bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–04–26
73 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Cholesterol overload promotes mitochondria-mediated apoptosis with impaired mitochondrial unfolded protein response and mitophagy in SH-SY5Y cells.
  2. Mitochondria at the heart of aging: structure, function, and failure.
  3. The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
  4. Targeting mitochondrial quality control in Alzheimer's disease: Mechanisms and therapeutic potential of phytomedicines.
  5. Mechanistic study on nonylphenol-induced depressive-like behavior: PINK1/parkin-mediated mitophagy regulates synaptic remodeling in neurons.
  6. Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.
  7. SLC25A30 Regulates Mitochondrial Autophagy Through the PINK1/PARKIN Signaling Pathway to Alleviate Sepsis-Associated Acute Kidney Injury.
  8. Regulation of mitochondrial fission by Drp1 in cardiomyopathy: possible mechanisms linking cellular processes to cell death.
  9. TFAM promotes mitochondrial division by increasing mitochondrial Sirt3.
  10. PMF proteins mediate mitochondrial fusion in Arabidopsis.
  11. [Effect of moxibustion on the PINK1/Parkin pathway and mitophagy in rats with rheumatoid arthritis].
  12. Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells.
  13. The multifaceted role of mitochondrial dysfunction in Alzheimer's disease pathogenesis.
  14. Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
  15. Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.
  16. Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response.
  17. Morroniside maintains mitochondrial homeostasis in microglia and mitigates neuroinflammation in experimental autoimmune encephalomyelitis.
  18. TDCIPP induces placental dysfunction and fetal growth restriction via oxidative stress-mediated PINK1/Parkin mitophagy.
  19. [Regulatory effects of serum containing Hedysari Radix Praeparata Cum Melle-vinegar processed Curcumae Rhizoma on mitochondrial function and mitophagy in HT-29 cells].
  20. Mechanism of Terpinen-4-ol in Suppressing β-Cell Dedifferentiation: Restoring Mitophagy and Alleviating Mitochondrial Calcium Overload via Parkin-Mediated MCU Degradation.
  21. Peroxiredoxin Ⅲ safeguards cardiac function against doxorubicin by regulating mitochondrial quality control via H2O2 detoxification.
  22. Corrigendum to "Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-dependent mitophagy" [Free Radic. Biol. Med. (2025) 150-160].
  23. The N6-methyladenosine (m6A) reader YTHDF3 increases PINK1/Parkin-mediated mitophagy by facilitating prohibitin 2 (PHB2) translation to promote retinal ganglion cell damage in diabetic retinopathy.
  24. m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction.
  25. CIDEC impairs mitochondrial fitness and blocks protective autophagy via the inhibition of cGMP/PKG pathway to exert tumor-suppressive effects in breast cancer.
  26. Mitochondrial dysfunction in sleep deprivation.
  27. Doxorubicin-induced apoptosis and mitochondrial fission are promoted by LncRNA TGFB2-AS1 through BMP7/Smad signaling.
  28. Ciliatoside A Improves Klebsiella pneumoniae-Induced Pneumonia by Modulating Mitochondrial Autophagy via the SIRT1/PINK1/Parkin Pathway.
  29. MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae.
  30. Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.
  31. MAPK15 Attenuates Intestinal Epithelial Cell Senescence-Like Phenotype to Regulate Gut Homeostasis and Inflammation by Phosphorylating Suz12 to Suppress Drp1-Mediated Mitochondrial Fission Damage.
  32. SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.
  33. Iron supplementation prevents abdominal aortic aneurysm by increasing Tregs via maintained mitochondrial homeostasis.
  34. Phytoestrogenic Isoflavone Formononetin Attenuates Motor Deficits and Mitochondrial Impairment by Regulating SIRT1/PGC-1α/NRF1/TFAM Axis in Parkinson's Disease.
  35. Paeoniflorin Ameliorates Liver Fibrosis by Inhibiting HIF-1α-Mediated Mitophagy in Hepatic Stellate Cells.
  36. Dual-targeting nanoparticles enhance microglial P2Y12R expression to promote neuronal mitophagy for repairing spinal cord injury.
  37. Lycopene Alleviates Deoxynivalenol-Induced Porcine Intestinal Epithelial Barrier Injury by Inhibiting PGAM5-Mediated Mitophagy-Dependent Ferroptosis.
  38. Myeloperoxidase (MPO) mediates LPS-induced mitophagy in murine macrophages through AMPK/ULK1 pathway.
  39. [Mechanism of Angelicae Pubescentis Radix-Taxilli Herba components in preventing nucleus pulposus cell apoptosis via regulating PINK1/Parkin and Nrf2 pathways based on "Qu-Zhi-Bu-Yi" theory].
  40. mtHsp70 overexpression enhances neuroprotection through ATF5-dependent UPRmt signaling after traumatic brain injury.
  41. Coronavirus infectious bronchitis virus spike protein inhibits FUNDC1-mediated mitophagy to prevent nucleocapsid protein degradation.
  42. Integrated RNA-seq and scRNA-seq to explore the biological mechanisms of mitophagy-related genes in ulcerative colitis.
  43. EGR2 affects mixed stroke repair through BNIP3L-mediated microglial mitophagy.
  44. Effects of MICT and HIIT on mitochondrial dynamics-related proteins in visceral adipose tissue of type 2 diabetic rats.
  45. TARGETING DRP1 ATTENUATES FERROPTOSIS AND DELAYS THE PROGRESSION OF DIABETIC RETINOPATHY.
  46. Exosomes secreted by ADMSCs preserve cartilage integrity in knee osteoarthritis via AMPK-mediated mitochondrial dynamics and apoptosis.
  47. Trimethyltin chloride triggers ferroptosis in myocardial injury: mitochondria-dependent protection by luteolin.
  48. Anmei Decoction alleviates myocardial injury in sleep-deprived rats by PI3K/Akt/mTOR/HIF-1 pathway.
  49. Protective Effects of Agrimonia pilosa Ledeb. In Myocardial Fibrosis: Inhibition of Mitophagy Mediated by the FOXO Signaling Pathway.
  50. Spermidine alleviates sepsis-induced cardiomyopathy by improving mitochondrial quality and quantity via a Metallothionein 1-dependent antioxidant pathway.
  51. Targeted biohybrid nanoplatform for spinal cord injury treatment: Restoring microglial mitophagy and alleviating oxidative stress.
  52. PKCδ-Drp1 Axis Mediates VIP-Induced Mitochondrial Fragmentation and Metabolic Crisis in Nasopharyngeal Carcinoma.
  53. Biomarkers of mitochondrial dynamics in idiopathic pulmonary fibrosis: Identification and validation through transcriptomic and single-cell analyses.
  54. Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.
  55. Proteolytic control of mitochondrial protein translocases.
  56. Mitochondrial Homeostasis Regulation in the Prefrontal Cortex: A Key Mechanism for Emodin-Mediated Attenuation of Insomnia.
  57. Reactivating mitochondrial quality control via the Nrf2 pathway to combat metabolic stress in diabetic osteoarthritis.
  58. [Effect of moxibustion on endothelial cell apoptosis in ApoE-/- atherosclerotic mice via PINK1/Parkin signaling pathway].
  59. Getting a handle on RAB1: from Golgi trafficking to mitophagy.
  60. Cardiac STIM1 deficiency triggers mitochondrial fission to impair electrophysiological function and exacerbate post-MI remodeling.
  61. Sakuranin attenuates UVB-induced skin damage by preserving mitochondria-ER coupling and restoring redox-organelle homeostasis.
  62. Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
  63. Inhibition of Microglial TRPV1 Ameliorates Brain Injury After Intracerebral Hemorrhage by Suppressing AMPK/PINK1-Mediated Mitophagy.
  64. Macrophage-mimetic photothermal nanotherapeutics regulate mitochondrial homeostasis and inflammatory cascades in lung ischemia-reperfusion injury.
  65. m6A-Mediated epitranscriptional reprogramming drives cardiac fibrosis by suppressing PGC-1α and boosting mitochondrial fission.
  66. Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.
  67. 5-Hydroxytryptamine 2B receptor antagonism restores ATP and reduces tubulointerstitial fibrosis in the renal cortices of aged mice.
  68. Quantitative analysis of autophagic flux reveals radiation-induced activation of SQSTM1-mediated degradation of protein aggregates and ER-phagy.
  69. IL-10-STAT3 axis preserves epithelial mitochondrial homeostasis during bacterial challenge.
  70. Melatonin attenuates mitochondrial apoptosis and improves mitochondrial quality by activating the AKT/BAD/BCL-XL signaling pathway, promoting oxidative muscle fiber formation.
