bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–01–18
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
  2. Sirtuin 4 Knockout Aggravates Sepsis-Induced Acute Liver Injury by Enhancing Mitochondrial Fission and Mitophagy in Hepatocytes.
  3. Mitochondrial homeostasis meets novel programmed cell death: crosstalk mechanisms underlying cardiovascular diseases progression.
  4. Inhibition of Pathological Mitochondrial Fission in Retinal Pigment Epithelium Mitigates Choroidal Neovascularization.
  5. Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated inflammation and inhibits post-infarct cardiac remodeling.
  6. Mechanism of Ershen Zhenwu Decoction in Treating Chronic Heart Failure by Regulating PTEN-induced putative kinase 1/Parkin pathway mediated mitophagy.
  7. Manipulating the Mitochondrial Unfolded Protein Response for Broad-Spectrum Genotoxicity Mitigation and Tumorigenesis Suppression by Ultrasmall Gold Nanoparticles.
  8. Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.
  9. Dual-faced PUMA in CRC: A cytoplasmic autophagy repressor and mitochondrial mitophagy promoter.
  10. TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.
  11. A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
  12. Desmopressin Induces Mitochondrial Fragmentation and Dysfunction in Human U87 MG Glioma Cells via CaMKII-Drp1 Signaling Pathway.
  13. Pollutant-regulated mitophagy: new perspectives in environmental toxicology.
  14. The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma.
  15. Targeting ANT1 to regulate PINK1/Parkin-mediated mitophagy is an effective treatment of trauma-induced tendon heterotopic ossification.
  16. Thonningianin A derived from Penthorum chinense Pursh alleviates cerebral ischemia/reperfusion-mediated apoptosis and pyroptosis through the activation of PINK1/Parkin-dependent mitophagy.
  17. What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
  18. Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
  19. SIRT3 attenuates AGEs-induced senescence in human granulosa cells through enhancing mitophagy.
  20. Tongmai Yangxin pill mitigates myocardial ischemia/reperfusion injury by improving mitochondrial function and mitophagy: A potential role of estrogen receptor alpha and PTEN-induced putative kinase 1/Parkin pathway.
  21. [Shihu Mixture alleviates diabetic cardiomyopathy in rats by Sirt3-mediated upregulation of myocardial mitochondrial mitophagy pathway].
  22. AMPK Modulates the Interplay Between PINK1/Parkin-Mediated Mitophagy and NLRP3-Driven Inflammation in Diabetic Periodontal Tissue Under Mechanical Loading.
  23. Naringenin-functionalized polyester nanoparticles improve oral urolithin A delivery and protect against cisplatin-induced kidney injury via heme oxygenase-1 activation and mitochondrial quality control.
  24. The dual regulation of mitophagy in myocardial injury: From molecular mechanisms to targeted therapies.
  25. Melatonin alleviates rheumatoid arthritis by promoting Src/Fundc1-mediated mitophagy to regulate macrophage polarization.
  26. Empagliflozin Supplementation in Cardioplegic Solution Improves Donor Heart Preservation by Maintaining Mitochondrial Homeostasis.
  27. New Insights of Punicalagin in Alleviating Diabetic Liver Injury: Inhibition of NEK7-NLRP3 via Modulating Mitochondrial Dynamics.
  28. Mitochondrial uncoupler BAM15 ameliorates liver lipid metabolism disorders by activating the AMPK pathway.
  29. UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson's disease.
  30. Targeting SPHK1 by 8-HETrE attenuates MASH-Driven fibrosis via restoration of hepatic stellate cell mitochondrial dynamics.
  31. Hesperetin alleviates neuronal pyroptosis by promoting mitophagy via DHCR24/BACE1 signaling pathway after subarachnoid hemorrhage in mice.
  32. Identification of prognostic signatures in pheochromocytomas and paragangliomas based on mitochondrial autophagy and ferroptosis in TCGA and GEO datasets.
  33. Advances in autophagy for Parkinson's disease pathogenesis and treatment.
  34. Inhibitory effect of blestriarene C on triple-negative breast cancer: inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis.
  35. Synergistic kidney toxicity of polylactic acid nanoplastics and Cr(VI): Ferroptosis aggravated by mitophagy.
  36. USP8-mediated mitochondrial regulation in osteoclasts is essential for skeletal development.
  37. Impaired Mitophagy-Induced Apoptosis of Gingival Fibroblasts Exacerbates Diabetic Periodontitis Via THBS-1/CD36-Dependent Macrophage Activation.
  38. Secoemestrin C exerts rapid and prominent anti-breast cancer effect in triple-negative breast cancer by inducing SLX4 and YAP degradation.
  39. Lactoferrin protects against radiation-induced intestinal injury by regulating pyroptosis and mitophagy.
  40. S100A4 triggeres the pyroptosis of vsmcs: association with mitochondrial damage, impaired mitophagy, and Ca2+ dysregulation.
  41. RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses.
  42. Natural exosome-like nanovesicles from Smilax China rhizome induce mitophagy-dependent ferroptosis in hepatocellular carcinoma via GPX4/ACSL4 axis.
  43. Arachidonic acid induces pyroptosis via a non-autophagic function of mitophagy and enhances immunotherapy in a PDAC model.
  44. Non-surgical periodontal treatment improves mitochondrial bioenergetics in circulating immune cells of patients with chronic periodontitis.
  45. Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.
  46. Lariciresinol and secoisolariciresinol enhance myogenic differentiation and mitochondrial biogenesis in C2C12 myotubes.
  47. Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression.
  48. Reversible phase dynamics of PsAF5 regulate mitophagy to balance redox levels in Phytophthora sojae.
  49. CircCramp1l targets the miR-532-3p/HMGB1/Drp1 axis to regulate allergic rhinitis.
  50. Cross-regulation of autophagy and pyroptosis: a new perspective on the inflammatory microenvironment of atherosclerosis.
  51. Retraction: SSBP1 Suppresses TGFβ-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling.
  52. Iron oxide nanoparticles-driven mitochondrial renewal rejuvenates the aged bone marrow niche.
  53. Mertk-driven tunneling nanotube formation in macrophages preserves mitochondrial homeostasis during kidney Ischemia-Reperfusion Attack.
  54. HMOX1 drives dihydroartemisinin-sensitized ferroptosis antagonized by mitochondrial fusion.
  55. 6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
  56. Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.
  57. Naphthylimide-based mitochondrial immobilized probes for polarity-specific imaging of mitochondrial autophagy in cells and mouse cardiac tissue.
  58. Myricanol modulates PPARγ/ACSL1/SCD1 metabolic signaling pathway to promote mitochondria biogenesis and fatty acid β-oxidation in high-fat diet-induced obese mice.
  1. EMBO Rep. 2026 Jan 13.
    Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
    Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Shun-Ichi Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Nobuo N Noda, Tomotake Kanki.
      Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.
    Keywords:  Atg44; Mfi2; Mitochondrial Fission; Mitofissin; Mitophagy
    DOI:  https://doi.org/10.1038/s44319-025-00689-x
  2. Mediators Inflamm. 2026 ;2026 7600668
    Sirtuin 4 Knockout Aggravates Sepsis-Induced Acute Liver Injury by Enhancing Mitochondrial Fission and Mitophagy in Hepatocytes.
    Na Li, Dan Ma, Suxin Luo, An He, Shuting Chang.
       Background: Sepsis leads to multiorgan damage, with the liver being the main target. Sirtuin 4 (Sirt4) plays a regulatory role in mitochondrial function and metabolism, but its mechanism in liver injury caused by sepsis remains unclear.
    Methods: The mouse model of liver injury caused by sepsis was established by cecal ligation and puncture (CLP) surgery. The degree of liver injury in wild-type (WT) and Sirt4 gene total knockout (Sirt4-KO) mice was compared by serum AST, alanine aminotransferase (ALT), and histological analysis. The expression of mitophagy and mitochondrial dynamic indicators was detected by biochemical experiments.
    Results: Liver injury in Sirt4-KO mice was more severe than that in WT mice after CLP, manifested as significant upregulation of mitophagy and mitochondrial dynamics imbalance. Mechanistically, Sirt4 deficiency increases mitochondrial fission and mitophagy, thereby leading to cellular damage.
    Conclusions: Sirt4 knockout (KO) aggravates liver injury in sepsis through increasing mitochondrial fission and mitophagy, which indicates a promising direction for future clinical treatment.
    Keywords:  DRP1; Parkin; mitophagy; sepsis-induced liver injury; sirtuin 4
    DOI:  https://doi.org/10.1155/mi/7600668
  3. Cell Commun Signal. 2026 Jan 15.
    Mitochondrial homeostasis meets novel programmed cell death: crosstalk mechanisms underlying cardiovascular diseases progression.
    Meng Li, Yue Zhang, Yue Hu, Yiqi Qin, Yawei Zheng, Shichao Lv, Junping Zhang.
      
    Keywords:  Cardiovascular diseases; Mitochondrial dynamics; Mitophagy; Programmed cell death
    DOI:  https://doi.org/10.1186/s12964-026-02673-x
  4. Invest Ophthalmol Vis Sci. 2026 Jan 05. 67(1): 4
    Inhibition of Pathological Mitochondrial Fission in Retinal Pigment Epithelium Mitigates Choroidal Neovascularization.
    Hiroto Yasuda, Shinsuke Nakamura, Aimi Shirakawa, Yoshiki Kuse, Masamitsu Shimazawa.
       Purpose: Mitochondria are highly dynamic organelles that continuously undergo fission and fusion, and their dysfunction is associated with various age-related disorders. This study aimed to elucidate the role of mitochondrial fission in the development of choroidal neovascularization (CNV), a hallmark of neovascular age-related macular degeneration (AMD), and to evaluate the therapeutic potential of its pharmacological inhibition.
    Methods: The murine CNV model was created by laser photocoagulation using C57BL/6J mice. Expression changes of mitochondrial fission-related protein during CNV development were examined using western blotting and immunofluorescence. To assess the effectiveness of pharmacological inhibition of mitochondrial fission, the effects of mitochondrial division inhibitor-1 (Mdivi-1) and mitochondrial fusion promoter (M1) were evaluated by CNV area measurement, fluorescein angiography, and western blot analysis. The pro-angiogenic mechanisms associated with mitochondrial fission were further investigated in RPE cells cultured under hypoxic condition.
    Results: In a murine laser-induced CNV model, mitochondrial fission-related proteins increased in the retinal pigment epithelium (RPE)-choroid complex, and the high expression of phosphorylated dynamin-related protein 1 (DRP1) was observed in RPE cells surrounding the CNV lesion. Additionally, intravitreal injection of Mdivi-1 or M1 suppressed CNV formation, vascular leakage, and pro-angiogenic factor production. In RPE cells exposed to hypoxia, DRP1-mediated mitochondrial fission was rapidly activated, accompanied by increased mitochondrial reactive oxygen species production. Moreover, inhibition of mitochondrial fission suppressed mitochondrial bioenergetic dysfunction and the upregulation of vascular endothelial growth factor.
    Conclusions: These findings support that pharmacological inhibition of activated mitochondrial fission could serve as a potential therapeutic approach for neovascular AMD.
    DOI:  https://doi.org/10.1167/iovs.67.1.4
  5. Cardiovasc Res. 2026 Jan 16. pii: cvag006. [Epub ahead of print]
    Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated inflammation and inhibits post-infarct cardiac remodeling.
    Yuki Kondo, Jun-Ichiro Koga, Nasanbadrakh Orkhonselenge, Lixiang Wang, Nao Hasuzawa, Shunsuke Katsuki, Tetsuya Matoba, Yosuke Nishimura, Masatoshi Nomura, Masaharu Kataoka.
       AIM: Ischemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in an ageing society. Macrophages play a central role in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion; however, the role of these morphological changes, particularly in macrophages, remains unknown. This study investigated the role of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, in macrophages and its involvement in the mechanisms of left ventricular remodeling after myocardial infarction (MI).
    METHODS AND RESULTS: This study utilized genetically altered mice lacking Drp1 in Lysozyme M-positive cells (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. Deletion of Drp1 in macrophages exacerbated LV remodeling, underpinned by reduced ejection fraction and increased LV diameter, which resulted in a poor prognosis after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in the infarcted hearts of Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) into the cytosol and the induction of inflammatory cytokines. This induction was abrogated by the autophagy inducer Tat-beclin1 or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by the Drp1 inhibitor Mdivi-1.
    CONCLUSION: Macrophage Drp1 plays a critical role in the pathobiology of post-infarct LV remodeling, particularly in mitochondrial quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.
    DOI:  https://doi.org/10.1093/cvr/cvag006
  6. J Ethnopharmacol. 2026 Jan 13. pii: S0378-8741(26)00067-X. [Epub ahead of print] 121216
    Mechanism of Ershen Zhenwu Decoction in Treating Chronic Heart Failure by Regulating PTEN-induced putative kinase 1/Parkin pathway mediated mitophagy.
    Xinyue Wang, Ruyu Zhang, Yulong Liu, Maomao Zhang, Mengzhao Wei, Zhenpeng Zhu, Dan Cheng, Xiaoyu Cheng, Lan Ge.
       ETHNOPHARMACOLOGICAL RELEVANCE: Chronic heart failure (CHF) is characterized by complex pathogenesis involving various pathogenic mechanisms such as dysregulated autophagy, mitochondrial dysfunction, cardiomyocyte apoptosis, and chronic inflammation. Ershen Zhenwu Decoction (ESZWD) is a traditional Chinese herbal formulation. Several prospective, randomized, controlled clinical trials have indicated its clinical efficacy. However, whether ESZWD confers cardioprotective effects by regulating mitophagy and the associated molecular pathways remains elusive.
    AIM OF THE STUDY: This study aimed to investigate whether ESZWD ameliorates CHF by modulating PTEN-induced putative kinase 1(PINK1)/Parkin pathway mediated mitophagy.
