: MFN2 may play a protective role in PD by regulating mitochondrial function, ferroptosis, inflammation and oxidative stress-related factors, providing a new theoretical basis and potential therapeutic targets for the treatment of PD.
    Keywords:  Parkinson’s disease; ferroptosis; inflammatory; mitochondrial function; mitofusin 2; oxidative stress
    DOI:  https://doi.org/10.3389/fnagi.2025.1611958
  54. Planta. 2025 Sep 29. 262(5): 110
    Arabidopsis Dynamin-Related Protein 1a is important for cell plate fusion with parent cell plasma membrane in cytokinesis during pollen mitosis I.
    Nan Wang, Qingchen Rui, Haoyue Xu, Xiaoyun Tan.
       MAIN CONCLUSION: Arabidopsis Dynamin-Related Protein 1a is important for mediating cell plate-parental membrane fusion during pollen mitosis I by regulating the formation of finger-like projections at the margin of the cell plate. Pollen mitosis I (PMI) is critical for pollen development, and the fusion of the cell plate with the parental plasma membrane is one of the most essential events during cytokinesis in PMI. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we show that Arabidopsis Dynamin-Related Protein 1a (DRP1a), a multidomain GTPase regulating membrane remodeling processes such as fission, fusion, and tubulation, is required for cell plate fusion with the parental plasma membrane during PMI. Loss of DRP1a function leads to pollen abortion, with most drp1a mutant pollen grains failing to complete cell plate-parental membrane fusion. Further analysis revealed that in wild-type microspores, finger-like projections extend from the margins of the expanding cell plate and establish contact at the plasma membrane's adhesion zone. However, these structures were absent in cytokinesis-defective pollen grains from drp1a/ + mutants. Notably, DRP1a-YFP localized specifically to the cell plate margins, suggesting its direct involvement in this process. Our findings demonstrate that DRP1a, a member of the Dynamin-Related Protein family known for its roles in membrane remodeling, is important for mediating cell plate-parental membrane fusion during PMI by regulating the formation of finger-like projections.
    Keywords:  Cell plate fusion; Cytokinesis; Dynamin-Related Protein; Pollen mitosis I (PMI)
    DOI:  https://doi.org/10.1007/s00425-025-04832-9
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