  71. Zishen Huoxue Decoction alleviates myocardial ischemia-reperfusion injury through dysregulation of endoplasmic reticulum-mitochondria homeostasis mediated by DUSP1-NDUFS4.
  72. Parkin regulates NLRP3 degradation through chaperone-mediated autophagy to suppress PANoptosis and protect dopaminergic neurons in Parkinson's disease.
  73. NSUN2-mediated GATM m5C methylation regulates creatine metabolism to drive mitochondrial fission and promote renal fibrosis.
  1. Food Chem Toxicol. 2026 Apr 20. pii: S0278-6915(26)00180-8. [Epub ahead of print] 116106
    Cholesterol overload promotes mitochondria-mediated apoptosis with impaired mitochondrial unfolded protein response and mitophagy in SH-SY5Y cells.
    Juhyun Chung, Je Won Ko, Young Hye Kwon.
      Cholesterol accumulation in the brain has been implicated in mitochondrial dysfunction and neurodegeneration; however, its specific effects on mitochondrial quality control pathways, including the mitochondrial unfolded protein response (UPRmt) and mitophagy, remain poorly defined. In this study, SH-SY5Y human neuroblastoma cells were treated with 25 or 50 μg/mL water-soluble cholesterol for 24 h. UPRmt, mitophagy, and inflammasome activation were assessed using molecular and cellular approaches, including immunoblotting, quantitative RT-PCR, and fluorescence-based imaging. Cholesterol treatment increased intracellular cholesterol levels up to 1.7-fold and induced dose-dependent cytotoxicity and apoptosis. UPRmt was suppressed, as evidenced by reduced expression of mitochondrial chaperones and proteases. In parallel, cholesterol impaired mitophagy by disrupting autophagic flux, leading to the accumulation of damaged mitochondria. This was accompanied by increased cytosolic mitochondrial DNA (mtDNA), caspase 1 activation, and interleukin-1β secretion. These findings indicate that impaired mitochondrial clearance promotes mtDNA release, thereby linking mitochondrial dysfunction to inflammasome activation. Collectively, cholesterol overload disrupts UPRmt and mitophagy, thereby promoting mitochondrial dysfunction, inflammasome activation, and neuronal apoptosis.
    Keywords:  Apoptosis; Cholesterol; Inflammasome; Mitochondria; Mitophagy; SH-SY5Y cells; UPRmt
    DOI:  https://doi.org/10.1016/j.fct.2026.116106
  2. J Transl Med. 2026 Apr 24.
    Mitochondria at the heart of aging: structure, function, and failure.
    Hany E Marei.
      
    Keywords:  Aging; Mitochondria; Mitochondrial biogenesis; Mitochondrial dysfunction; Mitophagy; NAD+; Oxidative stress; PGC-1α; Rejuvenation; Sirtuins
    DOI:  https://doi.org/10.1186/s12967-026-08047-8
  3. Autophagy. 2026 Apr 23.
    The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
    Shu-Q Cao, Juan Ignacio Jiménez-Loygorri, Patricia Boya, Evandro F Fang.
      Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain limited. Emerging evidence suggests that dietary molecules may influence mitochondrial health, although the underlying mechanisms are largely unknown. Here, we summarize our recent finding whereby we have identified a robust mitophagy inducer: α-amyrin (αA). This molecule is a lipid-like pentacyclic triterpenoid abundant in edible plants, such as passion fruit. Mechanistically, αA targets dual leucine zipper kinase (DLK), a neuron-enriched stress kinase that plays a central role in axonal degeneration signaling. Under pathological stress, DLK activates the degeneration mediator SARM1, which can sequester the key autophagy/mitophagy protein ULK1 leading to compromised autophagy and mitophagy. By specifically binding to DLK, αA releases ULK1 from SARM1-mediated restriction and promotes ULK1-dependent mitophagy, restoring mitochondrial homeostasis. This mechanism reveals the DLK-SARM1-ULK1 cascade as a previously underappreciated regulatory interface linking neuronal stress signaling to mitochondrial surveillance pathways. More broadly, these findings introduce lipid-like dietary molecules as potential "mitochondrial guardians" that preserve organelle integrity through physiological activation of mitophagy. Targeting the DLK-SARM1-ULK1 axis with such molecules may represent a promising strategy for maintaining mitochondrial health and mitigating neurodegenerative processes associated with aging.
    Keywords:  DLK; ULK1; lipid-like molecule; mitophagy; α-amyrin
    DOI:  https://doi.org/10.1080/15548627.2026.2664599
  4. Pharmacol Res. 2026 Apr 21. pii: S1043-6618(26)00117-9. [Epub ahead of print]228 108202
    Targeting mitochondrial quality control in Alzheimer's disease: Mechanisms and therapeutic potential of phytomedicines.
    Zhongying Lin, Shun Zhang, Miao Sun.
      Alzheimer's disease (AD) is a neurodegenerative disorder driven partly by mitochondrial dysfunction, notably the failure of mitochondrial quality control (MQC). Phytochemicals have emerged as multi-target agents capable of restoring MQC, offering a promising therapeutic avenue. This review outlines how dysregulated MQC contributes to AD pathogenesis and summarizes the current evidence on phytochemicals that target key MQC processes-including mitochondrial dynamics, biogenesis, mitophagy, oxidative stress, and apoptosis-to exert neuroprotection. In AD, MQC is broadly impaired, characterized by suppressed biogenesis, excessive mitochondrial fission, defective mitophagy, oxidative stress, and calcium dyshomeostasis. Phytochemicals counter these defects through diverse mechanisms: restoring fission-fusion balance, enhancing biogenesis and mitophagic clearance, attenuating oxidative stress via Nrf2 activation, and inhibiting mitochondria-dependent apoptosis by modulating Bcl-2 family proteins and caspases. Despite these promising preclinical findings, several challenges remain, including poor bioavailability, limited blood-brain barrier penetration, lack of standardized preparations, and insufficient clinical validation. This review provides a mechanistic rationale for targeting MQC in AD and highlights future directions for translating phytochemical-based strategies into effective therapies.
    Keywords:  Alzheimer’s disease; Mitochondrial quality control; Multi-target therapy; Neuroprotection; Phytochemicals
    DOI:  https://doi.org/10.1016/j.phrs.2026.108202
  5. Ecotoxicol Environ Saf. 2026 Apr 18. pii: S0147-6513(26)00478-1. [Epub ahead of print]316 120149
    Mechanistic study on nonylphenol-induced depressive-like behavior: PINK1/parkin-mediated mitophagy regulates synaptic remodeling in neurons.
    Huawen Yu, Jie Yu, Xiao Yang, Feng Wang, Kai Pan, Feng Li, Ya Luo, Jianling Zhang, Zhenghao He, Jie Xu.
       OBJECTIVE: To investigate the role of PINK1/Parkin-mediated mitophagy in regulating synaptic remodeling of neuronal cells in depression-like behaviors induced by nonylphenol (NP).
    METHODS: In vitro experiments: HT-22 neuronal cells were exposed to NP, and mitophagy and Parkin expression were inhibited using specific inhibitors. The cells were categorized into the following groups: (1) control (C) and low-dose NP group (L: 2.5 µM), medium-dose NP group (M: 50 µM), and high-dose NP groups (H: 100 µM); (2) control (C), NP (100 µM), Mdivi-1 (5 µM), and Mdivi-1 + NP (5 µM Mdivi-1 +100 µM NP) groups; (3) control (C), NP (100 µM), AC220 (2 nM), and AC220 + NP (2 nM AC220 +100 µM NP) groups. In vivo experiments: a total of 48 mice, including 24 C57BL/6 wild-type mice and 24 PKRK2 gene-knockout mice, were randomly assigned to the following four groups: control (C), NP (100 mg/kg/day), PKRK2-knockout (KO), and PKRK2-knockout + NP (100 mg/kg/day, KH) groups, with 12 mice in each group.
    RESULTS: In vitro: With increasing NP concentration, the ATP content reduced and the expressions of synaptic remodeling-related proteins (i.e., PSD-95, BDNF, SYN) decreased. In contrast, the expressions of mitophagy-related proteins and those involved in the PINK1/Parkin-signaling pathway (such as p62, Beclin1, PINK1, Parkin) increased (P < 0.05). Inhibition of mitophagy with Mdivi-1 alleviated the NP-induced changes in synaptic, mitophagy-related, and PINK1/Parkin pathway-related proteins. Similarly, the inhibition of Parkin with AC220 mitigated NP-induced effects on synaptic, mitophagy-related, and PINK1/Parkin-signaling pathway-related proteins and mRNA expression. In vivo: PKRK2 gene-knockout mice exhibited improved NP-induced depression-like behaviors and decreased NP-induced synaptic morphology and mitochondrial ultrastructure changes. Moreover, the gene knockout alleviated the downregulation of synaptic remodeling-related proteins and inhibited the PINK1/Parkin-signaling pathway-mediated mitophagy activated by NP.