    METHODS: UHPLC-Q-TOF MS was performed to identify the chemical compounds in ESZWD. Network pharmacology, molecular docking and dynamics were predict possible therapeutic targets. A rat model of CHF with heart-kidney yang deficiency syndrome was created for in vivo investigations via thyroidectomy and doxorubicin induction, followed by treatment with ESZWD. Furthermore, the impact of ESZWD was determined by monitoring cardiac function, serum biomarkers (ATP, ADP, NT-proBNP), myocardial histopathology, mitochondrial ultrastructure, and ROS levels. In addition, the expression of mitophagy-related proteins (PINK1, Parkin, LC3II/I, Beclin-1 and p62) in myocardial tissues was assessed via Western blotting. In vitro, DOX-stimulated AC16 cardiomyocyte injury model cells were exposed to ESZWD or the autophagy suppressor 3-methyladenine (3-MA). Then, the expression of PINK1, Parkin, LC3II/I, Beclin1 and p62 was assessed by PCR and Western blotting. Similarly, the cellular localization and expression of PINK1 and Parkin were confirmed by immunofluorescence staining.
    RESULTS: The data identified 785 compounds in ESZWD, with saponins, terpenes, alkaloids, phenolic acids and tanshinones being particularly abundant. Network pharmacology analysis revealed that ESZWD's therapeutic benefits via the PINK1/Parkin signaling pathway to regulate mitophagy, decreasing CHF onset and progression. Molecular dynamics simulations demonstrated persistent interactions between the active chemical 8-gingerol and the PINK1 protein. In vivo, ESZWD therapy improved cardiac function in CHF rats and mitophagy-related proteins, indicating its ability to inhibit mitophagy. In vitro experiments confirmed that ESZWD significantly reduced autophagy-related proteins, with effects consistent with those of the autophagy inhibitor 3-MA, validating that ESZWD mitigates pathological mitophagy.
    CONCLUSIONS: This study preliminarily revealed that ESZWD may alleviates CHF by modulating the PINK1/Parkin signaling pathway to inhibit mitophagy.
    Keywords:  Chronic heart failure; Ershen Zhenwu Decoction; Mitophagy; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.jep.2026.121216
  7. Bioconjug Chem. 2026 Jan 13.
    Manipulating the Mitochondrial Unfolded Protein Response for Broad-Spectrum Genotoxicity Mitigation and Tumorigenesis Suppression by Ultrasmall Gold Nanoparticles.
    Wendi Huo, Yaqi Jiang, Wencong Zhao, Liyuan Xue, Panpan Ruan, Kaidi Luo, Xiaofei Huang, Yunhao Ren, Xueyun Gao, Kai Cao.
      Mitochondrial dysregulation, represented by both imbalanced mitochondrial dynamics and dysfunction, has been found as a key driver of cell transformation and tumorigenesis due to enhanced apoptotic priming and genotoxic stress. The mitochondrial unfolded protein response (UPRmt) represents a protective mechanism that maintains mitochondrial function under mitochondrial damage, making it an attractive target for restoring mitochondrial homeostasis and preventing tumorigenesis. Here, we report an ultrasmall glutathione (GSH)-protected gold nanoparticle (GGNP) that exhibits mitochondrial presence. When mitochondria are damaged by various genotoxic insults, GGNP dramatically activates UPRmt and improves mitochondrial function without altering mitochondrial dynamics. As a result, GGNP significantly attenuates DNA damage and apoptosis, leading to the prevention of malignant transformation in vitro. More importantly, in a spontaneous lung cancer model, GGNP significantly delays tumorigenesis with reduced DNA damage and cell death within lung tissue without causing systemic toxicity. These findings not only reveal the role of UPRmt in tumorigenesis but also identify GGNP as a biocompatible nanomaterial that effectively modulates UPRmt to alleviate mitochondrial stress responses and thus acts as a broad-spectrum genotoxicity mitigator to offer a promising strategy for cancer prevention.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.5c00514
  8. Toxicol Appl Pharmacol. 2026 Jan 12. pii: S0041-008X(26)00011-6. [Epub ahead of print] 117715
    Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.
    Mariana Caprio Schiess, Gessica Sabrina de Assis Silva, Natália Gabriele Hösch, Vitória Carvalho Troitiño, Marcelo Medina de Souza, Carlos DeOcesano-Pereira, Talita Glaser, Alexander Henning Ulrich, Ana Marisa Chudzinski-Tavassi, Michelle Cristiane Bufalo, Vanessa Olzon Zambelli.
      Taxanes are considered first-line chemotherapeutic agents to treat solid cancer. Paclitaxel (PTX) is a commonly used taxane and although effective, it induces peripheral chronic neuropathy in around 60-70% of patients. Studies have demonstrated a correlation between impairment in bioenergetic metabolism and the development of neuropathies. However, the correlation between mitochondrial fusion-fission processes in sensory neurons and the development of neurodegeneration and pain remains poorly understood. Considering that neurons have a high metabolic demand and numerous mitochondria, and that chemotherapy-induced neuropathy is often accompanied by mitochondrial dysfunction, we investigated the role of mitochondrial plasticity in sensory-like neuron cells incubated with paclitaxel. Our findings indicate that neurotoxic concentrations of paclitaxel induce mitochondrial fragmentation by downregulating fusion proteins, such as mitofusin-1 and - 2 (MFN1 and MFN2), and upregulating fission proteins, such as dynamin-related protein 1 (Drp1). Also, paclitaxel increases superoxide release, impairs neuritogenesis, and activates pro-nociceptive signaling, measured by activating transcription factor 3 (ATF-3) expression, substance P release, and prostaglandin E2 (PGE2) - induced calcium influx. Of note, blocking excessive fission with P110, a pharmacological inhibitor of Drp1, PTX-induced cytotoxicity was prevented in sensory neuron-like cells. Together, our data suggest that impairment in mitochondrial dynamics of sensory neurons contributes to paclitaxel neurotoxicity and, consequently, to nociception. Therefore, preventing mitochondrial fission may be a strategy to prevent PTX-induced neurotoxicity, opening a new perspective to understanding the mechanisms involved in the development of PTX-induced neuropathy.
    Keywords:  Mitochondrial dynamics; Neuropathic pain; Oxidative stress; Paclitaxel; Sensory neuron
    DOI:  https://doi.org/10.1016/j.taap.2026.117715
  9. Cell Signal. 2026 Jan 10. pii: S0898-6568(26)00012-4. [Epub ahead of print]140 112363
    Dual-faced PUMA in CRC: A cytoplasmic autophagy repressor and mitochondrial mitophagy promoter.
    Meimei Jiang, Mingyi Zhao, Yeying Liu, Jing Liu, Nannan Liu, Jiehan Li, Wunan Mi, Guiyun Jia, Yang Fu, Lingling Zhang, Yingjie Zhang, Feng Wang.
      As Bcl-2 family members, PUMA and Bcl-XL played critical roles in mitochondrial apoptosis. However, whether they can regulate autophagy, especially mitophagy, is not understood at all. In this study, we explore the interaction among PUMA and Bcl-XL in different subcellular localizations, and their functions in autophagy and mitophagy respectively. The detailed mechanisms were determined by mitochondria purification, Co-IP, and western blot analysis. Moreover, living cell imaging was performed to determine the occurrence of mitophagy. We found that PUMA inhibited autophagy by interacting with Ulk1 and Beclin1 in the cytoplasm. Six mutants of PUMA were constructed to further study which part is responsible for the interaction, and the BH3 domain shows indispensability. When PUMA moved to mitochondria and formed a complex with Ulk1 and Bcl-XL, which played opposite roles, in promoting mitophagy. During this process, Ser96 of PUMA was indispensable for activating mitophagy. Besides, over-expressed PUMA or Bcl-XL promotes obvious mitophagy, and the real-time detection of lysosome and mitochondria shows fusion. Our results identified new functions and molecular mechanisms of PUMA and Bcl-XL in autophagy and mitophagy, which supplied theoretical bases for CRC therapy and other diseases.
    Keywords:  Bcl-X(L); CCCP; Macro-autophagy; Mitophagy; PUMA; Ulk1
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112363
  10. Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00023-7. [Epub ahead of print]
    TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.
    Yixiao Xu, Yishun Gong, Jiafa Zhong, Binghong Gao.
       OBJECTIVE: Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
    METHODS: A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
    RESULTS: In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
    CONCLUSION: TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.
    Keywords:  TRPV1; active heat acclimation; mitochondrial turnover; oxidative phosphorylation; skeletal muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.015
  11. Cell Mol Life Sci. 2026 Jan 12.
    A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
    Marlena Helms, Angelika B Harbauer.
      Neurons have adapted the transport and positioning of mitochondria to fit their extended shape and high energy needs. To sustain mitochondrial function, neurons developed systems that allow local biogenesis and adaption to locally regulate mitochondrial form and function. Likewise, fine-tuned degradative systems are required to protect the neurons from mitochondrial dysfunction. Throughout both domains of mitostasis, the local synthesis of the mitochondrial damage-induced kinase PINK1 emerges as a central player. Along with other nuclear encoded mitochondrial proteins, its mRNA associates with mitochondria to sustain mitochondrial function locally. It also regulates mitochondrial degradation, via regulation of proteases, the generation of mitochondria-derived vesicles and mitophagy. In this review, we provide a general overview of the mechanisms governing mitochondrial health in neurons, with a special focus on the role of PINK1 in this endeavor.
    Keywords:  Local translation; Mitochondrial proteases; Mitophagy; mRNA transport
    DOI:  https://doi.org/10.1007/s00018-025-06054-4
  12. Drug Dev Res. 2026 Feb;87(1): e70224
    Desmopressin Induces Mitochondrial Fragmentation and Dysfunction in Human U87 MG Glioma Cells via CaMKII-Drp1 Signaling Pathway.
    Sitao Liang, Yonghua Zhu, Jiahao Su, Chuangcai Luo, Chunhong Yang.
      Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog, on mitochondrial function in human U87 MG glioma cells. Our results demonstrate that dDAVP treatment induces dose-dependent cytotoxicity while upregulating vasopressin type 2 receptor expression. The compound significantly increased oxidative stress markers and impaired mitochondrial function, as evidenced by reduced ATP production, compromised respiratory chain activity, and decreased oxygen consumption. Furthermore, dDAVP promoted mitochondrial fragmentation through Drp1 activation, enhancing its phosphorylation at Ser616 and subsequent mitochondrial translocation. Mechanistically, dDAVP was found to activate CaMKII signaling, which mediated the observed changes in Drp1 phosphorylation and mitochondrial dynamics. The CaMKII inhibitor KN-93 effectively reversed dDAVP-induced mitochondrial fragmentation, Drp1 phosphorylation, and energy metabolism impairment. The AVPR2 antagonist tolvaptan blocked dDAVP effects, confirming receptor specificity. These findings reveal that dDAVP disrupts mitochondrial homeostasis in glioma cells through AVPR2-mediated CaMKII-dependent regulation of Drp1 activity, leading to mitochondrial dysfunction and cell damage. The study provides new insights into the molecular mechanisms underlying dDAVP's effects on glioma cells and suggests potential therapeutic applications targeting the CaMKII-Drp1 axis in glioma treatment.
    Keywords:  AVPR2; CaMKII; Drp1; desmopressin; glioma; mitochondrial dynamics
    DOI:  https://doi.org/10.1002/ddr.70224
  13. Apoptosis. 2026 Jan 10. 31(1): 24
    Pollutant-regulated mitophagy: new perspectives in environmental toxicology.
    Menglan Yan, Chunxia Huang, Shiqi Li, Wenjia Luo, Jiaqiang Wu, Xianhuan Zhou, Kangping Yang, Liang Yang.
      Environmental pollutants such as heavy metals, pesticides, air pollutants, and industrial chemicals pose serious threats to human health, in part by disrupting mitochondrial function. Mitophagy, a selective autophagic process that eliminates impaired mitochondria, is essential for maintaining mitochondrial and cellular homeostasis. Recent studies have shown that various pollutants can impair or dysregulate mitophagy, particularly through pathways such as PTEN-induced kinase 1 (PINK1)/Parkin-mediated mechanisms, leading to mitochondrial dysfunction, oxidative stress, inflammation, and ultimately contributing to diseases including neurodegeneration, cancer, and metabolic disorders. This review comprehensively summarizes the mechanisms by which different classes of environmental pollutants regulate mitophagy, the molecular signaling pathways involved, and the downstream effects on cellular health. Furthermore, this review also discusses current drugs and natural interventions that can alleviate pollutant-induced mitophagy dysfunction, such as melatonin, resveratrol, selenium, and stem cell therapy. By integrating the latest advances in environmental toxicology and mitochondrial biology, the review offers novel perspectives on the role of mitophagy in pollutant toxicity and highlights promising strategies for mitigating the adverse health effects of environmental exposures.
    Keywords:  Disease; Environmental pollutants; Mitophagy; Toxicology
    DOI:  https://doi.org/10.1007/s10495-025-02242-6
  14. Free Radic Biol Med. 2026 Jan 12. pii: S0891-5849(26)00024-9. [Epub ahead of print]246 93-106
    The non-metabolic role of MTHFD2 in regulating mitochondrial fission-dependent mitophagy via stabilizing TOP2A mRNA in glioblastoma.
    Zhuolin Du, Xingwu Liu, Yanhan Yang, Xudong Min, Jirui Wei, Yang She, Abudushalamu Abulaiti, Xiayu Jin, Zequn Su, Shizhong Zhang, Jian Liu, Karrie M Kiang, Gilberto Ka-Kit Leung, Xiaozheng He, Zhiyuan Zhu.
      Mitochondrial integrity is essential for tumor cell proliferation and survival. Our previous study has demonstrated the oncogenic role of the metabolic enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in glioblastoma (GBM). Given that the non-metabolic function of certain enzymes has been reported, we aim to interrogate whether MTHFD2 has potential roles in mitochondrial integrity and dynamics, especially beyond catabolism. By using multi-faceted approaches including single-cell RNA sequencing, mt-Keima mitophagy flux assays, RNA immunoprecipitation sequencing and luciferase reporter assays, we elucidated a novel, non-canonical function of MTHFD2 in stabilizing mRNA in GBM. We found that MTHFD2 was upregulated in GBM and was enriched in specific tumor subtypes cells such as ependymal-like and OPC-like cells. Knockdown of MTHFD2 profoundly promoted mitochondrial fission that triggered excessive mitophagy and cellular apoptosis. Mechanistically, MTHFD2 directly bound to the 3'-untranslated region (3'-UTR) of TOP2A mRNA and enhanced its stability, implying the RNA binding function of this catabolic enzyme. Overexpression of TOP2A attenuated mitophagy and cellular apoptosis induced by MTHFD2 depletion, indicating a vital role of MTHFD2-TOP2A axis in modulating mitochondrial integrity. Importantly, targeting MTHFD2 impeded GBM growth in orthotopic mouse models, which could be a promising therapeutic strategy. In conclusion, we proposed a non-canonical function of MTHFD2, which bound to and stabilized the mRNA of TOP2A. Targeting MTHFD2 triggered excessive mitophagy and cell apoptosis in GBM via destabilizing TOP2A mRNA.
    Keywords:  Glioblastoma; MTHFD2; Mitochondrial fission; Mitophagy; RNA-Binding protein
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.016
  15. J Orthop Translat. 2025 Nov;55 1-21
    Targeting ANT1 to regulate PINK1/Parkin-mediated mitophagy is an effective treatment of trauma-induced tendon heterotopic ossification.
    Guanzhi Li, Tong Li, Ye Deng, Xiao Deng, Chao Chen, Bin Yu, Kairui Zhang.
       Background: Heterotopic ossification (HO) is a common degenerative disease following trauma. Tendon HO is primarily attributed to osteogenic differentiation of stem/progenitor cells within the tendon. However, the precise mechanism underlying this process remains unclear. Recent studies suggest that PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy plays a crucial role in biomineralization. Adenine nucleotide translocase 1 (ANT1), an upstream regulator of the PINK1/Parkin pathway, may influence tendon ossification development by modulating mitophagy.
    Methods: This study investigated the role of mitophagy in tendon osteogenesis in clinical specimens, mouse tissues, and cells. The impact of ANT1 on tendon osteogenesis through mitophagy regulation was assessed by knocking down solute carrier family 25 member 4 (Slc25a4) both in vitro and in vivo. Furthermore, elamipretide was identified as a potential targeted drug for ANT1 through computer virtual screening and experimental verification. Its therapeutic efficacy on tendon ossification was validated using mouse cells, tissues, and human cells.
    Results: This study found that PINK1/Parkin-mediated mitophagy was activated during tendon ossification, and the regulation of mitophagy could impact the osteogenesis of injured tendon-derived progenitor cells (inTPCs). Loss of Slc25a4 inhibited tendon ossification by downregulating the excessive mitophagy. Elamipretide, a targeted drug for ANT1, showed significant efficacy in treating HO.
    Conclusion: Modulating PINK1/Parkin-mediated mitophagy by targeting ANT1 mitigated the progression of trauma-induced tendon HO, indicating ANT1 can be a potential therapeutic target for HO, with elamipretide emerging as a promising drug for its treatment.
    The translational potential of this article: This study identifies ANT1 as a therapeutic target and supports elamipretide as a promising treatment strategy for HO.
    Keywords:  ANT1; Elamipretide; Heterotopic ossification; Mitophagy; Tendon; Trauma
    DOI:  https://doi.org/10.1016/j.jot.2025.08.002
  16. Chin Med. 2026 Jan 16. 21(1): 40
    Thonningianin A derived from Penthorum chinense Pursh alleviates cerebral ischemia/reperfusion-mediated apoptosis and pyroptosis through the activation of PINK1/Parkin-dependent mitophagy.
    Qianfang Yao, Guishan Hu, Can Yin, Anguo Wu, Guangqiang Hu, Dalian Qin, Xiaogang Zhou, Betty Yuen-Kwan Law, Xi Du, Li Chen, Jianqiao Li, Hong Lin, Xin Long, Jianming Wu, Lu Yu.
       BACKGROUND: Cerebral ischemia/reperfusion injury (CI/RI) remains a critical barrier to effective ischemic stroke (IS) treatment. While mitophagy activation has been shown to attenuate apoptosis and pyroptosis, thereby ameliorating CI/RI, the therapeutic potential of natural compounds targeting this pathway remains underexplored. Penthorum chinense Pursh (PCP), a traditional hepatoprotective herb, contains Thonningianin A (TA), a bioactive compound with reported autophagic properties. However, the role and mechanisms of TA in CI/RI mitigation remain unclear.
    METHODS: In vivo, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established to evaluate TA's neuroprotective effects via TTC staining, Longa neurological scoring, and immunofluorescence staining. In vitro, oxygen-glucose deprivation/reoxygenation (OGD/R)-treated HT22 and BV2 cells were used to assess TA's impact on cell viability (MTT, Hoechst/PI staining), mitochondrial oxidative stress (DHE, TMRM, JC-1, Mito-Tracker staining and Western blot), apoptosis (flow cytometry, immunofluorescence staining, Hochest and PI staining and Western blot), and pyroptosis (EthD-2/YO-PRO-1 staining and Western blot). Autophagy and mitophagy modulation was investigated using rapamycin (Rap), 3-MA (autophagy inhibitor), CCCP (mitophagy inducer), and AC220 (mitophagy inhibitor) in EGFP-LC3-U87 and mCherry-GFP-FIS1-293T cells. Co-localization immunofluorescence and Western blotting were employed to validate PINK1/Parkin pathway involvement.
    RESULTS: TA administration significantly improved neurological function, reduced cerebral infarct volume, and attenuated neuronal damage in MCAO/R rats. In vitro, TA suppressed OGD/R-induced mitochondrial oxidative stress and apoptosis in HT22 cells while mitigating pyroptosis in BV2 microglia. Mechanistically, TA activated PINK1/Parkin-dependent mitophagy, as evidenced by enhanced LC3-II/I ratio, and increased mitochondrial-autophagosome co-localization. Crucially, TA's anti-apoptotic and anti-pyroptotic effects were abolished upon mitophagy inhibition. These findings were corroborated in the MCAO/R model, where TA upregulated PINK1/Parkin signaling and mitigated cell damage.
    CONCLUSION: This study identifies TA as a novel natural agent alleviating CI/RI by activating PINK1/Parkin-mediated mitophagy, thereby concurrently suppressing apoptosis and pyroptosis. These findings provide the first elucidating the molecular mechanis underlying TA's potential as a therapeutic candidate for IS.
    Keywords:   Penthorum chinense Pursh; Apoptosis; Autophagy; Cerebral ischemia/reperfusion injury; Mitophagy; PINK1/Parkin signaling pathway; Pyroptosis; Thonningianin A
    DOI:  https://doi.org/10.1186/s13020-025-01247-2
  17. Neurology. 2026 Feb 10. 106(3): e214618
    What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
    Eduardo Benarroch.
      Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.
    DOI:  https://doi.org/10.1212/WNL.0000000000214618
  18. Nat Cell Biol. 2026 Jan 12.
    Programmed mitophagy at the oocyte-to-zygote transition promotes lineage endurance.
    Siddharthan B Thendral, Sasha Bacot, Ian T Ryde, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.
      The quality of mitochondria inherited from the oocyte determines embryonic viability, lifelong metabolic health of the progeny and lineage endurance. High levels of endogenous reactive oxygen species and exogenous toxicants pose threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in mature oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here, we discover that in Caenorhabditis elegans, the onset of oocyte-to-zygote transition developmentally triggers a rapid mitophagy event. We show that mitophagy at oocyte-to-zygote transition (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. MOZT reduces the transmission of deleterious mtDNA and as a result, protects embryonic survival. Impaired MOZT drives the increased accumulation of mtDNA mutations across generations, leading to the extinction of descendant populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and safeguards lineage continuity.
    DOI:  https://doi.org/10.1038/s41556-025-01854-z
  19. Cell Biol Toxicol. 2026 Jan 13.
    SIRT3 attenuates AGEs-induced senescence in human granulosa cells through enhancing mitophagy.
    Shuhang Li, Mingge Tang, Sihui Zhu, Zhiguo Zhang, Yunxia Cao, Rufeng Xue.
      Age-related decreases in follicle numbers and oocyte quality are major contributors to the decline in female fertility, which is associated with increased infertility rates. Emerging evidence suggests that targeting granulosa cell senescence could delay ovarian aging and depletion of the ovarian reserve, highlighting the potential for therapeutic interventions focused on granulosa cells. Advanced glycation end products (AGEs) accumulate with age and result in oxidative stress in the follicular microenvironment, but their direct impact on human granulosa cell (hGC) senescence and the fundamental processes are still mostly unknown. In this study, we found that AGEs treatment significantly exacerbated hGC senescence, impaired mitochondrial function, and suppressed mitophagy in a concentration-dependent manner. Importantly, these deficits were lessened by urolithin A-induced mitophagy activation, whereas Cyclosporine A-induced mitophagy inhibition had the reverse consequences. In addition, silencing Sirtuin 3 (SIRT3) or PINK1 further aggravated these adverse effects, while SIRT3 overexpression attenuated senescence and restored mitochondrial function by enhancing mitophagy. Furthermore, SIRT3 overexpression promoted the synthesis of estradiol-17β and progesterone, key hormones for ovarian function. Our findings demonstrated that AGEs induced hGC senescence by disrupting mitochondrial function and inhibiting mitophagy, with SIRT3 playing a protective role. Enhancing mitophagy by targeting SIRT3 may be a promising treatment approach to counteract age-related declines in female fertility.
    Keywords:  Advanced glycation end products; Cellular senescence; Human granulosa cells; Mitophagy; Sirtuin 3
    DOI:  https://doi.org/10.1007/s10565-026-10138-7
  20. J Ethnopharmacol. 2026 Jan 13. pii: S0378-8741(26)00046-2. [Epub ahead of print]360 121195
    Tongmai Yangxin pill mitigates myocardial ischemia/reperfusion injury by improving mitochondrial function and mitophagy: A potential role of estrogen receptor alpha and PTEN-induced putative kinase 1/Parkin pathway.
    Lu Yu, Shu Liu, Xu Wang, Xue Liu, Shuo Wang, Zhu Li, Yutong Liu, Qina Lei, Shan Gao, Nan Li, Chunquan Yu, Lin Li.
       ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial ischemia/reperfusion injury (MI/RI) is a common complication of acute myocardial infarction, with significant effects on clinical outcomes. Tongmai Yangxin pill (TMYX), a traditional Chinese medicine formula, is approved by the National Medical Products Administration (NMPA) for treating cardiovascular and cerebrovascular diseases. While empirical evidence supports its therapeutic efficacy for MI/RI, the underlying mechanisms remain incompletely understood.
    AIM OF THE STUDY: This study aimed to determine the effects of TMYX on mitophagy during MI/RI and explore its potential mechanisms.
    MATERIALS AND METHODS: A rat model of MI/RI and an H9c2 cell hypoxia/reoxygenation (H/R) model were established to evaluate the cardioprotective effects of TMYX. After identifying the drug components, serum and tissue samples post-administration, network pharmacology was combined with WGCNA to predict the mechanisms of TMYX in treating MI/RI. Additionally, gene silencing was employed to validate the mechanisms by which TMYX exerts its cardioprotective effects.
    RESULTS: TMYX treatment significantly reduced myocardial fibrosis and alleviated oxidative stress in MI/RI rats. A total of 148 compounds in TMYX were identified across different samples. Bioinformatics analysis identified estrogen receptor α (ERα) as a key factor in TMYX-mediated regulation of mitophagy. TMYX restored mitochondrial biogenesis and downregulated the genes associated with the PINK1/Parkin pathway. Silencing ERα in cardiomyocytes abolished the cardioprotective effects of TMYX.
    CONCLUSIONS: TMYX regulates the PINK1/Parkin signaling pathway via ERα activation, restores mitophagy balance, and protects against MI/RI-induced cardiac injury. This study identifies potential new therapeutic targets for TMYX in MI/RI treatment. However, given the complex multi-component composition of traditional Chinese medicine formulas, additional studies are necessary to confirm the findings of this research.
    Keywords:  Mitophagy; Molecular mechanisms; Myocardial ischemia-reperfusion injury; Plant estrogens; Tongmai Yangxin pill
    DOI:  https://doi.org/10.1016/j.jep.2026.121195
  21. Nan Fang Yi Ke Da Xue Xue Bao. 2026 Jan 20. pii: 1673-4254(2026)01-0047-08. [Epub ahead of print]46(1): 47-54
    [Shihu Mixture alleviates diabetic cardiomyopathy in rats by Sirt3-mediated upregulation of myocardial mitochondrial mitophagy pathway].
    Xinjun Lin, Yulin He, Hong Shi, Jiaxiu Liu, Haixia Hu.
       OBJECTIVES: To explore the mechanism of Shihu Mixture (SHM) for improving diabetic cardiomyopathy.
    METHODS: Thirty male SD rats were randomized into 3 groups (n=10) for type 2 diabetes mellitus modeling by high-fat and -sugar feeding for 12 weeks and intraperitoneal streptozotocin injection, followed by treatment with daily gavage of normal saline (model group), metformin solution, or SHM extract for 4 weeks, with 10 normally fed rats as the normal control group. Fasting blood glucose and cardiac weight index of the rats were monitored, and their TG, TC, LDL-C, HDL-C, and LDH levels were determined; serum and myocardial levels of BNP, CRP, TNF‑α and IL-6 were detected with ELISA. Myocardial pathological changes and ultrastructures of myocardial mitochondria and autophagosomes were examined with HE and Masson staining and transmission electron microscopy. Myocardial expressions of Sirt3, FoxO3a, PINK1, Parkin, P62, and LC3 mRNAs and proteins were detected with RT-qPCR, Western blotting, and immunohistochemistry.