    CONCLUSION: Mitophagy inhibition or PKRK2 knockout can alleviate NP-induced downregulation of synaptic remodeling-related proteins, protect synaptic morphology and ultrastructure, and improve NP-induced depression-like behaviors.
    Keywords:  Depressive-like behavior; Mitophagy; Nonylphenol; PINK1/Parkin signaling pathway; Synaptic remodeling
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120149
  6. Neuropharmacology. 2026 Apr 22. pii: S0028-3908(26)00163-2. [Epub ahead of print] 110990
    Oxidative stress-induced mitochondrial fragmentation inhibits CREB-mediated PV regulation and facilitates caspase-3-mediated PV neuronal degeneration following status epilepticus.
    Ji-Eun Kim, Su Hyeon Wang, Tae-Cheon Kang.
      Parvalbumin (PV)- expressing neurons (PV neurons) are a subpopulation of γ-aminobutyric acid (GABA)-ergic interneurons that are highly vulnerable to oxidative stress. Although mitochondrial homeostasis is an essential housekeeping function for maintaining PV expression level, the underlying mechanisms of PV downregulation caused by aberrant mitochondrial dynamics are largely unknown. In this study, using an in vivo male rat model, we found that oxidative stress induced by L-buthionine sulfoximine (BSO) reduced PV expression and cAMP-response-element-binding protein (CREB) serine (S) 133 phosphorylation through cyclin-dependent kinase 5 (CDK5)-dynamin-related protein 1 (DRP1)-mediated mitochondrial fission within hippocampal PV neurons under normal control conditions. These effects were ameliorated by roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission). Similar to BSO, WY14643-induced mitochondrial fission decreased PV expression and CREB S133 phosphorylation in PV neurons. Furthermore, CREB knockdown also led to PV downregulation without altering CDK5 activity or mitochondrial dynamics. Notably, these treatments did not lead to PV neuronal degeneration. In a pilocarpine-induced status epilepticus (SE) model, however, massive PV neuronal degeneration was observed accompanied by decreased CREB S133 phosphorylation and excessive mitochondrial fragmentation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 attenuated SE-induced PV neuronal degeneration by preserving CREB S133 phosphorylation and mitochondrial integrity. These findings indicate that the CDK5-DRP1-CREB pathway may evoke PV downregulation under sublethal oxidative stress and lead to irreversible PV neuronal degeneration under severe pathological conditions such as SE. Therefore, our findings suggest that this signaling pathway may be a therapeutic target to preserve PV neurons in neurological and psychiatric diseases.
    Keywords:  BSO; ROS; apoptosis; caspase-3; epilepsy; parvalbumin; pilocarpine
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110990
  7. DNA Cell Biol. 2026 Apr 23. 10445498261442835
    SLC25A30 Regulates Mitochondrial Autophagy Through the PINK1/PARKIN Signaling Pathway to Alleviate Sepsis-Associated Acute Kidney Injury.
    Mingyu Xu, Yuchen Wang, Wuyang Lv, Yingyue Ding, Jing Liu, Ruxue Diao, Xiaotong Ma, Mengjiao Yin, Yingyu Jin.
      This study aims to investigate the expression of the SLC25 subfamily in sepsis-associated acute kidney injury (SA-AKI) and the role of SLC25A30 in regulating PINK1/PARKIN-mediated mitophagy. Transcriptome sequencing of renal tissues from lipopolysaccharide (LPS)-induced SA-AKI rats at multiple time points revealed time-dependent differential expression of SLC25 genes. At 12 h post-LPS injection (renal injury peak), 11 differentially expressed genes were identified. Intersection with Gene Expression Omnibus datasets and Gene Ontology enrichment highlighted 11 codifferentially expressed genes enriched in mitochondrial transmembrane transport. Notably, SLC25A30 was significantly negatively correlated with KIM-1 (r = -0.96) and LCN2 (r = -0.98). SLC25A30 was significantly downregulated in SA-AKI rat renal tissues and LPS-induced HK-2 cells, accompanied by upregulated PINK1/PARKIN, excessive mitophagy (elevated LC3B-II, decreased p62), and increased renal injury markers. SLC25A30 overexpression inhibited PINK1/PARKIN, reversed excessive mitophagy, reduced KIM-1 and LCN2 levels, alleviated mitochondrial dysfunction, enhanced cell viability, and exerted cytoprotective effects. PINK1 knockdown attenuated the regulatory effect of SLC25A30 on excessive mitophagy, indicating a dependence on the PINK1/PARKIN pathway. In conclusion, downregulated SLC25A30 is closely associated with excessive mitophagy in SA-AKI. SLC25A30 overexpression inhibits excessive mitophagy via downregulating the PINK1/PARKIN pathway, improves mitochondrial function, and alleviates HK-2 cell injury, suggesting that SLC25A30 may be a novel molecular target for SA-AKI-targeted therapy.
    Keywords:  AKI; SA-AKI; SLC; SLC25A; mitophagy
    DOI:  https://doi.org/10.1177/10445498261442835
  8. Mol Biol Rep. 2026 Apr 21. pii: 640. [Epub ahead of print]53(1):
    Regulation of mitochondrial fission by Drp1 in cardiomyopathy: possible mechanisms linking cellular processes to cell death.
    Nandini Dubey, Pranav Panchbhai, Gauri Chaturvedi, Satnam Singh, Ahsas Goyal, Neeraj Parakh, Rajiv Narang, Sudhir Kumar Arava, Arvind Kumar, Mayank Yadav, Harlokesh Narayan Yadav.
      
    Keywords:  Autophagy; Cardiomyopathy; Drp1; Mitophagy; Phosphorylation
    DOI:  https://doi.org/10.1007/s11033-026-11831-w
  9. Cell Death Dis. 2026 Apr 21.
    TFAM promotes mitochondrial division by increasing mitochondrial Sirt3.
    Shixian Zhai, Zihong Huang, Zewei Luo, Chunchun An, Lu Gao, Tongsheng Chen.
      Mitochondrial transcription factor A (TFAM) plays a crucial role in mitochondrial fission beyond its canonical function in mtDNA maintenance. However, how TFAM regulates mitochondrial fission remains only partially understood. Fluorescence microscopy and TEM analyses showed that TFAM knockdown inhibited mitochondrial fission, whereas TFAM overexpression promoted mitochondrial fragmentation, and this mitochondrial morphology phenotype was supported by TEM-based ultrastructural observations in zebrafish embryos with tfam disruption. Depletion of Drp1 and MFF in TFAM-overexpressing cells led to elongated mitochondria, indicating that TFAM promotes Drp1- and MFF-dependent mitochondrial fission, which was further supported by the inhibitory effects of Mdivi-1 (Drp1 inhibitor) and Compound C (AMPK inhibitor) on TFAM-induced mitochondrial fission. Western blot and immunofluorescence analyses revealed that TFAM overexpression enhanced the mitochondrial localization and Sirt3-dependent mitochondrial protein deacetylation of Sirtuin 3 (Sirt3), increased phosphorylation of AMPK and MFF, and promoted mitochondrial recruitment of phosphorylated Drp1. Proteinase K protection and cycloheximide chase assays further supported intramitochondrial localization of Sirt3 and increased stability of mitochondrial Sirt3 upon TFAM overexpression. FRET imaging and co-immunoprecipitation demonstrated a direct TFAM-Sirt3 interaction mediated by TFAM's HMG-box A domain. Targeted mutagenesis or deletion of the HMG-box A domain disrupted the TFAM-Sirt3 interaction, impaired Sirt3 mitochondrial localization and Sirt3-dependent mitochondrial protein deacetylation, and abolished TFAM-mediated mitochondrial fission. Analysis of TCGA data showed that high TFAM-SIRT3 co-expression is associated with overall survival across cancers, particularly in Kidney Renal Clear Cell Carcinoma (KIRC), where TFAM is downregulated (whereas SIRT3 is not). Together, these findings demonstrate that TFAM promotes mitochondrial fission via direct interaction with Sirt3, thereby activating the AMPK/MFF/Drp1 pathway.
    DOI:  https://doi.org/10.1038/s41419-026-08750-w
  10. Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2601242123
    PMF proteins mediate mitochondrial fusion in Arabidopsis.
    Ryan P Kenneally, Yu Tang, Wesley J Bobst, Rui Tong Khor, Lily Garibyan, Neha R Jag, Yangnan Gu.