    RESULTS: Compared with those in the control group, the rats in the other 3 groups showed significantly increased fasting blood glucose, cardiac weight index, serum TC, TG, LDL-C, LDH, CRP and BNP levels and myocardial levels of TNF‑α and IL-6 with lowered HDL-C level, obvious myocardial and mitochondrial pathologies, and dysregulated expression of Sirt3, FoxO3a, p-FoxO3a, PINK1, Parkin, LC3 and P62. Treatment of the rat models with SHM extract significantly reduced fasting blood glucose level and cardiac weight index, lowered the levels of LDH, CRP, BNP, TNF‑α, IL-6, TC, TG, and LDL-C, increased HDL-C level, alleviated myocardial and mitochondrial damages, promoted autophagosome formation, and improved dysregulation of mitochondrial autophagy-related gene expression, showing similar effects to metformin.
    CONCLUSIONS: SHM alleviates myocardial damage and improves mitochondrial function in rats with diabetic cardiomyopathy by regulating the mitochondrial autophagy pathway through Sirt3.
    Keywords:  Shihu Mixture; Sirt3 pathway; diabetic cardiomyopathy; mitophagy
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2026.01.05
  22. FASEB J. 2026 Jan 31. 40(2): e71460
    AMPK Modulates the Interplay Between PINK1/Parkin-Mediated Mitophagy and NLRP3-Driven Inflammation in Diabetic Periodontal Tissue Under Mechanical Loading.
    Shuo Chen, Ruijiao Yan, Yiling Chen, Shushu He, Chenchen Zhou, Shujuan Zou, Yuyu Li.
      Mechanical force induces a series of biological responses such as inflammation in force-loaded tissues and cells. The periodontal ligament (PDL) fibroblasts act as vital sensors and transducers in response to mechanical loading within periodontium. Studies have shown that PDL fibroblasts also participate in mediating periodontal inflammatory responses under physiological or pathological conditions. Mitophagy is a selective form of autophagy that eliminates damaged or dysfunctional mitochondria to maintain cellular health. It plays a vital role in inflammation alleviation, cell survival, and tissue homeostasis. However, whether mitophagy is involved in mechanical force-related inflammation and the precise mechanisms remain unclear. In addition, the elucidation of the interplay between mitophagy and periodontal inflammation during mechanical loading is of great significance for maintaining periodontal homeostasis under systemic conditions. In our study, we first focused on validating the crosstalk between mitophagy and inflammation in PDL fibroblasts under mechanical loading and aimed to elucidate the upstream regulatory role of adenosine monophosphate-activated protein kinase (AMPK). Moreover, based on both in vivo and in vitro experiments, we found that high glucose conditions exacerbated inflammation by suppressing mitophagy. Additionally, targeted activation of AMPK enhanced mitochondrial turnover through mitophagy, thereby disrupting proinflammatory cascades and offering a promising strategy for inflammation resolution in periodontal diseases, especially those combined with diabetic conditions.
    Keywords:  AMPK activation; inflammation; mechanical loading; mitophagy; periodontal ligament fibroblasts
    DOI:  https://doi.org/10.1096/fj.202502330R
  23. J Pharmacol Exp Ther. 2025 Dec 15. pii: S0022-3565(25)40307-3. [Epub ahead of print]393(2): 103794
    Naringenin-functionalized polyester nanoparticles improve oral urolithin A delivery and protect against cisplatin-induced kidney injury via heme oxygenase-1 activation and mitochondrial quality control.
    Abiodun T Wahab, Raghu Ganugula, David Sheikh-Hamad, Subhashini Bolisetty, Meenakshi Arora, M N V Ravi Kumar.
      Cisplatin remains a cornerstone of chemotherapy, but its clinical use is often limited by cisplatin-induced acute kidney injury, a condition driven by oxidative stress, inflammation, and mitochondrial dysfunction. Here, we developed naringenin-functionalized polyester nanoparticles (P2Ns-NAR) to enhance the oral delivery and therapeutic efficacy of urolithin A (UA), a mitochondrial-targeting metabolite with cytoprotective properties. The resulting formulation, P2Ns-NAR-UA, conferred kidney protection in vitro and in vivo, outperforming the nontargeted nanoparticle formulation (P2Ns-UA). Notably, in vivo efficacy was achieved at a 50% lower dose. Molecular docking studies suggest UA exhibits a favorable heme oxygenase-1 binding energy of -7.43 kcal/mol, supporting its potential as a promising drug candidate. Mechanistic studies demonstrated that P2Ns-NAR-UA upregulate heme oxygenase-1 and activate PTEN-induced putative kinase 1/Parkin-mediated mitophagy, promoting mitochondrial quality control and preserving dynamics by increasing mitofusin-1/2 and reducing dynamin-related protein 1 and mitochondrial fission protein 1 expression. Treatment also attenuated inflammatory cytokines (interleukin 6, interleukin 8, and tumor necrosis factor-α), immune activation markers (cluster of differentiation 80 and 45), and kidney injury biomarkers (neutrophil gelatinase-associated lipocalin, cystatin C, and osteopontin). Histological analysis confirmed reduced tubular damage and fibrosis. These findings establish P2Ns-NAR-UA as a promising oral therapeutic platform to mitigate cisplatin-induced acute kidney injury through coordinated modulation of inflammation, oxidative stress, and mitochondrial homeostasis. Further investigation in cisplatin-resistant cancer models is warranted to establish this platform's dual therapeutic potential and translational value. SIGNIFICANCE STATEMENT: This study shows that naringenin-functionalized polyester nanoparticles improves intestinal uptake of encapsulated agents through intestinal folate receptors. Naringenin-functionalized polyester nanoparticles loaded with urolithin A (P2Ns-NAR-UA) doubles the efficacy of polyester nanoparticles loaded with urolithin A, achieving comparable results at half the dose. The formulation enhances cell health, reduces inflammation, and restores kidney function, making it a promising adjuvant to cisplatin therapy by improving outcomes while minimizing toxicity.
    Keywords:  Cisplatin-induced acute kidney injury; Heme oxygenase-1; Naringenin; Naringenin-functional nanoparticles; Receptor-mediated oral delivery; Urolithin A
    DOI:  https://doi.org/10.1016/j.jpet.2025.103794
  24. Tissue Cell. 2026 Jan 08. pii: S0040-8166(26)00010-8. [Epub ahead of print]99 103318
    The dual regulation of mitophagy in myocardial injury: From molecular mechanisms to targeted therapies.
    Haiyan Yang, Lei Zhang, Haixia Qian.
      Cardiovascular diseases (CVDs) are the leading cause of death worldwide, far exceeding other diseases such as cancer. Myocardial injury is a key link in various CVDs; reducing myocardial injury is an effective means of preventing and treating CVDs. Mitochondrial dysfunction is the pathological basis of various CVDs. Mitophagy, as a process that selectively eliminates damaged or dysfunctional mitochondria, is of enormous significance in maintaining the normal function and structure of mitochondria in cardiomyocytes and alleviating myocardial injury. Therefore, this review systematically analyzes the role of mitophagy in myocardial injury, explores targeted intervention strategies, and hopes to provide a theoretical basis and effective therapeutic targets for clinical practice.
    Keywords:  Cardiovascular Diseases; Mitophagy; Molecular Mechanisms; Myocardial Injury
    DOI:  https://doi.org/10.1016/j.tice.2026.103318
  25. Phytomedicine. 2026 Jan 07. pii: S0944-7113(26)00045-0. [Epub ahead of print]151 157808
    Melatonin alleviates rheumatoid arthritis by promoting Src/Fundc1-mediated mitophagy to regulate macrophage polarization.
    Wenhao Li, Wenyu Xia, Xiaolong Liang, Yi Qin, ZeBin Wu, Wenming Li, Wei Zhang, Minggang Wei, Gaoran Ge, Lu Mao, Dechun Geng.
       BACKGROUND: Rheumatoid arthritis (RA) is marked by joint pain, reduced functionality, and structural damage. The infiltration of immune cells, especially macrophages, is critical in the development of RA. Melatonin is a versatile hormone which possesses anti-inflammatory, antioxidant, and immunomodulatory properties. The efficacy of melatonin in treating diverse inflammatory autoimmune diseases has been well-documented, indicating its potential utility in the management and treatment of rheumatoid arthritis. Our study aimed to investigate whether melatonin could mitigate inflammation by orchestrating macrophage polarization in RA.
    METHODS: Utilizing a collagen-induced arthritis (CIA) mouse model and the macrophage cell line RAW264.7 induced with lipopolysaccharide (LPS), we assessed melatonin's potential to counteract RA. The molecular mechanism of melatonin involved in mitophagy and macrophage polarization was investigated using transmission electron microscopy, RNA-seq, western blot, RT-qPCR and immunofluorescence in CIA mouse and RAW264.7 cells.
    RESULTS: The findings revealed that melatonin markedly alleviated paw swelling, inhibited cartilage degeneration, and prevented bone erosion in CIA mice. Moreover, melatonin exhibited a dose-dependent inhibition of the M1 macrophage while concurrently enhancing the presence of the M2 macrophage. In addition, melatonin treatment promoted the expression of M2 macrophage-related cytokines and inhibited the expression of M1 macrophage-related cytokines in LPS-induced Raw264.7 cells. Melatonin treatment can also promote the mitophagy through the Src/Fundc1 signaling pathway. The effect of melatonin on regulating M1 macrophage polarization can be inhibited by blocking Fundc1 or using Mdivi-1 (mitophagy inhibitor).
    CONCLUSION: Collectively, our data suggest that melatonin improves RA outcomes by recalibrating the balance of different macrophage phenotypes, facilitated by Fundc1-mediated mitophagy promotion. Overall, this study indicates that mitophagy may be a target for RA treatment. It also indicates that the potential of melatonin as a complementary therapy for RA patients warrants further exploration through clinical trials.
    Keywords:  Macrophages; Melatonin; Mitochondria; Mitophagy; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.phymed.2026.157808
  26. Cardiovasc Drugs Ther. 2026 Jan 12.
    Empagliflozin Supplementation in Cardioplegic Solution Improves Donor Heart Preservation by Maintaining Mitochondrial Homeostasis.
    Rui-Lin Liu, Qing-Chun Song, Kai Yang, Lei Wang, Kai-Lu Jiao, Li Xie, Yi-Feng Yang.
       BACKGROUND: Prolonged cold ischemia and subsequent reperfusion are major causes of primary graft dysfunction in heart transplantation. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown cardioprotective effects in ischemia-reperfusion injury, but its role in donor heart preservation and the underlying mechanisms remain unexplored.
    METHODS: We evaluated the effects of empagliflozin supplementation in University of Wisconsin (UW) preservation solution using both in vitro and in vivo models. HL-1 cardiomyocytes were subjected to cold hypoxia/reoxygenation injury to simulate donor preservation conditions. A murine heterotopic heart transplantation model with 24-hour cold storage was used to assess graft function, myocardial injury, fibrosis, and immune response. Mechanistic studies were conducted using AMPK and Drp1 inhibitors to investigate mitochondrial signaling pathways.
    RESULTS: Empagliflozin (500 nM) significantly improved cardiomyocyte viability, reduced apoptosis, and preserved mitochondrial membrane potential under cold hypoxia/reoxygenation stress. In vivo, empagliflozin-supplemented UW solution improved early graft contractility, attenuated myocardial injury, reduced serum injury markers, and alleviated histological damage and immune cell infiltration. Long-term follow-up revealed mitigation of chronic rejection, with reduced fibrosis, vasculopathy, and immune activation. Mechanistically, empagliflozin activated AMPK, inhibited Drp1 phosphorylation at Ser616, promoted mitochondrial fusion (Mfn1, OPA1), and preserved mitochondrial morphology. These protective effects were abolished by AMPK inhibition and restored by Drp1 inhibition, confirming AMPK-Drp1 pathway involvement.
    CONCLUSIONS: Empagliflozin enhances donor heart preservation by mitigating cold ischemia-reperfusion injury through modulation of the AMPK-Drp1 signaling axis. This study extends the pharmacological profile of empagliflozin from metabolic regulation to donor heart preservation, highlighting its translational potential in clinical transplantation.
    Keywords:  AMPK–Drp1 signaling; Donor heart preservation; Empagliflozin; Heart transplantation; Ischemia-reperfusion injury; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s10557-026-07834-1
  27. Phytother Res. 2026 Jan 13.
    New Insights of Punicalagin in Alleviating Diabetic Liver Injury: Inhibition of NEK7-NLRP3 via Modulating Mitochondrial Dynamics.
    Xiuying Tan, Rou Zhang, Yuhan Zhang, Ziyi You, Lina Yang.
      Diabetic liver injury (DLI) is a chronic complication of the liver caused by diabetes mellitus, and its pathomechanism has not been fully elucidated. Punicalagin (PU), a polyphenol extracted from pomegranate peel, has physiological activities such as anti-inflammatory. In this study, the effects of PU on DLI and its molecular mechanisms were investigated. In vitro and in vivo studies were conducted using streptozotocin-induced diabetic mouse models and high glucose-induced HepG2 cells. After PU intervention, the effects of PU on DLI were assessed by histopathology, immunohistochemistry, western blot, immunofluorescence and transmission electron microscopy. The results showed that PU improved the pathological damage of liver tissue in diabetic mice, reduced the levels of inflammatory factors such as TNF-α, IL-18 and IL-1β in serum and liver, down-regulated the protein levels of NEK7, NLRP3 and Caspase1 in liver and HepG2 cells, and attenuated the fluorescence co-localization of NEK7 and NLRP3 in HepG2 cells. Additionally, PU up-regulated the expression of mitochondrial fusion-related proteins OPA1 and Mfn2 and their transfer to mitochondria, and inhibited the expression of mitochondrial fission-related proteins Drp1 and p-Drp1 (Ser616). The mitochondrial fusion inhibitor MYLS22 reversed the inhibitory effect of PU on NEK7-NLRP3 complex. In conclusion, the present study shows that PU inhibits NEK7-NLRP3 complex activation by regulating mitochondrial dynamics, thereby reducing liver inflammation and alleviating DLI.