      Mitochondrial dynamics-continuous fission and fusion-are hallmarks of these organelles and essential for mitochondrial function across eukaryotes. While fission is relatively well understood in plants, the mechanism of fusion remains incompletely defined. In animals and fungi, dynamin-related proteins are emerging fusion factors, but their plant homologs do not localize to mitochondria, suggesting plants rely on a distinct fusion mechanism. Here, we identify PMF1 (Promoter of Mitochondrial Fusion 1) and its paralog PMF2 as plant-specific outer mitochondrial membrane proteins that promote mitochondrial fusion. PMF abundance directly correlates with fusion capacity: overexpression markedly enlarges mitochondria and increases fusion rates, producing megamitochondria, whereas pmf1 pmf2 mutants show reduced mitochondrial volume and severe fusion defects under hypoxic stress. We further show that PMF1's cytoplasmic, intrinsically disordered N terminus undergoes liquid-liquid phase separation, a property necessary and sufficient to promote mitochondria fusion in vivo. These results reveal PMF-mediated protein condensation as a kingdom-specific mechanism regulating mitochondrial dynamics in plant cells.
    Keywords:  Promoter of Mitochondria Fusion 1/2; liquid–liquid phase separation; megamitochondria; mitochondrial fusion; outer mitochondrial membrane protein
    DOI:  https://doi.org/10.1073/pnas.2601242123
  11. Zhen Ci Yan Jiu. 2026 Apr 25. pii: 1000-0607(2026)04-0447-08. [Epub ahead of print]51(4): 447-454
    [Effect of moxibustion on the PINK1/Parkin pathway and mitophagy in rats with rheumatoid arthritis].
    Jie Wang, Wen-Xuan Hu, Tian-Cheng Wang, Qian-Nan Liu, Lei Liu, Zi-Jian Wu, Rong-Lin Cai, Chuan-Yu Peng.
       OBJECTIVES: To observe the effect of moxibustion at "Shenshu" (BL23) and "Zusanli" (ST36) on the PTEN-induced putative kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) pathway and mitophagy in rats with rheumatoid arthritis (RA), so as to explore its possible mechanism in improving RA.
    METHODS: Twenty-four SD rats were randomly divided into normal, model, moxibustion, and medication groups, with 6 rats in each group. The RA model was established by Freund's complete adjuvant solution injection combined with freezing and wind-cold dampness method. Suspended moxibustion was applied to BL23 and ST36 for 20 min, once daily for 15 consecutive days. Methotrexate (0.35 mg/kg) was administered via oral gavage twice a week for 15 consecutive days. The morphological changes of mitochondria in synovial tissue were observed by transmission electron microscopy. JC-1 staining was used to detect the level of mitochondrial membrane potential in synovial tissue. The ROS level in serum of rats was detected by fluorescence probe method. The content of ATP in synovial tissue was detected by luciferase assay. The co-localization of mitochondrial outer membrane translocation enzyme 20 (TOMM20) and microtubule-associated protein light chain 3 (LC3) B in synovial tissue was observed by immunofluorescence. The expression levels of Beclin1, selective autophagy adaptor protein (p62), PINK1 and Parkin and the ratio of LC3 Ⅱ/LC3 Ⅰ in synovial tissue were detected by Western blot.
    RESULTS: Compared with the normal group, the model group showed swollen mitochondria, disordered structure, disrupted cristae, and increased autophagosomes in synovial tissue;the mitochondrial membrane potential level and ATP content, and the protein expression level of p62 were decreased (P<0.01), while the serum ROS level, the co-localization expression of TOMM20 and LC3B in synovial tissue, and the protein expression levels of Beclin1, PINK1, and Parkin and the ratio of LC3 Ⅱ/LC3 Ⅰ were increased (P<0.01). In contrast to the model group, the increased and decreased indexes mentioned above were reversed (P<0.05, P<0.01) in both moxibustion and medication groups;and the mitochondrial membrane potential was obviously higher (P<0.05) in the medication group than that in the moxibustion group.
    CONCLUSIONS: Moxibustion at BL23 and ST36 can ameliorate mitochondrial structural damage and reduce the level of mitochondrial autophagy in RA model rats, which may be related to its function in inhibiting the abnormal activation of PINK1/Parkin pathway.
    Keywords:  Autophagy; Mitochondria; Moxibustion; PINK1/Parkin signaling pathway; Rheumatoid arthritis
    DOI:  https://doi.org/10.13702/j.1000-0607.20250632
  12. Cell Death Dis. 2026 Apr 23.
    Targeting PTDSS1 to modulate GSH synthesis triggers mitophagy and induces ferroptosis in esophageal squamous cell carcinoma cells.
    Xiao Zhang, Shurui Cao, Chenchen Zhou, Wen Jiang, Hongshun Wang, Bingqing Hui, Xiaheng Deng, Yanhong Gu.
      PTDSS1 is an emerging oncogenic protein associated with poor survival rates across various cancer types, including esophageal squamous cell carcinoma (ESCC). However, its regulatory mechanisms and therapeutic potential in ESCC remain incompletely understood. Through single-cell RNA sequencing (scRNA-seq) analysis, we identified a PTDSS1-high malignant epithelial subpopulation characterized by resistance to ferroptosis and mitophagy. Our investigations demonstrated that PTDSS1 regulates glutathione (GSH) synthesis and coordinates mitophagy in ESCC cells. Mechanistically, PTDSS1 knockdown promotes interaction between TRIM21 and SLC3A2, leading to diminished SLC3A2 protein expression and subsequent reduction in GSH synthesis. This elevates cellular oxidative stress, thereby triggering PINK1/Parkin mitophagy pathway and ultimately inducing apoptosis and ferroptosis. Furthermore, at the mitochondrial level, the knockdown of PTDSS1 decreases phosphatidylserine (PS) and facilitates mitochondrial fusion protein 2 (MFN2) translocation, providing substrates for mitophagy. Collectively, our findings elucidate a novel mechanism by which PTDSS1 protects ESCC cells from death and offer new perspectives for therapeutic strategies that target PTDSS1 to induce mitophagy and ferroptosis in ESCC.
    DOI:  https://doi.org/10.1038/s41419-026-08702-4
  13. Metab Brain Dis. 2026 Apr 23. pii: 88. [Epub ahead of print]41(1):
    The multifaceted role of mitochondrial dysfunction in Alzheimer's disease pathogenesis.
    Rasoul Ebrahimi, Ida Mohammadi, Kiana Ghafourian, Shahryar Rajai Firouzabadi, Mobina Saleh, Samin Davoody, Ghazal Azad, Khadijeh Esmaeilpour.
      
    Keywords:  Alzheimer’s disease; Bioenergetics; Mitochondria; Mitochondrial biogenesis; Mitophagy; Oxidative stress; Therapeutic approaches
    DOI:  https://doi.org/10.1007/s11011-026-01850-8
  14. Autophagy. 2026 Apr 23. 1-15
    Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
    Madhuri Chaurasia, Milana Fraiberg, Nemanja Subic, Oren Shatz, Kamilya Kokabi, Olee Gogoi, Olena Trofimyuk, Bat Chen Tamim-Yecheskel, Saskia Freud, Alik Demishtein, Ekaterina Kopitman, Inna Goliand, Sabita Chourasia, Yoav Peleg, Elena Ainbinder, Nili Dezorella, Zvulun Elazar.
      HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the TECPR2 gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.Abbreviations: Baf. A1: bafilomycin A1; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.
    Keywords:  HSAN9; TECPR2; integrated stress response; mitophagy; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.1080/15548627.2026.2660850
  15. Sci Adv. 2026 Apr 24. 12(17): eaed6824
    Enterovirus-induced cleavage of Mitofusin 2 generates mitophagosomes for enveloped virion release.
    Alagie Jassey, Bimal Paudel, Michael A Wagner, Noah Pollack, I-Ting Cheng, Raquel Godoy-Ruiz, David J Weber, William T Jackson.
      Enterovirus D68 (EV-D68) is a plus-strand RNA virus that primarily causes respiratory infections in infants but, in rare cases, has been associated with the pediatric paralytic disease acute flaccid myelitis. We previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that the 3C protease of EV-D68 cleaves the mitochondrial fusion protein Mitofusin 2 near its C-terminal HR2 domain, inducing fragmentation of the mitochondrial network. This, in turn, triggers the formation of mitophagosomes, a hallmark of mitophagy, a selective form of autophagy that recycles mitochondria. Multiple hallmarks of mitophagy are observed during infection, including loss of mitochondrial membrane potential and Parkin translocation to the mitochondria, but mitochondrial degradation is blocked during infection. While autophagy plays multiple roles in enterovirus infection, depleting Mitofusin 2 or transiently overexpressing Mitofusin 2, particularly the cleavage-resistant mutant, specifically reduces EV-D68 release from cells without affecting intracellular titers. Our results show that enteroviruses induce mitophagosomes as vectors for nonlytic release of virions from cells.
    DOI:  https://doi.org/10.1126/sciadv.aed6824
  16. Sci Immunol. 2026 Apr 24. 11(118): eaed2623
    Mitochondrial fission mediates an evolutionarily conserved antibacterial defense response.
    Ronan Kapetanovic, Syeda Farhana Afroz, James E B Curson, Ina Kirmes, Divya Ramnath, Stephan Nothjunge, Jinting Liu, Jordan D Atkinson, Arnaud Ahier, Karoline D Raven, Marta Bosch, Bernhard Keller, Grace M E P Lawrence, Kaustav Das Gupta, Melanie R Shakespear, Charles Ferguson, Claudia J Stocks, Nilesh J Bokil, Gabriele Matthias, Tam T K Nguyen, Zeinab G Khalil, Robert C Reid, Karl A Hansford, Philip M Hansbro, Matthew A Cooper, Mark A Schembri, Antje Blumenthal, Kate Schroder, David P Fairlie, Albert Pol, Patrick Matthias, Robert G Parton, Steven Zuryn, Matthew J Sweet.
      Animals engage pleiotropic immune defense mechanisms to survive infections. Here, we present a function for mitochondrial fission in host defense. Challenge of macrophages with Escherichia coli increased mitochondrial fission, with this response promoting bacterial clearance in mammalian macrophages and Caenorhabditis elegans. E. coli-induced mitochondrial fission engaged dual antibacterial responses via the mitochondrial unfolded protein response (UPRmt) and inducible lipid droplet production. Mitochondrial fission-triggered UPRmt, characterized by activation of activating transcription factor 5 (ATF5) in mouse macrophages and the paralog ATFS-1 in C. elegans, curtailed inducible lipid droplets to cross-regulate these pathways. The intramacrophage pathogen Salmonella enterica suppressed antibacterial mitochondrial fission, but restoring this response by inhibiting mitochondrial fusion-promoting histone deacetylase 6 (HDAC6) reactivated lipid droplet production and bacterial clearance. Therefore, we propose that mitochondrial fission is an ancient host defense pathway that can be exploited for anti-infective design.
    DOI:  https://doi.org/10.1126/sciimmunol.aed2623
  17. J Neuropathol Exp Neurol. 2026 Apr 20. pii: nlag038. [Epub ahead of print]
    Morroniside maintains mitochondrial homeostasis in microglia and mitigates neuroinflammation in experimental autoimmune encephalomyelitis.
    Shaopeng Zhai, Taotao Jiang, Xiaorong Cheng, Xin Li, Qi Wang, Qing Fu, Boyao Yuan, Fengjuan Wu, Manxia Wang.
      Microglia-mediated neuroinflammation in the central nervous system is a hallmark of both multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Current immunosuppressive therapies for MS have limited efficacy and notable side effects. This study aimed to investigate mechanisms underlying anti-neuroinflammatory effects of morroniside, an iridoid glycoside derived from Cornus officinalis, which is used in Chinese herbal medicine. Morroniside treatment significantly attenuated lipopolysaccharide-induced alterations and mitochondrial dysfunction in BV2 microglia cells. In vivo, morroniside treatment improved clinical scores and ameliorated pathological findings and neurological deficits in a mouse EAE model. Mechanistic investigations revealed that morroniside activated the Nrf2/HO-1 signaling axis, promoted Nrf2 nuclear translocation and elevated HO-1 expression. This activation also upregulated p62, thereby enhancing LC3-II/PINK1/Parkin-mediated mitophagosome formation. The resultant mitophagy suppressed p65 phosphorylation leading to anti-inflammatory effects. Collectively, our findings suggest that morroniside ameliorates EAE by increasing anti-inflammatory microglial activation through upregulating the Nrf2/HO-1/p62 axis to mitigate mitochondrial oxidative stress and enhance mitophagy. These results identify morroniside as a promising therapeutic candidate for MS and emphasize the importance of the Nrf2-p62-mitophagy axis in resolving neuroinflammation and maintaining mitochondrial homeostasis.
    Keywords:  Nrf2; experimental autoimmune encephalitis (EAE); microglia; mitochondrial homeostasis; mitophagy; morroniside
    DOI:  https://doi.org/10.1093/jnen/nlag038
  18. Food Chem Toxicol. 2026 Apr 17. pii: S0278-6915(26)00177-8. [Epub ahead of print]213 116103
    TDCIPP induces placental dysfunction and fetal growth restriction via oxidative stress-mediated PINK1/Parkin mitophagy.
    Ziming Lin, Mingqi Hu, Ruijie Li, Xiaorui Gong, Man Zhao, Haiyan Zhang, Jin Xuan, Wenlan Qiao, Anna Li.
      Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used organophosphate flame retardant increasingly linked to reproductive toxicity, yet its placental toxic mechanisms remain unclear. This study demonstrates that TDCIPP exposure disrupts placental homeostasis by inducing oxidative stress, which triggers excessive PINK1/Parkin-mediated mitophagy in both human trophoblasts (HTR-8/SVneo) and pregnant mice. Integrated network toxicology analysis predicted mitochondrial dysfunction and oxidative stress as central pathways, validated by upregulation of ATG5 and HMOX1, downregulation of SOD2, elevated ROS and mitochondrial superoxide, loss of mitochondrial membrane potential, and ultrastructural evidence of mitophagic vacuoles. TDCIPP activated the PINK1/Parkin pathway-evidenced by increased PINK1, Parkin, LC3-II/I, p62, reduced TOMM20, and enhanced Parkin-TOMM20 colocalization-while alternative mitophagy receptors FUNDC1 and BNIP3 remained unaffected. Mechanistically, oxidative stress acted upstream, as N-acetylcysteine (NAC) pretreatment suppressed ROS accumulation and PINK1/Parkin activation. Functionally, TDCIPP impaired trophoblast proliferation, induced apoptosis, and caused fetal growth restriction (FGR) in vivo. Notably, both genetic knockdown of Parkin in vitro and pharmacological inhibition of mitophagy with Mdivi-1 in vivo significantly alleviated trophoblast apoptosis and rescued placental and fetal weights. These findings establish that TDCIPP-induced placental injury is driven by an oxidative stress-PINK1/Parkin-mitophagy axis, revealing dysregulated mitophagy as a pivotal mechanism underlying TDCIPP-associated developmental toxicity and offering new insights into the reproductive risks of environmental flame retardant exposure.
    DOI:  https://doi.org/10.1016/j.fct.2026.116103
  19. Zhongguo Zhong Yao Za Zhi. 2026 Mar;51(6): 1747-1756
    [Regulatory effects of serum containing Hedysari Radix Praeparata Cum Melle-vinegar processed Curcumae Rhizoma on mitochondrial function and mitophagy in HT-29 cells].
    Rui-Long Lyu, Fen-Yu Dou, Meng-Na Chai, Ting Liu, Er-Dan Xin, Ding-Cai Ma, Mao-Mao Wang, Zhe Wang, Yu-Gui Zhang, Yue-Feng Li.
      This study aimed to investigate the effects of the serum containing Hedysari Radix Praeparata Cum Melle-vinegar processed Curcumae Rhizoma(HRCR) on mitochondrial damage and mitophagy in human colon cancer HT-29 cells. The serum containing HRCR was prepared, and a blank group, a 5-fluorouracil(5-FU) group, and serum containing HRCR groups(low, medium, and high doses) were established. The optimal intervention concentration and time of HRCR and 5-FU on HT-29 cells were screened by the cell counting kit-8(CCK-8) method. Changes in the mitochondrial morphology and ultrastructure were observed by transmission electron microscopy and laser confocal microscopy. Mitochondrial membrane potential was detected by the JC-10 fluorescent probe. Intracellular reactive oxygen species(ROS) level was determined by the 2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA) method. Adenosine triphosphate(ATP) content was detected by the ATP kit. Apoptosis rate was detected by Annexin V-FITC/PI double staining flow cytometry. Mitophagy was observed by laser confocal microscopy, and the expression levels of mitochondrial autophagy-related proteins were detected by Western blot. The results showed that after 24, 48, and 72 h of intervention with serum containing HRCR, HT-29 cell proliferation was significantly inhibited in groups at all concentrations. The cell proliferation inhibition of the 5-FU group showed concentration and time dependence. After intervention by 10% HRCR-containing serum for 72 h, the mitochondrial morphology and structure of HT-29 cells were significantly damaged and deformed, with decreased mitochondrial membrane potential, increased intracellular ROS level, decreased ATP content, and increased total apoptosis rate. Under laser confocal microscopy, it was observed that there was almost no co-localization of mitochondria and lysosomes after HRCR intervention. Additionally, HRCR could inhibit the expression of Parkin protein(Parkin), PTEN-induced putative kinase 1(PINK1), and microtubule-associated protein 1A/1B-light chain 3(LC3) in cells, thus inhibiting mitophagy. Through combined treatment of the mitophagy inhibitor Mdivi-1 and HRCR, the inhibitory effect of HRCR on cell proliferation could be further enhanced to promote HRCR-induced apoptosis. In conclusion, the serum containing HRCR can induce apoptosis through the inhibition of HT-29 cell proliferation and mitophagy, which are achieved by damaging mitochondrial morphology, reducing mitochondrial membrane potential, increasing ROS level, decreasing ATP content, and inhibiting the Parkin, PINK1, and LC3 signaling pathways, thereby exerting anti-colon cancer effects.