    Keywords:  NEK7; NLRP3; diabetic liver injury; mitochondrial dynamics; punicalagin
    DOI:  https://doi.org/10.1002/ptr.70208
  28. FEBS J. 2026 Jan 12.
    Mitochondrial uncoupler BAM15 ameliorates liver lipid metabolism disorders by activating the AMPK pathway.
    Zunhai Liu, Wentao Wang, Simeng Wang, Rui Lv, Chaowei Li, Chao Sun.
      N5,N6-bis(2-Fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (BAM15) is a recently identified mitochondrial uncoupler with antitumor, anti-inflammatory, antioxidant and antiobesity properties. Although it has been shown that BAM15 has a high targeting ability to the liver, its capacity to improve liver metabolic disorders and the underlying mechanisms are not well understood. This study examined how BAM15 works in high-fat-diet (HFD) induced obese mice. Our results showed that compared with 2,4-Dinitrophenol (DNP) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), BAM15 has a higher binding capacity and stronger activity in mediating proton uncoupling, and effectively promoted mitochondrial fusion, division, autophagy, and the tricarboxylic acid cycle. BAM15 improved hepatic lipid metabolism disorders by enhancing mitochondrial autophagy through activation of the 5'-AMP-activated protein kinase (AMPK) pathway. This indicates that BAM15 could be used to treat liver lipid metabolism issues and offers a solid theoretical foundation for managing lipid-related diseases.
    Keywords:  AMPK pathway; BAM15; lipid metabolism; liver; mitophagy
    DOI:  https://doi.org/10.1111/febs.70400
  29. NPJ Parkinsons Dis. 2026 Jan 15.
    UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson's disease.
    Jeng-Lin Li, Shu-Yi Huang, Po-Yu Huang, Ssu-Ju Fu, Yu-Jung Tsao, Wenying Chang, Cheng-Li Hong, Yu-Chien Hung, Pei-Han Liu, Liang-Chuan Lai, Chin-Hsien Lin, Wei-Chung Chiang, Chih-Chiang Chan.
      Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson's disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.
    DOI:  https://doi.org/10.1038/s41531-026-01262-6
  30. Cell Biol Toxicol. 2026 Jan 17.
    Targeting SPHK1 by 8-HETrE attenuates MASH-Driven fibrosis via restoration of hepatic stellate cell mitochondrial dynamics.
    Shuling Chen, Jiayan Li, Kan Xu, Junyi Wen, Feng Zhang, Yuzheng Zhuge, Lei Wang, Yongxiang Yi, Hao Zhang, Wei Zhang.
      Metabolic dysfunction-associated steatohepatitis (MASH) drives hepatic stellate cell (HSC) activation and extracellular matrix deposition, leading to liver fibrosis, for which effective treatments remain lacking. Here, we report that 8-hydroxyoctacosatrienoic acid (8-HETrE), an arachidonic acid metabolite generated through cytochrome P450 or lipoxygenase pathways, significantly ameliorates MASH-related fibrosis by targeting sphingosine kinase 1 (SPHK1) and restoring mitochondrial function. Clinical observations revealed markedly reduced circulating 8-HETrE levels in patients with MASH fibrosis. In vivo studies demonstrated that 8-HETrE administration improved liver function, enhanced expression of mitochondrial fusion proteins (Mfn1, Mfn2, Opa1), and attenuated fibrosis in Gubra-Amylin-NASH (GAN)-diet-induced MASH models. In TGF-β1-activated human HSCs cell line (LX-2 cells), 8-HETrE treatment suppressed fibrotic markers (α-SMA, COL1A1) and improved mitochondrial dynamics. Mechanistic investigations revealed that 8-HETrE exerted its anti-fibrotic effects primarily through SPHK1 inhibition: SPHK1 knockdown moderately reduced HSC activation, decreased sphingosine-1-phosphate (S1P), lactate, and nitrite levels, enhanced glucose uptake, and promoted mitochondrial fusion, while completely abolishing 8-HETrE's therapeutic effects. Conversely, SPHK1 overexpression exacerbated fibrotic and metabolic abnormalities, which were effectively reversed by 8-HETrE treatment. Critically, HSC-specific Sphk1 knockout independently improved MASH fibrosis, mitochondrial function, and metabolic parameters, while completely blocking 8-HETrE's benefits. Our findings identify 8-HETrE as a novel mediator that targets the SPHK1-mitochondrial dynamics axis in HSCs, providing both mechanistic insights and therapeutic potential for MASH-related fibrosis treatment.
    Keywords:  8-HETrE; Hepatic stellate cells; MASH-driven fibrosis; Mitochondrial dynamics; SPHK1
    DOI:  https://doi.org/10.1007/s10565-026-10142-x
  31. Apoptosis. 2026 Jan 10. 31(1): 21
    Hesperetin alleviates neuronal pyroptosis by promoting mitophagy via DHCR24/BACE1 signaling pathway after subarachnoid hemorrhage in mice.
    Hongjiang Ye, Xin Wang, Yidan Liang, Yin Tang, Jiahe Tan, Yinrui Ma, Daiqi Xu, Han Xiong, Yiming Zhuang, Wenqiao Fu, Zhaohui He.
      
    Keywords:  BACE1; DHCR24; Hesperetin; Mitophagy; Pyroptosis; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.1007/s10495-025-02238-2
  32. Discov Oncol. 2026 Jan 16.
    Identification of prognostic signatures in pheochromocytomas and paragangliomas based on mitochondrial autophagy and ferroptosis in TCGA and GEO datasets.
    Qingke Chen, Zhiyong Xian, Qian Zou, Junming Bi.
      Pheochromocytomas (PCCs) and paragangliomas (PGLs), collectively PPGLs, are rare tumors with significant molecular heterogeneity, which complicates prognosis and treatment. This study analyzed publicly available datasets (TCGA-PPGLs, GSE19422, GSE60459) to identify differentially expressed genes (DEGs) related to mitochondrial autophagy and ferroptosis in PPGLs. We identified 6,286 DEGs, including 31 mitochondrial ferroptosis-related DEGs (MFRDEGs). A prognostic model based on four genes (AMBRA1, EIF2S1, SRC, PHGDH) demonstrated high predictive accuracy (AUC > 0.9). Functional enrichment analysis highlighted key pathways, including mitophagy and Fc epsilon receptor I (FcεRI) signaling. Protein-protein interaction (PPI) and ceRNA network analyses revealed potential regulatory mechanisms. Calibration and decision curve analyses confirmed the model's clinical utility. These findings offer insights into PPGL molecular mechanisms, suggest prognostic biomarkers, and propose candidate therapeutic targets to improve risk stratification and personalized treatment. However, experimental validation is required to confirm their biological relevance before clinical application.
    Keywords:  Ferroptosis; Mitochondrial autophagy; Paragangliomas (PGLs); Pheochromocytomas (PCCs); Prognostic risk model
    DOI:  https://doi.org/10.1007/s12672-026-04393-7
  33. Ageing Neurodegener Dis. 2025 ;pii: 6. [Epub ahead of print]5(1):
    Advances in autophagy for Parkinson's disease pathogenesis and treatment.
    Xiaojie Zhang, Huan Zhang, Jie Dong, Huaibin Cai, Weidong Le.
      Autophagy is a cellular process essential for maintaining neuronal homeostasis by degrading and recycling damaged organelles and proteins. Impairments in canonical autophagy pathways, such as macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy, are linked to Parkinson's disease (PD) pathogenesis, contributing to α-synuclein aggregation and dopaminergic neuronal loss. Moreover, the recent discovery of noncanonical autophagy highlights the unexpected roles of autophagy-related proteins in protein degradation beyond the canonical autophagy pathways. Advances in understanding the molecular mechanisms of autophagy provide potential therapeutic strategies to modulate this pathway in PD. Key therapeutic targets include mTOR and AMPK, with compounds like rapamycin, trehalose, and resveratrol showing promise in preclinical models. Enhancing lysosomal function and mitophagy also presents a viable strategy to alleviate PD symptoms. This review emphasizes the complex roles of autophagy in PD and highlights the potential of autophagy modulation as a promising therapeutic strategy for treating the disease.
    Keywords:  Parkinson’s disease; autophagy; chaperone-mediated autophagy; lysosome; mitophagy
    DOI:  https://doi.org/10.20517/and.2024.33
  34. Chin Med J (Engl). 2026 Jan 13.
    Inhibitory effect of blestriarene C on triple-negative breast cancer: inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis.
    Junsha An, Pingting Chen, Mingyu Han, Heng Zhang, Yajie Lu, Hailin Tang, Qian Bi, Weiwei Pan, Cheng Peng, Zhaokai Zhou, Fu Peng.
       BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive and treatment-resistant subtype of breast cancer, characterized by high rates of metastasis and mortality. This study aimed to identify and evaluate the therapeutic potential of blestriarene C (BC), a novel diphenanthrene compound, in the treatment of TNBC. The study also sought to explore the underlying mechanisms and signaling pathways involved in BC's antitumor effects.
    METHODS: A multiomics analysis was conducted to identify key genes and pathways involved in TNBC treatment. We performed experiments related to cell viability, ferroptosis, and mitophagy to explore the effects of BC in the treatment of TNBC, utilizing the TNBC cell lines BT-549 and 4T1 cells. The impact of sestrin 2 (SESN2) knockout on BC's effects was also studied. We also conducted in vivo experiments using the patient-derived xenograft (PDX) model in zebrafish to assess the antitumor effects of BC.
    RESULTS: The results of RNA sequencing and proteomics showed that ferroptosis and mitophagy may be the main mechanisms of BC acting on TNBC cells. BC could inhibit cell proliferation by modulating the phosphoinositide 3-kinase/protein kinase B/forkhead box O4 and SESN2/ mechanistic target of rapamycin signaling pathways, and inducing ferroptosis and mitophagy. SESN2 and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), as hub genes, participated in regulating the therapeutic effect of BC on TNBC. TNBC tumors in zebrafish treated with BC were smaller and lighter, indicating that BC had antitumor effect.
    CONCLUSIONS: BC emerges as a promising therapeutic agent for TNBC by targeting SESN2 and MAP1LC3B, modulating associated signaling pathways, and inducing ferroptosis and mitophagy. These findings provide the basis for further investigation of BC's potential as a targeted therapy for TNBC.
    Keywords:  Blestriarene C; Ferroptosis; Mitophagy; Sestrin 2; Triple-negative breast cancer
    DOI:  https://doi.org/10.1097/CM9.0000000000003960
  35. Chem Biol Interact. 2026 Jan 12. pii: S0009-2797(26)00023-2. [Epub ahead of print] 111915
    Synergistic kidney toxicity of polylactic acid nanoplastics and Cr(VI): Ferroptosis aggravated by mitophagy.
    Yuankun Zhou, Jiajun Guo, Xiaoyan Feng, Hengyi Xu.
      Nanoplastics (NPs) and chromium (Cr) are ubiquitous in the environment, causing severe pollution and posing significant potential threats to human health. Polylactic acid (PLA) and Cr are among widely used bioplastic and heavy metal, respectively, both capable of contaminating water sources through corresponding pathways and posing substantial risks to human health. Nanoplastics can act as carriers for heavy metals, thereby enhancing their bioaccumulation and toxicity. Therefore, this study investigated the effects of combined exposure to Cr(VI) and PLA NPs on mice kidneys and its potential mechanisms. Results indicated that exposure to PLA NPs alone did not exhibit significant toxic effects on the kidneys. However, combined exposure to Cr(VI) and PLA NPs caused severe kidney damage in mice. This indirectly suggests that Cr(VI) and PLA NPs exhibit synergistic toxicity rather than simple additive effects. Furthermore, combined exposure exacerbated the toxic mechanism by inducing mitochondrial damage and excessive reactive oxygen species (ROS) production, thereby triggering mitophagy. Overactivated mitophagy exacerbated lipid peroxidation by releasing free iron, thereby amplifying ROS-mediated ferroptosis. This study investigates the synergistic renal toxicity of Cr(VI) and PLA NPs, providing scientific evidence for the combined toxicity mechanism of exposure to MNPs and heavy metals.
    Keywords:  Chromium; Ferroptosis; Mitophagy; Polylactic acid nanoplastics; Renal toxicity
    DOI:  https://doi.org/10.1016/j.cbi.2026.111915
  36. Cell Mol Life Sci. 2026 Jan 15.
    USP8-mediated mitochondrial regulation in osteoclasts is essential for skeletal development.
    Sachin Chaugule, Yeon-Suk Yang, Tadatoshi Sato, Emma Mayer, Jae-Hyuck Shim.
      Aberrant protein regulatory pathways disrupt bone development and contribute to skeletal diseases. The cysteine protease family of deubiquitinating enzymes (DUBs) are critical for regulation of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we demonstrate that the DUB ubiquitin-specific protease 8 (USP8) is highly expressed in osteoclasts and its deletion impairs osteoclast development and bone resorption activity. Deletion of Usp8 in osteoclasts (Usp8Ctsk) results in low trabecular bone mass due to defective endochondral bone formation and short stature resulting from abnormal growth plate structure. Usp8 deficiency in osteoclasts reduces the number of mitochondrial, mitochondrial activity, oxidative phosphorylation, and mitophagy, while ROS production and inflammatory responses increased. USP8 mediates the regulation of mitophagy in osteoclasts through the stabilization of Parkin. Moreover, Usp8-deficient osteoclasts in metaphysis secrete factors that impair both growth plate development and trabecular bone formation. Collectively, these findings identify USP8 as a key regulator of osteoclast development and secretory factor production, shaping the microenvironment essential for skeletal development.
    Keywords:  Mitochondria; Mitophagy; Osteoclasts; Parkin; Skeletal development; USP8
    DOI:  https://doi.org/10.1007/s00018-025-06012-0
  37. Inflammation. 2026 Jan 14.
    Impaired Mitophagy-Induced Apoptosis of Gingival Fibroblasts Exacerbates Diabetic Periodontitis Via THBS-1/CD36-Dependent Macrophage Activation.