    Keywords:  Hedysari Radix Praeparata Cum Melle-vinegar processed Curcumae Rhizoma; colon cancer; drug-containing serum; mitochondria; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20251029.402
  20. Diabetes Obes Metab. 2026 Apr 20.
    Mechanism of Terpinen-4-ol in Suppressing β-Cell Dedifferentiation: Restoring Mitophagy and Alleviating Mitochondrial Calcium Overload via Parkin-Mediated MCU Degradation.
    Yanyan Zhang, Hongyu Chen, Li He, Dezuo Bai, Jun Bi, Yuting Wang, Xiaoxia Hu, Qianqian Guo, Xiangchun Shen.
       BACKGROUND AND OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterised by insulin resistance and β-cell impairment. Dedifferentiation of pancreatic β-cells contributes to the progression of T2DM, influencing insulin secretion through mechanisms such as mitochondrial dysfunction, Ca2+ overload and impaired autophagy. This study investigated the effects of terpinen-4-ol (T4O) on β-cell dedifferentiation and mitochondrial autophagy, with an emphasis on the role of the Parkin/MCU signalling pathway.
    METHODS: A T2DM mouse model was generated using a high-fat diet (HFD, 60% fat) and STZ (50 mg/kg) injection, and β-cell dedifferentiation was induced by high glucose (HG) treatment in MIN6 cells. T4O was administered, and its effects on mitochondrial autophagy and β-cell dedifferentiation were evaluated. The mitochondrial autophagy agonist NMN and the MCU inhibitor RU360 were used to assess the interplay between mitophagy and Ca2+ signalling. Parkin was overexpressed in vitro and in vivo to determine its contribution to mitochondrial autophagy and Ca2+ regulation. The investigation of the mechanism of the Parkin/MCU signalling pathway involved co-immunoprecipitation (Co-IP), mass spectrometry (MS) and protein synthesis inhibition assays.
    RESULTS: T4O improved blood glucose levels and insulin resistance in diabetic mice. In vitro and in vivo, T4O reduced the expression of dedifferentiation markers (such as OCT4, MafA and Pdx1 and Ngn3), increased the expression of mitochondrial autophagy-related proteins (PINK1, Parkin, Beclin and LC3-II/I) and modulated the expression of MCU and Drp1 (downregulated) as well as MFN2 (upregulated). T4O also alleviated HG-induced mitochondrial damage, including ultrastructural abnormalities, decreased membrane potential, elevated reactive oxygen species and Ca2+ overload. In addition, preincubation of MIN6 cells with T4O or the mitochondrial autophagy agonist NMN can reduce HG-induced mitochondrial Ca2+ overload, promote mitochondrial autophagy, reduce MCU protein levels and inhibit pancreatic β-cell dedifferentiation. Similar results were observed when Parkin was overexpressed both in vivo and in vitro. Moreover, the opposite results were obtained in Parkin-knockdown MIN6 cells. Mechanistically, T4O facilitated Parkin-mediated MCU ubiquitination degradation by interacting with MCU at lysine residue K320; notably, mutation of K320 to arginine (K320R) abolished T4O-induced MCU ubiquitination and reversed the protective effects against β-cell dedifferentiation. These findings indicate that T4O increases Parkin expression, increases MCU ubiquitination and reduces mitochondrial Ca2+ accumulation, thereby protecting against T2DM-induced β-cell dedifferentiation.
    CONCLUSION: T4O enhances Parkin expression and targets the K320 site of MCU to promote Parkin-mediated, ubiquitination-mediated degradation of MCU, thereby alleviating mitochondrial calcium overload and mitophagy and consequently inhibiting the transdifferentiation of pancreatic islet β-cells in diabetes. These data support T4O as a potential therapeutic candidate for T2DM by targeting mitochondrial Ca2+ signalling and autophagy.
    Keywords:  MCU; diabetic pancreatic β‐cell dedifferentiation; mitochondrial Ca2+ overload; mitophagy; parkin; terpinen‐4‐ol
    DOI:  https://doi.org/10.1111/dom.70774
  21. Redox Biol. 2026 Apr 16. pii: S2213-2317(26)00174-6. [Epub ahead of print]93 104176
    Peroxiredoxin Ⅲ safeguards cardiac function against doxorubicin by regulating mitochondrial quality control via H2O2 detoxification.
    Ji Won Park, Se Yeon Jang, Mi Yeon Kim, Ho Jin Yi, Seong Keun Sonn, Okhee Kweon, Byung-Hoon Lee, Goo Taeg Oh, Hyun Ae Woo, Tong-Shin Chang.
      Doxorubicin (DOX) is a widely used anticancer drug associated with severe cardiotoxicity primarily driven by mitochondrial dysfunction and reactive oxygen species (ROS) production. Hydrogen peroxide (H2O2), a major mitochondrial ROS, significantly contributes to cardiotoxicity, yet its precise mechanistic role in DOX-induced cardiotoxicity remains incompletely understood. Here, we investigated the critical role of mitochondrial H2O2 in DOX-induced cardiotoxicity using rat cardiomyocyte H9c2 cells with stable knockdown or reconstitution of mitochondrial antioxidant enzyme peroxiredoxin Ⅲ (PrxⅢ), which specifically regulates mitochondrial H2O2 levels. Our results demonstrated that severe mitochondrial H2O2 accumulation (>10-fold compared to control) in PrxⅢ-depleted cells exacerbated mitochondrial oxidative stress, evidenced by increased cardiolipin oxidation and mitochondrial membrane potential dissipation. Furthermore, excessive mitochondrial H2O2 impaired mitochondrial fusion by reducing fusion-related protein expression, disrupted autophagic flux via lysosomal dysfunction, and significantly attenuated mitophagy, ultimately leading to enhanced apoptosis. Conversely, moderate mitochondrial H2O2 levels (5- to 8-fold increase compared to control) observed in PrxⅢ-expressing cells promoted mitochondrial elongation, enhanced mitophagy, and preserved autophagic flux, suggesting a protective adaptation against DOX-induced oxidative stress. In vivo experiments using PrxⅢ knockout mice confirmed that loss of PrxⅢ aggravated DOX-induced cardiac dysfunction. Bioinformatic analysis of independent public transcriptome datasets and targeted qPCR validation in PrxⅢ-deficient cardiac tissues further confirmed that the mitochondrial quality control pathways identified in vitro are robustly dysregulated in vivo. Additionally, PrxⅢ deficiency markedly increased mitochondrial structural damage without significantly affecting cardiac fibrosis or hypertrophy. Notably, mitigating the mitochondrial H2O2 burden and protecting the mitochondrial inner membrane using the mitochondria-targeted antioxidant peptide SS-31 successfully rescued this exacerbated cardiac dysfunction. In conclusion, our findings establish mitochondrial H2O2 as a pivotal determinant in DOX-induced mitochondrial dysfunction and cardiotoxicity, highlighting PrxⅢ as a promising therapeutic target for mitigating oxidative cardiac injury.
    Keywords:  Cardiotoxicity; Doxorubicin; Mitochondrial quality control; Oxidative stress; Peroxiredoxin Ⅲ
    DOI:  https://doi.org/10.1016/j.redox.2026.104176
  22. Free Radic Biol Med. 2026 Apr 23. pii: S0891-5849(26)00304-7. [Epub ahead of print]
    Corrigendum to "Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-dependent mitophagy" [Free Radic. Biol. Med. (2025) 150-160].
    Lin Zhu, Mei Huang, Lu He, Zhihui Rong.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.020
  23. J Neuropathol Exp Neurol. 2026 Apr 23. pii: nlag027. [Epub ahead of print]
    The N6-methyladenosine (m6A) reader YTHDF3 increases PINK1/Parkin-mediated mitophagy by facilitating prohibitin 2 (PHB2) translation to promote retinal ganglion cell damage in diabetic retinopathy.
    Zeyi Lv, Peilin Lv, Long Pang, Yanmin Song, Deren Kong, Fulan Gui.
      Retinal ganglion cells (RGCs) are particularly vulnerable to damage during the early stages of diabetic retinopathy (DR). Emerging evidence indicates that dysregulated expression of N6-methyladenosine (m6A) methylation regulators contributes to DR pathogenesis. In particular, the m6A reader protein YTHDF3 has been found to be highly expressed in human proliferative DR membranes although its functional role in DR progression remains unclear. In this study, diabetic rat models were established via streptozotocin injection. Subsequently, YTHDF3 expression was knocked down in the retina by intravitreal delivery of AAV-sh-YTHDF3. Additionally, high glucose (HG) conditions were used to induce injury in RGCs in vitro. Our results demonstrated that downregulation of YTHDF3 significantly mitigated HG-induced RGC damage both in vivo and in vitro. YTHDF3 silencing reduced HG-triggered RGC apoptosis by suppressing mitochondrial dysfunction and PINK1-Parkin-mediated excessive mitophagy. Moreover, YTHDF3 functioning as an m6A reader enhanced the translation of PHB2 in an m6A-dependent manner. Notably, PHB2 overexpression effectively counteracted the protective effects of YTHDF3 knockdown, reinstating HG-induced mitochondrial damage and mitophagy. In conclusion, our findings indicate that YTHDF3 exacerbates RGC injury under high glucose conditions by promoting m6A-dependent PHB2 translation, which in turn aggravates mitochondrial damage and PINK1-Parkin-driven mitophagy, thereby contributing to DR progression.
    Keywords:  PHB2; YTHDF3; diabetic retinopathy; m6A; mitophagy; retinal ganglion cells
    DOI:  https://doi.org/10.1093/jnen/nlag027
  24. Redox Biol. 2026 Apr 19. pii: S2213-2317(26)00176-X. [Epub ahead of print]93 104178
    m6A epitranscriptomic remodeling links redox stress to mitochondrial quality control and programmed cell death in sepsis-induced myocardial dysfunction.
    Meilian Chen, Binlan Fu, Qiaomin Wu.
      Sepsis-induced myocardial dysfunction (SIMD) is a major contributor to sepsis-related mortality and is characterized by excessive oxidative stress, mitochondrial dysfunction, and heterogeneous forms of programmed cell death. However, how cardiomyocytes interpret redox stress and commit to distinct death pathways remains incompletely understood. Increasing evidence suggests that N6-methyladenosine (m6A), the most abundant internal RNA modification, functions as a dynamic post-transcriptional regulator linking redox signaling to mitochondrial homeostasis and cell fate decisions. This review summarizes recent advances indicating that m6A-dependent regulatory networks integrate mitochondrial reactive oxygen species (mtROS), mitochondrial quality control (MQC), and downstream cell death pathways in SIMD. Under septic conditions, sustained inflammation and oxidative stress perturb the balance of m6A writers, erasers, and readers, leading to maladaptive remodeling of mitochondrial dynamics, mitophagy, and biogenesis. Such epitranscriptomic dysregulation is associated with mtROS accumulation, impaired mitochondrial renewal, and a shift from adaptive redox compensation toward irreversible cardiomyocyte injury. Importantly, emerging evidence suggests that m6A remodeling does not uniformly activate cell death but modulates redox signal processing in a context-dependent manner. Preferential amplification of inflammatory sensing and inflammasome signaling may bias mtROS toward pyroptotic execution, whereas compromised antioxidant capacity, iron handling, and lipid metabolism may increase vulnerability to ferroptosis. On this basis, we propose the m6A-ROS-MQC axis as a unifying, hypothesis-driven framework for understanding SIMD pathogenesis, in which m6A acts as a redox-responsive epitranscriptomic regulator coordinating mitochondrial adaptation and programmed cell death decisions.
    Keywords:  Ferroptosis; Mitochondria; Oxidative stress; Pyroptosis; Sepsis; m6A
    DOI:  https://doi.org/10.1016/j.redox.2026.104178
  25. Cell Oncol (Dordr). 2026 Apr 20. pii: 78. [Epub ahead of print]49(3):
    CIDEC impairs mitochondrial fitness and blocks protective autophagy via the inhibition of cGMP/PKG pathway to exert tumor-suppressive effects in breast cancer.
    Xuchu Jin, Yu Liu, Xinyu Zheng, Yangke He.
      
    Keywords:  Breast cancer; CIDEC; Mitophagy; cGMP/PKG pathway
    DOI:  https://doi.org/10.1007/s13402-026-01211-8
  26. Metab Brain Dis. 2026 Apr 24. pii: 90. [Epub ahead of print]41(1):
    Mitochondrial dysfunction in sleep deprivation.
    Meng Zhao, Adeel Ahmed Abbasi, Peijun Li, Peiyuan Lu.
      
    Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Neurodegeneration; Oxidative stress; Parkinson’s disease; Sleep deprivation
    DOI:  https://doi.org/10.1007/s11011-026-01853-5
  27. Toxicol Appl Pharmacol. 2026 Apr 22. pii: S0041-008X(26)00130-4. [Epub ahead of print] 117834
    Doxorubicin-induced apoptosis and mitochondrial fission are promoted by LncRNA TGFB2-AS1 through BMP7/Smad signaling.
    Hailan Gao, Kai Lan, Hui Gong.
      Doxorubicin-induced cardiotoxicity (DIC) features cardiomyocyte loss and maladaptive remodeling. Mitochondrial damage, oxidative stress, autophagy, and different types of cell death, including ferroptosis, pyroptosis, and apoptosis, are recognized as the principal biological mechanisms contributing to DIC, in which disrupted mitochondrial dynamics play a pivotal role. The role of long noncoding RNAs (lncRNAs) in DIC is becoming more well understood; however, the function of TGFB2-AS1 remains unclear. Here, DIC was established in doxorubicin-treated male C57BL/6 mice and in doxorubicin-treated AC16/HL-1 cardiomyocytes. TGFB2-AS1 expression and subcellular localization were determined, and gain- and loss-of-function analyses were performed. Flow cytometry was used to quantify apoptosis and intracellular reactive oxygen species (ROS), and apoptosis-associated proteins and mitochondrial dynamics regulators were assessed by immunoblotting. Mitochondrial morphology was visualized using MitoTracker staining. Bone morphogenic protein 7 (BMP7) signaling was evaluated via recombinant BMP7 supplementation and BMP7 knockdown. Cardiac structure and injury were evaluated by echocardiography and histology. TGFB2-AS1 expression was markedly upregulated in DIC models, and TGFB2-AS1 overexpression exacerbated doxorubicin-induced hypertrophy, apoptosis, ROS accumulation, and mitochondrial fragmentation, whereas TGFB2-AS1 silencing partially reversed these effects. Mechanistically, TGFB2-AS1 knockdown restored BMP7/Smad1/5/9- inhibitor of DNA binding protein 2 (Id2) signaling, and BMP7 depletion attenuated the cardioprotective effects of TGFB2-AS1 silencing. Consistently, BMP7 supplementation mitigated cardiomyocyte apoptosis and Drp1-associated mitochondrial fission in vitro and improved doxorubicin-induced remodeling in vivo through the activation of BMP7/Smad signaling. Collectively, TGFB2-AS1 promotes DIC by suppressing BMP7/Smad/Id2 signaling and enhancing mitochondrial fission, positioning TGFB2-AS1 as a candidate intervention point.
    Keywords:  Apoptosis; BMP7; Doxorubicin; Mitochondrial fission; TGFB2-AS1
    DOI:  https://doi.org/10.1016/j.taap.2026.117834
  28. Clin Exp Pharmacol Physiol. 2026 May;53(5): e70125
    Ciliatoside A Improves Klebsiella pneumoniae-Induced Pneumonia by Modulating Mitochondrial Autophagy via the SIRT1/PINK1/Parkin Pathway.
    Jingxuan Zhu, Lingling Zhou, Xiaoqin Li.
       BACKGROUND: Klebsiella pneumoniae (KP)-induced pneumonia has a high incidence rate, and current treatment options remain limited. The efficacy and mechanism of the novel natural compound Ciliatoside A (CA) against KP-induced pneumonia remain unclear.
    AIMS: Investigating whether CA improves KP-induced pneumonia through the sirtuin 1 (SIRT1)/PTEN-induced putative kinase 1 (PINK1)/Parkin axis.