    Rundong Yuan, Lingxiao Meng, Minglei Zhang, Hongrui Liu, Jie Guo, Minqi Li.
      Diabetic periodontitis (DPD) is a severe inflammatory complication characterized by accelerated destruction of periodontal tissues and dysregulated immune responses. Gingival fibroblast (GF)-macrophage interactions drive DPD progression, but the mechanisms linking hyperglycemia, mitochondrial dysfunction, and immune activation remain unclear. Single-cell sequencing analysis of diabetic gingival tissues revealed significant apoptotic activation of GFs, closely linked to mitochondrial dysregulation. Inflammation and metabolic stress disrupt mitochondrial quality-control pathways and promote the overproduction of reactive oxygen species, inducing defective mitophagy. Crucially, apoptotic GFs secrete thrombospondin-1 (THBS-1), which binds to the CD36 receptor on the surface of macrophages, triggering NF-κB-mediated M1 polarization and pro-inflammatory cytokine production. Molecular modelling demonstrated a high-affinity interaction between THBS-1 and CD36. Gene silencing of THBS-1 in GFs or CD36 in macrophages effectively inhibited these changes, confirming the specificity of this cellular crosstalk mechanism. These findings together indicate mediation of hyperglycemia-induced mitochondrial dysfunction through the promotion of GF apoptosis and subsequent THBS-1/CD36/NF-κB-signaling-dependent macrophage activation. Thus, enhanced mitophagy and modulation of the THBS-1/CD36 axis are promising therapeutic strategies to break the self-perpetuating cycle of inflammation and tissue destruction in DPD.
    Keywords:  CD36 protein; Cell interaction; Mitophagy; Periodontal diseases; Thrombospondin-1; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s10753-025-02390-6
  38. Acta Pharmacol Sin. 2026 Jan 12.
    Secoemestrin C exerts rapid and prominent anti-breast cancer effect in triple-negative breast cancer by inducing SLX4 and YAP degradation.
    Xiao-Jun Zhao, Yang Xu, Cong-Hui Zhang, Cong Zhao, Li Liu, Xiao-Wei Wang, Meng-Yan Wang, Zi-Xiang Gao, Rong-Guang Shao, Li-Qiang Qi, Yong-Sheng Che, Wu-Li Zhao.
      Mitochondrial DNA (mtDNA) mutations are the most common cause in aberrant mitochondrion-leading cancer, exploration of direct targeting mutated mtDNA still remains incomplete. Secoemestrin C (Sec C) is epitetrathiodioxopiperazine derived from the endophytic fungus, which exhibited a rapid and prominent anti-breast cancer effect in triple-negative breast cancer (TNBC). In this study we investigated the anticancer mechanism of Sec C, especially its effect on TNBC cells. We showed that Sec C potently inhibited the viability of both TNBC (MDA-MB-231, HS578T, BT-549) and non-TNBC (MCF-7, T47D, SK-BR-3) cells in vitro with IC50 values of 1-2 μM. In MDA-MB-231 cells, treatment with Sec C (2 μM) induced DNA breakage and subsequent apoptosis. Furthermore, treatment with Sec C (2 μM) caused mtDNA damage, mitochondrial ubiquitination and subsequent mitophagy in MDA-MB-231 and MCF-7 cells. RNA-seq analysis revealed that Sec C mitigated YAP level in time and dose-dependent manner either in MDA-MB-231 and MCF-7 cells. By re-analyzing the Sec C-responsive gene network proteins, we identified SLX4 as an oncogene promoting breast cancer development, potentially by stabilizing mtDNA to suppress pathologic mitochondrion mitophagy. Specifically, Sec C initiated MDA-MB-231 cells to yield ROS that induced SLX4 ubiquitination and degradation, leading to mtDNA damage and exacerbated mitophagy and promoted YAP degradation bypassing YAP-driven DNA repair pathways. This study not only demonstrates that Sec C is a rapid and prominent anti-breast cancer drug for TNBC, but also reveals SLX4 as a novel mtDNA stabilizer supporting breast cancer progression, positioning it as both a prognostic biomarker and therapeutic target.
    Keywords:  SLX4; YAP; mitophagy; mtDNA stability; secoemestrin C; triple-negative breast cancer
    DOI:  https://doi.org/10.1038/s41401-025-01730-4
  39. Food Funct. 2026 Jan 12.
    Lactoferrin protects against radiation-induced intestinal injury by regulating pyroptosis and mitophagy.
    Wenyue Shan, Wei Wei, Yuqi Zhang, Lili Zhang, Yu Zhao, Jia Gu, Le Zhao, Khemayanto Hidayat, Yulong Liu, Yu Chong, Lin Zhao, Liqiang Qin, Jiaying Xu.
      The imbalance between pyroptosis and mitophagy constitutes a key pathogenic axis in radiation-induced intestinal injury (RIII). Lactoferrin (Lf), a multifunctional glycoprotein with well-recognized antioxidant and anti-inflammatory properties, has not been fully characterized in relation to RIII. This study investigated the potential protective effects of Lf on RIII using rat intestinal epithelial IEC-6 cells exposed to 4 Gy X-ray irradiation and male C57BL/6J mice subjected to 10 Gy total-abdominal irradiation. Radiation induced pyroptosis and mitochondrial dysfunction in vitro and in vivo. Lf pretreatment reduced radiation-induced ROS accumulation, inhibited activation of the NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin-D (GSDMD) pyroptosis pathway, and activated mitophagy to remove damaged mitochondria in irradiated IEC-6 cells. Consistently, Lf protected against RIII in irradiated mice by promoting mitophagy and suppressing pyroptosis. Mechanistically, these effects involved activation of ubiquitin-dependent (PINK1/Parkin-mediated) and ubiquitin-independent (FUNDC1/BNIP3/NIX receptor-driven) mitophagy pathways. The mitophagy-promoting effect of Lf was more pronounced on day 3.5 after radiation than on day 14. Notably, pharmacological inhibition of mitophagy with 3-Ma and Mdivi-1 abolished the protective effects of Lf. Collectively, our in vivo and in vitro findings demonstrate that Lf mitigates RIII by facilitating early clearance of damaged mitochondria, thereby inhibiting NLRP3 inflammasome activation and suppressing pyroptosis.
    DOI:  https://doi.org/10.1039/d5fo04989j
  40. Biol Direct. 2026 Jan 12.
    S100A4 triggeres the pyroptosis of vsmcs: association with mitochondrial damage, impaired mitophagy, and Ca2+ dysregulation.
    Junjie Huang, Binbin Zhou, Lie Wang, Qingjin Huang, Xiaowen Lin, Hu Zhao, Yin Xia.
      
    Keywords:  Atherosclerosis; Mitophagy; Pyroptosis; S100A4; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1186/s13062-025-00723-x
  41. Redox Biol. 2026 Jan 06. pii: S2213-2317(26)00004-2. [Epub ahead of print]90 104006
    RIPK3-driven phosphorylation of MFN2 orchestrates endoplasmic reticulum-mitochondria interaction and cardiomyocyte stress responses.
    Yu Wang, Tao Xu, Qi Li, Lin Ye, Peiyan Wang, Puhan Wang, Yihan Song, Xiang Ao, Jianxun Wang, Wei Ding.
       BACKGROUND: Recent studies have demonstrated that necroptosis is one of the main forms of cardiomyocyte death in heart diseases. However, the crosstalk between the death-receptor necroptosis pathway and the mitochondrial necroptosis pathway remains largely unknown. It has been reported that Mitofusin 2 (MFN2) can promote myocardial injury by inducing Endoplasmic Reticulum (ER)-mitochondria interaction. The purpose of this study was to investigate whether MFN2 promotes cardiac necroptosis and myocardial ischemia/reperfusion (I/R) injury by regulating ER-mitochondrial interactions, and whether this function of MFN2 can be regulated by the death-receptor necroptosis pathway.
    METHODS: Myocardial necroptosis was induced by H2O2 in H9c2 cardiomyocytes in vitro and through left anterior descending (LAD) ligation and subsequent reperfusion in C57/BL6 mice in vivo. ER-mitochondria interaction was detected by immunofluorescence. Calcium levels were analyzed by Rhod-AM staining. The interaction between MFN2 and Receptor-interacting protein kinase 3 (RIPK3) was explored by co-immunoprecipitation and immunofluorescence. The phosphorylation site of MFN2 was examined and measured via mass spectrometry analysis. Additionally, a customized MFN2 phosphorylation-specific antibody was used to detect the role of the Threonine 130 site of MFN2 in myocardial necroptosis. In vivo, MFN2 cardiac-specific knockout mice were constructed to further explore the effect of MFN2 on myocardial I/R injury and necroptosis.
    RESULTS: Our results showed that MFN2 participated in H2O2-induced cardiomyocyte necroptosis by promoting the formation of ER-mitochondrial interactions and ER-mitochondrial Ca2+ transfer, which could be regulated by RIPK3 via phosphorylating MFN2 at the Threonine 130 site. Moreover, mitochondrial Ca2+ overload induced mPTP opening and subsequent activation of Calpain1, resulting in the inhibition of mitophagy initiation. Both of these pathways could promote cardiac necroptosis. Furthermore, our results revealed that cardiac-specific knockout of MFN2 could attenuate myocardial I/R injury.
    CONCLUSION: Our findings reveal that RIPK3 can mediate MFN2 phosphorylation to promote ER-mitochondria interaction and mitochondrial Ca2+ overload, leading to the induction of cardiac necroptosis.
    Keywords:  Ishchemia/reperfusion injury; MFN2; Myocardium; Phosphorylation; RIPK3
    DOI:  https://doi.org/10.1016/j.redox.2026.104006
  42. Biochem Biophys Res Commun. 2026 Jan 09. pii: S0006-291X(26)00033-1. [Epub ahead of print]800 153270
    Natural exosome-like nanovesicles from Smilax China rhizome induce mitophagy-dependent ferroptosis in hepatocellular carcinoma via GPX4/ACSL4 axis.
    Xiayi Fang, Zicheng Liang, Zhen Zhang, Mengjuan Tao, Wenling Gong, Xiaoning Tan, Puhua Zeng.
       BACKGROUND: Hepatocellular carcinoma (HCC) remains challenging due to limited therapies and resistance. Mitophagy-associated ferroptosis, an iron-dependent cell death mechanism, emerges as a novel strategy, while plant-derived extracellular nanovesicles offer the possibility for nanotherapeutics.
    METHODS: Natural exosome-like nanovesicles from Smilax china Rhizome (SCRENs) were isolated via sucrose density gradient ultracentrifugation and characterized (TEM, NTA, SDS-PAGE). Anti-HCC effects were assessed in vitro (EdU, colony formation, migration assays). Ferroptosis and mitophagy mechanisms were studied using inhibitors (Fer-1, 3-MA), inducers (CCCP, Erastin), and biochemical assays (ROS, Fe2+, GSH, MDA). Mitochondrial dysfunction was evaluated via JC-1, mtDNA, morphology, and protein analysis (ACSL4, SLC7A11, GPX4).
    RESULTS: SCRENs (139.7 nm diameter) inhibited HCC proliferation, migration, and induced apoptosis, with HepG2 cells most sensitive. SCRENs triggered ferroptosis (Fe2+, ROS, MDA, GSH) and altered ferroptosis markers (ACSL4, SLC7A11, GPX4). Mitophagy was evidenced by mitochondrial depolarization, mtDNA loss, and ultrastructural damage. Pharmacological inhibition confirmed mitophagy-ferroptosis crosstalk. SCRENs mediated dual GPX4/ACSL4 regulation, GPX4 suppression impaired antioxidant capacity, while ACSL4 upregulation promoted lipid peroxidation. Ferrostatin-1 reversed SCRENs' effects, whereas GPX4 activation failed to rescue viability, highlighting ACSL4/mitophagy-driven iron release as critical.
    CONCLUSIONS: Our study successfully isolated SCRENs from Smilax china rhizomes and demonstrated their inhibitory effects on HCC cell proliferation, migration, and invasion through in vitro cellular experiments. Mechanistic investigations revealed that SCRENs mediate their anti-tumor effects primarily through modulation of mitophagy-associated ferroptosis via GPX4/ACSL4 axis.
    Keywords:  Ferroptosis; GPX4/ACSL4 axis; Hepatocellular carcinoma; Mitophagy; Natural exosome-like nanovesicles; Smilax China Rhizom
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153270
  43. Nat Commun. 2026 Jan 10.
    Arachidonic acid induces pyroptosis via a non-autophagic function of mitophagy and enhances immunotherapy in a PDAC model.
    Tongjia Chu, Ziyu Liu, Huan Liu, Wentao Mu, Yao Zhi, Nan Sheng, Jian Zhang, Xinyu Peng, Shengnan Lv, Kehang Duan, Fengxiang Lou, Han Liu, Chuanlei Wang, Jianpeng Zhou, Xingyu Liu, Haocheng Yang, Yunzhi Liu, Jingtong Xu, Zhongqi Fan, Feng Wei.
      Pancreatic ductal adenocarcinoma (PDAC) presents a therapeutic hurdle owing to its immunotherapy resistance and limited treatment options. Pyroptosis, a lytic inflammatory cell death pathway, holds promise for reversing immunosuppression in "cold" tumors, yet tumor-specific induction strategies remain unclear. Here, we employ a contrastive learning graph neural network to identify arachidonic acid (AA), an endogenous ω-6 polyunsaturated fatty acid, as a pan-cancer pyroptosis inducer operating through irreversible mitochondrial permeability transition inducing Caspase 3/GSDME activation. Crucially, a repurposed mitophagy machinery for non-autophagic functional scaffolding of Caspase 3/GSDME on autophagosomal membranes enables rapid pyroptotic execution. Pharmacological accumulation of autophagosomes amplifies AA-induced pyroptosis in PDAC organoids and patient-derived xenografts. Furthermore, AA-triggered pyroptosis, remodels immunosuppressive tumor microenvironments, boosting cytotoxic T cell infiltration and synergizing with anti-PD-1 therapy in immunocompetent models. Thus, our findings position AA as a candidate dual-function agent for pyroptosis-immune synergy, while autophagosome manipulation emerges as a strategy to potentiating strategy.
    DOI:  https://doi.org/10.1038/s41467-025-68267-2
  44. Free Radic Biol Med. 2026 Jan 08. pii: S0891-5849(26)00016-X. [Epub ahead of print]
    Non-surgical periodontal treatment improves mitochondrial bioenergetics in circulating immune cells of patients with chronic periodontitis.
    Jonathan Hermenejildo, María Pelechá-Salvador, Meylin Fernández-Reyes, Laura Perea-Galera, Jordi Mota-Plaza, Javier Silvestre-Rangil, Celia Bañuls, Carlos Morillas, Francisco Javier Silvestre, Víctor M Víctor, Sandra López-Domènech, Milagros Rocha.
       INTRODUCTION: Chronic periodontitis (CP) is an inflammatory disease associated with local and systemic oxidative stress and leads to mitochondrial homeostasis disruption. Although non-surgical periodontal therapy (NSPT) has been proved to reduce the bacterial load and inflammation, the mechanisms underlying its effects on mitochondrial function and systemic redox balance remain poorly understood.
    METHODS: Eighty patients with CP underwent NSPT. Clinical, anthropometric, and biochemical parameters were evaluated at baseline and 12 weeks after therapy. Mitochondrial redox status, membrane potential, markers of mitochondrial biogenic signalling (PGC-1α), electron transport chain (ETC) complexes, and bioenergetic function were assessed in peripheral blood mononuclear cells (PBMCs). Correlation and multivariable analyses were performed to explore relationships between periodontal improvement and mitochondrial parameters.
    RESULTS: After NSPT, patients presented significant reductions in mitochondrial ROS and increased GPX1 expression. PBMCs also showed elevated PGC-1α and ETC I-IV protein levels, together with enhanced mitochondrial membrane potential, mass, and spare respiratory capacity. Baseline mitochondrial parameters were associated with the percentage of reduction of periodontal clinical parameters following NSPT.
    CONCLUSIONS: NSPT not only ameliorates local periodontal inflammation but also modulates mitochondrial-related homeostasis and bioenergetic efficiency in circulating immune cells. The present findings support mitochondrial remodelling as a systemic mechanism underlying the benefits of periodontal therapy and a promising target for the treatment of inflammation-related comorbidities.
    Keywords:  Bioenergetics; Chronic Periodontitis; Mitochondrial Biogenesis; Non-Surgical Periodontal Therapy; Oxidative Stress; Peripheral Blood Mononuclear Cells; Reactive Oxygen Species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.010
  45. Int J Biol Sci. 2026 ;22(2): 731-749
    Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex.
    Nai-Jia Xue, Yi Liu, Zhi-Hao Lin, Wen-Hao Huang, Feng Zhang, Ran Zheng, Xiao-Li Si, Lu-Yan Gu, Yi Fan, Jia-Li Pu, Bao-Rong Zhang.
      Disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium homeostasis has been implicated in the pathogenesis of Parkinson's disease (PD). Parkin, a PD-associated E3 ubiquitin ligase, has been shown to regulate MAM integrity and calcium dynamics. However, the mechanisms of Parkin recruitment and its substrate specificity have not been well understood. This investigation has demonstrated that loss of Parkin enhances ER-mitochondria associations and leads to excessive calcium flux in MAM, resulting in abnormal mitochondrial permeability transition pore (mPTP) opening and decreased cell viability. Further, Parkin physically interacts with IP3R-Grp75-VDAC1 complex at ER-mitochondria contact sites, where it is recruited by IP3R-mediated calcium flux and mitophagy. More importantly, Parkin deficiency leads to the accumulation of IP3R levels, particularly in MAM region. In addition, Parkin fine-tunes the stability of the complex and ubiquitinates IP3R for degradation via the ubiquitin-proteasomal system, ensuring suitable calcium transfer. Taken together, our study reveals a novel role of Parkin in regulating ER-mitochondria contacts, providing insights into PD pathogenesis and potential therapeutic strategies targeting MAMs.
    Keywords:  IP3R; Parkin; calcium; mitochondria-associated ER membrane; ubiquitination
    DOI:  https://doi.org/10.7150/ijbs.121759
  46. Food Sci Biotechnol. 2026 Jan;35(1): 193-201
    Lariciresinol and secoisolariciresinol enhance myogenic differentiation and mitochondrial biogenesis in C2C12 myotubes.
    Hyun Young Jeong, Jungae Jeun, Yeyoung Yoon, Young Jin Jang.
      Lariciresinol (LR) and secoisolariciresinol (SLR), phytochemicals found in pine bark and flaxseed, are known for their anticancer effects, risk reduction of cardiovascular disease, hormone regulation, and antioxidant activities. However, researches on their effects on skeletal muscle function are scarce. Therefore, this study aimed to investigate the efficacy of LR and SLR in promoting muscle hypertrophy and mitochondrial function in C2C12 mouse-derived myoblasts. LR and SLR were found to enhance myogenic differentiation as indicated by increased fusion index via myotube immunostaining and upregulation of MHC-Myogenin expression. These effects are caused by upregulated Akt phosphorylation, which is associated with protein synthesis pathways. In addition, LR and SLR supplementation led to increased mitochondrial biogenesis and enhanced mitochondrial function through upregulation of PGC-1α/SIRT1. These findings indicate that LR and SLR supplementation promotes muscle development and suggests potential for the prevention and treatment of sarcopenia.
    Keywords:  Lariciresinol; Muscle function; Muscle mass; Sarcopenia; Secoisolariciresinol
    DOI:  https://doi.org/10.1007/s10068-025-02014-7
  47. Sci Rep. 2026 Jan 10.
    Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression.
    Takanori Murakami, Kazuki Ohuchi, Masanori Kiuchi, Hisaka Kurita, Kanta Kawai, Ryo Kakiuchi, Tasuku Hirayama, Hideko Nagasawa, Zhiliang Wu, Yoichi Maekawa, Isao Hozumi, Masatoshi Inden.
      Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration, yet the underlying mechanism accounting for this iron accumulation is unclear. Although iron is an essential element, excessive amounts produce toxicity. Here, we focused on the role of iron and ATP13A2, the causative gene of PARK9 neurodegeneration with brain iron accumulation, using a cellular model. ATP13A2 deficiency resulted in impaired lysosomal function and iron accumulation in cell organelles. Further, we found dysfunction of mitophagy, which is involved in managing mitochondrial quality, as well as mitochondrial damage. Furthermore, we confirmed a decreased heme synthesis capacity, which is important to maintain intracellular iron homeostasis. Overall, our study indicates that lysosome-derived mitochondrial impairment can disrupt intracellular iron homeostasis in a cell model of PD pathology. This could help better understand the mechanisms underlying PD.
    Keywords:  ATP13A2; Heme; IRP2; Intracellular iron homeostasis; Lysosome; Mitochondria; Mitophagy; PARK9; Parkinson’s disease; Transferrin receptor
    DOI:  https://doi.org/10.1038/s41598-026-35368-x
  48. Sci Adv. 2026 Jan 16. 12(3): eadz2785
    Reversible phase dynamics of PsAF5 regulate mitophagy to balance redox levels in Phytophthora sojae.
    Jinzhu Chen, Wenhao Li, Qin Peng, Hongwei Zhu, Tan Dai, Jianqiang Miao, Xili Liu.
      Redox balance is essential for normal cellular functions. PsAF5, a FYVE domain-containing protein, functions as an essential sensor and adapter, particularly in mitophagy triggered by reactive oxygen species in Phytophthora sojae. However, the regulatory role of PsAF5 in maintaining the dynamic equilibrium of the intracellular redox state has not yet been fully elucidated. Here, we identify that specific cysteine residues in the FYVE domain of PsAF5 sense cellular redox states to form and resolve disulfide bonds in a redox-dependent manner. Under reducing conditions, PsAF5 undergoes redox-dependent phase separation to form cytoplasmic condensates that are functionally decoupled from mitophagy execution. Under oxidative conditions, PsAF5 exhibits increased cytosolic solubility and enhanced interaction with PsATG8, thereby promoting mitophagy. This mechanism enables P. sojae to toggle between "detoxification" (oxidizing stress) and "metabolic resilience" (reducing stress) states, ensuring survival across hostile host niches.
    DOI:  https://doi.org/10.1126/sciadv.adz2785
  49. Biochem Pharmacol. 2026 Jan 08. pii: S0006-2952(26)00030-4. [Epub ahead of print] 117699
    CircCramp1l targets the miR-532-3p/HMGB1/Drp1 axis to regulate allergic rhinitis.
    Yalin Zhang, Jiangang Wang, Yilan Song, Jingmei Chai, Liangchang Li, Hainan Jin, Yi Yang, Chongyang Wang, Yongde Jin, Guanghai Yan.
      The pathogenesis of allergic rhinitis (AR) remains incompletely understood, and the role of circular RNAs (circRNAs) in its progression warrants further investigation. This study aimed to elucidate the underlying mechanisms of circRNA-mediated regulation in AR and identify potential therapeutic targets. By collecting nasal mucosa specimens from AR patients, establishing house dust mite(HDM)-induced AR mouse models and human nasal epithelial cell(HNEpCs) models, and combining circRNA/miRNA sequencing with GEO data analysis, it was found that HDM triggers a significant upregulation of circCramp1l in AR. Mechanistically, circCramp1l acts as a ceRNA to sponge miR-532-3p, thereby relieving the suppression of HMGB1, an response-related DAMP molecule. Further validation through dual-luciferase reporter(DLR)assays, Co-IP combined with mass spectrometry, and molecular dynamics(MD) simulations demonstrated that HMGB1 directly binds to Drp1(binding free energy ΔG = -480.02 kcal/mol; key domain: amino acids 86-164 of HMGB1), driving Drp1 Ser616 phosphorylation. This leads to excessive mitochondrial fission, ROS accumulation, P2X7R/TLR4/NLRP3 axis. This signaling cascade induces Th2 polarization(elevated IL-4/IL-5/IL-13), eosinophil infiltration, and epithelial damage. Intervention experiments showed that conditional knockout of HMGB1, silencing of circCramp1l, administration of miR-532-3p mimics, or treatment with the Drp1 inhibitor Mdivi-1 all reversed mitochondrial dysfunction and significantly alleviated AR symptoms. This study reveals that the circCramp1l/miR-532-3p/HMGB1/Drp1 signaling axis contributes to AR pathogenesis by modulating mitochondrial dynamics and P2X7R/TLR4/NLRP3 axis. These results offer a novel target for the diagnosis and treatment of AR.
    Keywords:  Allergic rhinitis; CircCramp1l; Drp1; HMGB1; P2X7R/TLR4/NLRP3axis; miR-532-3p
    DOI:  https://doi.org/10.1016/j.bcp.2026.117699
  50. Apoptosis. 2026 Jan 10. 31(1): 18
    Cross-regulation of autophagy and pyroptosis: a new perspective on the inflammatory microenvironment of atherosclerosis.
    Yu-Mei Gan, Nai-Shen Qin, Jun Ouyang, Yu-Ming Tang, Jia-Hui Qin, Shu-Min Wei, Hui Wang, Jiang-Nan Huang.
      The pathogenesis of atherosclerosis (AS) is a chronic disease marked by inflammation, and there are intimate associations with various forms of programmed cell death (PCD). Recently, the mechanisms of pyroptosis and autophagy in AS have attracted much attention. Pyroptosis is a form of PCD mediated by inflammasomes, which worsens local inflammatory responses by releasing proinflammatory factors (e.g., IL-18 and IL-1β) and favors plaque instability and thrombosis. Autophagy is a process that helps to keep cells healthy by breaking down damaged cell structures and abnormal proteins. Mitophagy, a specialized form of autophagy, is of major importance to redox homeostasis and the regulation of inflammation. However, the dysregulation of autophagy may disturb the cellular homeostasis, which then accelerates the progression of AS. Studies have found a complex mutual regulation between pyroptosis and autophagy. Autophagy can block the occurrence of pyroptosis by degrading the components of such as NLRP3. The inflammatory mediators released during pyroptosis may cause the disorder of autophagy, which aggravates the cell death and inflammatory response. The disorder of autophagy will also promote pyroptosis' occurrence and progress. Both of them play a vital role in AS. This study is mainly focused on clarifying the relationship and molecular mechanism between pyroptosis and autophagy in the context of AS. These findings pave the way for new avenues for understanding its pathogenesis and potentially therapeutic decision-making.
    Keywords:  Atherosclerosis; Autophagy; Inflammation; Mitophagy; Pyroptosis
    DOI:  https://doi.org/10.1007/s10495-025-02221-x
  51. Cancer Res. 2026 Jan 16. 86(2): 557
    Retraction: SSBP1 Suppresses TGFβ-Driven Epithelial-to-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer by Regulating Mitochondrial Retrograde Signaling.
    Hong-Lin Jiang, He-Fen Sun, Shui-Ping Gao, Liang-Dong Li, Sheng Huang, Xin Hu, Sheng Liu, Jiong Wu, Zhi-Ming Shao, Wei Jin.
      
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5106
  52. Biomaterials. 2026 Jan 12. pii: S0142-9612(26)00013-X. [Epub ahead of print]330 123989
    Iron oxide nanoparticles-driven mitochondrial renewal rejuvenates the aged bone marrow niche.
    Xiaoqing Sun, Xingyou Wang, Meihua Zhang, Shuyao Liu, Yue Zhu, Jing He, Yao Wu.
      With the aging population, treating age-related osteoporosis remains challenging due to the dysfunctional bone marrow microenvironment characterized by chronic inflammation, metabolic dysregulation, and impaired mitochondrial function in senescent cells. While mitochondrial transfer from macrophages to bone marrow mesenchymal stem cells (BMSCs) offers a promising therapeutic avenue, its efficacy is limited in aged niches where donor mitochondria exhibit functional deficits and poor recipient compatibility. We engineered KGM-PEG-SPIONs, functionalized Fe3O4 nanoparticles that enhance donor mitochondrial quality via autophagy activation and Fe-S cluster biogenesis, promote M2 macrophage polarization, and improve compatibility with the oxidative and inflammatory environment of senescent BMSCs. These M2-like mitochondria are transferred through connexin 43 gap junctions, restoring membrane potential, ATP production, calcium homeostasis, and osteogenic differentiation in recipient cells. In aged osteoporotic models, KGM-PEG-SPION-functionalized scaffolds remodel immune niches and promote bone formation. By integrating organelle quality control with environment-adapted mitochondrial transfer, this strategy surpasses approaches focusing solely on transfer quantity or polarization, establishing a programmable nanoplatform for organelle-based regeneration.
    Keywords:  Autophagy; Fe–S cluster; Mitochondrial biogenesis; Mitochondrial transfer; Senescent macrophage polarization; Senile osteoporotic
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.123989
  53. Biochem Pharmacol. 2026 Jan 14. pii: S0006-2952(26)00044-4. [Epub ahead of print] 117713
    Mertk-driven tunneling nanotube formation in macrophages preserves mitochondrial homeostasis during kidney Ischemia-Reperfusion Attack.
    Jun Zeng, Ruoqing Li, Liyin Chai, Ying Zhang, Li Gong, Xiaolin Yuan, Qiufang Bai, Shuping Xiao, Jialian Wang, Sha Xiang, Haili Sun, Zhengyang Liu, Xingqing Chen, Ning Li, Bailin Niu, Mei Mei, Bingbing Shen.
      Renal ischemia-reperfusion (I/R) injury is a critical pathological process in organ transplantation and acute kidney injury (AKI), involving oxidative stress, inflammation, and mitochondrial dysfunction. Macrophage-expressed Mertk, a key regulator of tissue homeostasis, remains understudied in renal I/R injury. Mertk knockout (Mertk-KO) mice and their wild-type (WT) littermates were subjected to renal I/R injury. Mertk deficiency exacerbated renal tubular injury, inflammation, and oxidative stress in I/R-induced AKI. ATP production decreased, and mitochondrial morphology was disrupted in RTECs from Mertk-KO mice compared to WT mice. In vitro studies demonstrated that knockdown of Mertk in kidney-resident macrophages (KRMs) aggravated renal tubular epithelial cells (RTECs) injury, proliferation inhibition, apoptosis, and mitochondrial dysfunction under hypoxia-reoxygenation (H/R) conditions. Conversely, Mertk overexpression in KRMs attenuated these detrimental effects. Notably, Mertk overexpression facilitated tunneling nanotubes (TNTs) formation and promoted intercellular mitochondrial trafficking between KRMs and RTECs, maintaining mitochondrial homeostasis in RTECs. LAT-A treatment inhibited TNTs formation and abrogated the protective effects of Mertk overexpression. This study established Mertk as a critical mediator of KRMs-RTECs crosstalk through TNTs-dependent mitochondrial homeostasis regulation, providing mechanistic insights into AKI progression. Mertk-expressed KRMs-mediated mitochondrial transfer through TNT formation, providing a potential therapeutic target for AKI.
    Keywords:  Acute kidney injury; Ischemia–reperfusion; Kidney-resident macrophages; Mertk; Mitochondrial homeostasis; Tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.bcp.2026.117713
  54. iScience. 2026 Jan 16. 29(1): 114382
    HMOX1 drives dihydroartemisinin-sensitized ferroptosis antagonized by mitochondrial fusion.
    Zi-Jie Deng, Jing Zhang, Zhang-Zhong Yang, Qing-Zhang Tuo, Peng Lei.
      Artemisinin is the key component of artemisinin-based combination therapy (ACT) for malaria. Combinations of artemisinin with partner drugs demonstrate significant therapeutic potential in various diseases, including cancer. However, the precise mechanisms by which artemisinin, in combination with partner drugs, induces cell death are still not fully understood. Ferroptosis, a distinct form of cell death characterized by its dependence on iron, oxygen, and phospholipids (PLs), represents one potential pathway. In this study, we discovered that dihydroartemisinin (DHA), the active metabolite of artemisinin and its derivatives, sensitizes cells to ferroptosis induced by GPX4 inhibition. Through integrated data analysis and experimental validation, we found that DHA enhances ferroptosis sensitivity by promoting heme oxygenase 1 (HMOX1, HO-1)-mediated mitochondrial oxidative stress, thereby triggering a feedback loop that promotes mitochondrial fusion. These results broaden our understanding of the mechanisms of DHA in combination with partner drugs, and provide insights for clinical translation of ferroptosis.
    Keywords:  Drug delivery system; Drug dispensing; Pharmacology; Therapeutics
    DOI:  https://doi.org/10.1016/j.isci.2025.114382
  55. Nat Commun. 2026 Jan 14. 17(1): 229
    6-Phosphogluconate dehydrogenase promotes mitochondrial fusion and immune suppression in tumor-associated monocytic suppressor cells.
    Saeed Daneshmandi, Qi Yan, Eduardo Cortes Gomez, Jee Eun Choi, Eriko Katsuta, Ehsan Gharib, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Elizabeth A Repasky, Philip L McCarthy, Hemn Mohammadpour.
      The mechanisms underlying the metabolic adaptation of myeloid cells within the tumor microenvironment remain incompletely understood. Here, we identify 6-phosphogluconate dehydrogenase (6PGD), a rate-limiting enzyme in the pentose phosphate pathway (PPP), as an important regulator of monocytic-myeloid derived suppressor cell (M-MDSC) function. Our findings reveal that tumor M-MDSCs upregulate 6PGD expression via IL-6/STAT3 signaling. Blocking 6PGD, using either genetic or pharmacological approaches, impairs the immunosuppressive function of M-MDSCs and suppresses tumor growth. Mechanistically, 6PGD inhibition leads to the accumulation of its substrate, 6-phosphogluconate (6PG), within M-MDSCs, activates the JNK1-IRS1 and PI3K-AKT-pDRP1 signaling pathways, leading to mitochondrial fragmentation and elevated mitochondrial reactive oxygen species (ROS). This metabolic shift drives M-MDSCs toward an M1-like proinflammatory phenotype. Furthermore, 6PGD blockade synergizes with anti-PD-1 immunotherapy in a preclinical tumor model, substantially improving therapeutic outcomes. Our data reveals 6PGD as a possible therapeutic target to disrupt M-MDSC function and improve cancer immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-68102-8
  56. Nucleic Acids Res. 2026 Jan 14. pii: gkaf1390. [Epub ahead of print]54(2):
    Mrx6 binds the Lon protease Pim1 N-terminal domain to confer selective substrate specificity and regulate mtDNA copy number.
    Simon Schrott, Ilaria Marafelli, Charlotte Gerle, Sebastian Bibinger, Lea Bertgen, Giada Marino, Serena Schwenkert, Romina Rathberger, Johannes M Herrmann, Christof Osman.
      Mitochondrial DNA (mtDNA) copy number regulation remains incompletely understood, despite its importance in cellular function. In Saccharomyces cerevisiae, Mrx6 belongs to the Pet20-domain-containing protein family, consisting of Mrx6, Pet20, and Sue1. Notably, absence of Mrx6 leads to increased mtDNA copy number. Here, we identify the C-terminus of Mrx6 as essential for its stability and interaction with the mitochondrial matrix protein Mam33. Deletion of Mam33 mimics the effect of Mrx6 loss, resulting in elevated mtDNA copy number. Bioinformatics, mutational analyses, and immunoprecipitation studies corroborate that a subcomplex of Mam33 and Mrx6 trimers interacts with the substrate recognition domain of the conserved mitochondrial Lon protease Pim1 through a bipartite domain in the Pet20 domain of Mrx6. Loss of Mrx6, its paralog Pet20, Mam33, or mutations disrupting the interaction between Mrx6 and Pim1 stabilize key proteins required for mtDNA maintenance, the RNA polymerase Rpo41 and the HMG-box-containing protein Cim1. We propose that Mrx6, alongside Pet20 and Mam33, regulates mtDNA copy number by modulating substrate degradation through Pim1. Additionally, Mrx6 loss alters Cim1's function, preventing the detrimental effect on mtDNA maintenance observed upon Cim1 overexpression. The presence of three Pet20-domain proteins in yeast implies broader roles of Lon protease substrate recognition beyond mtDNA regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf1390
  57. J Mater Chem B. 2026 Jan 15.
    Naphthylimide-based mitochondrial immobilized probes for polarity-specific imaging of mitochondrial autophagy in cells and mouse cardiac tissue.
    Yukun Zhang, Lie Li, Ruiyuan Liu, Jinqing Qu.
      Mitochondrial autophagy is closely related to various diseases such as neurodegenerative diseases and cancer, and changes in mitochondrial polarity are key markers of these diseases. Traditional fluorescent probes rely on membrane potential and often lose signal during key stages of autophagy. This work develops a mitochondria-immobilized fluorescent probe, Mito-NT, which uses naphthylimide as the fluorescent moiety, triphenylamine as the electron donor, pyridine salt as the electron acceptor, and a mitochondrial-targeting group. The probe achieves polarity-dependent fluorescence response through the activation of an intramolecular charge transfer (ICT) mechanism. The active chlorine unit in its structure ensures that the probe remains stable in the mitochondria and is not affected by changes in the membrane potential. Mito-NT exhibits high polarity sensitivity, pH stability, strong interference resistance, and low cytotoxicity, enabling dynamic monitoring of the mitochondrial autophagy process, tracking the fusion of mitochondria and lysosomes, and distinguishing mouse hunger-induced cardiac mitochondrial autophagy (manifested as enhanced fluorescence). This probe provides a powerful tool for mitochondrial autophagy research and related disease diagnosis.
    DOI:  https://doi.org/10.1039/d5tb02337h
  58. J Ethnopharmacol. 2026 Jan 09. pii: S0378-8741(26)00034-6. [Epub ahead of print]360 121183
    Myricanol modulates PPARγ/ACSL1/SCD1 metabolic signaling pathway to promote mitochondria biogenesis and fatty acid β-oxidation in high-fat diet-induced obese mice.
    Xiaoying Zhang, Sha Xiang, Siyun Tang, Xiaoxia Luo, Lingyang Fan, Xianlei Fang, Hua Chen, Zaiqi Zhang, Kai He.
       ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Myrica rubra (Lour.) Siebold & Zucc (MR). is a natural remedy commonly used in China and other Asian nations because of its antioxidant, antiinflammation and antibacterial activities. Myricanol is the main lipid-lowering compounds in the bark of MR. The effects of myricanol on alleviating hyperlipidemia have rarely been reported. No study has investigated the role of the ACSL-SCD axis in the management of hyperlipidemia in vivo.
    AIM OF THE STUDY: This study employed a high-fat diet (HFD)-induced hyperlipidemic C57BL/6J mouse model to explore the lipid-lowering effects and underlying mechanisms of myricanol through the ACSL1-SCD1 axis.
    MATERIALS AND METHODS: An olive oil and lard mixture was used to establish a hyperlipidemic C57BL/6J mouse model. Rosiglitazone (RSG) a peroxisome proliferator-activated receptor γ (PPARγ) agonist, and ACSL inhibitor was used as a positive control. After 8 weeks of high-fat modeling, the mice were randomly divided into the M group, RSG group (0.4 ml, 0.78 mg/kg RSG solution daily), low-dose myricanol group (MYL, 100 mg/kg), and high-dose myricanol group (MYH, 150 mg/kg). After 25 days of treatment, the lipid-lowering effects of myricanol were evaluated by measuring serum lipid levels and histopathological observation. Western blotting, metabolomics, 16S rRNA sequencing, RNA sequencing, ELISA, immunofluorescence staining, double-fluorescence labeling and cellular thermal shift assay (CETSA) were used to explore the underlying mechanisms.
    RESULTS: Only 7 days of myricanol treatment significantly reduced body weight in obese mice. Myricanol normalized serum levels of TC, TG, HDL-C, and LDL-C; reduced lipid droplet accumulation in hepatocytes; and decreased the epididymal fat volume in mice. Mechanistic studies revealed that myricanol upregulated the expression of ACSL1, PPARγ, CYP7A1, SCD1, ACLY, and SREBF1 in the mouse liver. Additionally, myricanol increased the expression of PPARγ, CPT1A, ACC1, ACSL1, APOE4, and SREBF1 in the mouse epididymal fat. Multimodal omics analyses indicated that the lipid-lowering activity of myricanol was partially mediated by modulating the gut microbiota, such as that of Monoglobus and Lachnospiraceae bacterium 28-4; regulating the interferon (IFN) pathway and IFN-stimulated genes; and influencing the expression of miRNAs such as miR-203b-3p, miR-205-5p, and miR-184-3p. Cellular thermal shift assay, molecular docking, and ELISA confirmed that myricanol directly bound to ACSL1 and decreased the concentrations of ACSL1 and SCD1 in mouse serum. Intriguingly, myricanol promoted mitochondrial biogenesis in a time- and dose-dependent manner and increased ketone body and acetyl-CoA levels in obese mice.
    CONCLUSION: This study reveals a novel cellular mechanism through which myricanol reduces lipid levels via the PPARγ/ACSL1/SCD1 signaling pathway. Myricanol also promotes mitochondrial biogenesis and fatty acid β-oxidation; therefore, it holds great promise as a phytotherapeutic agent for hyperlipidemia.
    Keywords:  Fatty acid β-oxidation; Hyperlipidemia; Mitochondria biogenesis; Multimodal omics; Myricanol; PPARγ/ACSL1/SCD1 signaling pathway
    DOI:  https://doi.org/10.1016/j.jep.2026.121183
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒23 at 23:36.