    METHODS: KP was used to infect A549 cells, and resistance genes expression was detected using qRT-PCR. To evaluate CA's effect on cell viability, the Cell Counting Kit-8 assay was utilised. Different kits were employed to measure mitochondrial membrane potential, mitochondrial reactive oxygen species (mtROS), and ATP production. Transmission electron microscopy was used to observe autophagosome formation, and cellular autophagy was assessed via Western blot and LC3 fluorescence analysis. Flow cytometry, PI/Hoechst staining, and ELISA were employed to investigate the impacts of CA on A549 cell death and cytokine secretion. A KP mouse pneumonia model was established. Pathological staining was used to observe lung tissue damage and inflammatory infiltration, and Western blot was employed to validate protein expression in vivo. To verify whether CA alleviates KP-induced pneumonia through the SIRT1/PINK1/Parkin axis, intervention with SIRT1 agonists/inhibitors was conducted.
    RESULTS: CA treatment downregulated drug resistance genes in KP and A549 cells, enhanced the viability of A549 cells following KP infection, and inhibited apoptosis. CA reduced mtROS accumulation, increased mitochondrial membrane potential and ATP production, promoted mitochondrial autophagy, and inhibited NLRP3-mediated inflammasome-mediated cell death. Additionally, CA alleviated pulmonary edema and pathological damage in mice following KP infection, while inhibiting apoptosis and pulmonary inflammation. Following KP infection, the SIRT1/PINK1/Parkin axis was blocked in A549 cells and mouse lung tissue; CA treatment activated this pathway. SIRT1 agonists enhanced the protective impact of CA against KP infection in A549 cells and mouse lung tissue, while SIRT1 inhibitors reduced the protective effect of CA.
    CONCLUSION: CA improves KP-induced pneumonia through activating the SIRT1/PINK1/Parkin axis to regulate mitochondrial autophagy.
    Keywords:   Klebsiella pneumoniae ; Ciliatoside A; SIRT1/PINK1/parkin pathway; mitophagy; pneumonia
    DOI:  https://doi.org/10.1111/1440-1681.70125
  29. Nat Microbiol. 2026 Apr 20.
    MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae.
    Ming-Hua Wu, Ya-Nan Lv, Hui Li, Hui Qian, Yun-Yun Wei, Yun-Ran Zhang, Shuang Liang, Xue-Ming Zhu, Jian-Ping Lu, Maurizio Del Poeta, Zong-Hua Wang, Yong-Hwan Lee, Naweed I Naqvi, Richard A Wilson, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.
      Mitophagy is a selective autophagic process that maintains cellular homeostasis by degrading damaged mitochondria and is a promising antifungal target. However, few inner mitochondrial membrane (IMM) regulators of mitophagy are known. Here we identify cytochrome c oxidase subunit 6 (MoCox6) as an IMM regulator in Magnaporthe oryzae that binds MoAtg5 and MoAtg14 following outer mitochondrial membrane rupture to mediate mitophagy. MoSirt5 regulates this process by desuccinylating MoCox6 at K144. Structural analysis revealed that residue D95 at the MoSirt5-MoCox6 interface mediates the dual role of MoCox6 in mitophagy and mitochondrial metabolic competence. Deletion of the COX6 gene significantly reduced vegetative growth and virulence in both M. oryzae and Alternaria alternata. Through high-throughput screening, we identified a small-molecule compound, Pan-RAS-IN-1, which targets MoCox6 to inhibit mitophagy, thereby suppressing M. oryzae virulence. Pan-RAS-IN-1 exhibits broad-spectrum antifungal activity, and its application to rice plants significantly suppressed rice blast incidence.
    DOI:  https://doi.org/10.1038/s41564-026-02329-z
  30. ACS Chem Neurosci. 2026 Apr 24.
    Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.
    Samir Ranjan Panda, Ujjawal Soni, Pallabi Panja, Bishal Rajdev, Meenakshi Singh, Snehashis Kundu, Anagha Ranade, Sharad D Pawar, Rabinarayan Acharya, V G M Naidu.
      Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, which refers to forgetting facts and experiences. Apart from being a classical neuropathological hallmark, AD is connected with pronounced mitochondrial fragmentation, although the exact contribution of mitochondrial dynamics in AD progression is poorly defined. Therefore, this study is aimed at investigating the role of loganic acid (LGA) in mitochondrial dynamics, hippocampal plasticity, and cognitive deficits in the scopolamine (SC)-induced cognitive impairment model. The results showed significant decline of p-Drp1 protein and elevation of Mfn2 proteins in LGA-treated SC-induced mice, indicating reduced mitochondrial fragmentation and restoration of mitochondrial dynamics. In addition, LGA treatment promotes the reduction of fragmented and spherical-shaped mitochondria in SC-induced mice. LGA treatment alleviated reactive oxygen species (ROS) production and elevated mitochondrial membrane potential, reducing neurodegeneration in SC mice. Moreover, the decline of inflammatory cytokines (TNF-α and IL-1β) and downregulation of NF-kB expression in LGA-treated SC-induced mice suggested improved neuronal health. In parallel, LGA also increased the regulation of the cytoskeleton within neuronal dendrites, synaptic plasticity, and neuronal dendrites outgrowth, which was validated with increased expression of MAP2. In conclusion, the present study findings suggest that LGA exerts neuroprotection via preserving the mitochondrial ultrastructure and modulating the mitochondrial dynamics. All of these changes further restore neuronal cell density and myelination, leading to the mitigation of neurodegeneration, and restore cognitive deficits and spatial memory in SC-induced C57BL/6 mice.
    Keywords:  Alzheimer’s disease; computational studies; hippocampal plasticity; loganic acid; mitochondrial dynamics; oxidative stress and neuroinflammation
    DOI:  https://doi.org/10.1021/acschemneuro.6c00012
  31. Inflammation. 2026 Apr 24.
    MAPK15 Attenuates Intestinal Epithelial Cell Senescence-Like Phenotype to Regulate Gut Homeostasis and Inflammation by Phosphorylating Suz12 to Suppress Drp1-Mediated Mitochondrial Fission Damage.
    Juan Li, Gang Chen, Xinyi Bao.
      
    Keywords:  Cellular senescence; MAPK15; Mitochondrial fission; Suz12/Drp1 axis; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s10753-026-02514-6
  32. Metabolism. 2026 Apr 17. pii: S0026-0495(26)00133-2. [Epub ahead of print]180 156623
    SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.
    Junchao Lin, Tong Wu, Chen Wang, Wei Zhou, Yutong Liu, Gang Yang, He Zhou, Jingyan Luo, Zhenzhen Fan, Yu Da, Jie He, Bing Xu, Mingzhuo Jiang, Daiming Fan, Kaichun Wu, Jie Liang.
       BACKGROUND: The progression of metabolic dysfunction-associated steatohepatitis (MASH) involves chronic, irreversible inflammatory responses linked to intracellular organelle dysfunction. While endoplasmic reticulum (ER) stress and mitochondrial impairment are recognized as critical drivers, the precise molecular mechanisms governing inter-organelle communication in this disease context remain incompletely understood.
    AIM: This study aimed to investigate the role of the ER transmembrane protein SEC62 in MASH pathogenesis. Specifically, it sought to determine whether SEC62 expression is altered in MASH, define its functional impact on disease phenotypes, and elucidate the mechanistic pathway through which it regulates mitochondrial homeostasis and inflammation.
    RESULTS: SEC62 was upregulated in both human and mouse MASH livers. Hepatocyte-specific SEC62 overexpression worsened hepatic steatosis, inflammation, and mitochondrial damage, whereas SEC62 knockout ameliorated these features. Mechanistically, SEC62 interacted directly with ATAD3B at the mitochondria-associated membranes (MAMs) interface, leading to the significant downregulation of ATAD3B expression. This SEC62-ATAD3B axis resulted in defective mitophagy, increased mitochondrial reactive oxygen species (ROS) production, and amplified inflammatory responses.
    CONCLUSION: Our results demonstrate that SEC62 is a novel regulator of MAMs that drives MASH progression. By interacting with and suppressing ATAD3B, SEC62 disrupts mitochondrial quality control, leading to oxidative stress and inflammation. Together, these findings define a specific molecular mechanism of organelle interplay in MASH and position SEC62 as a potential therapeutic target for intervention.
    Keywords:  ATAD3B; Endoplasmic reticulum; FOXO3a; Metabolic-associated steatohepatitis; Mitochondria; SEC62
    DOI:  https://doi.org/10.1016/j.metabol.2026.156623
  33. Int Immunopharmacol. 2026 Apr 22. pii: S1567-5769(26)00550-3. [Epub ahead of print]180 116704
    Iron supplementation prevents abdominal aortic aneurysm by increasing Tregs via maintained mitochondrial homeostasis.
    Huagang Liu, Yuanyang Chen, Yunzhao Yang, Zhen Wang, Xiaoping Hu, Qi Wu.
      Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease with few effective treatments. Iron, an essential trace element, influences cellular functional states through multiple pathways and has been implicated in the pathogenesis and development of AAA. Previous studies have associated iron deficiency (ID) with the phenotypic switching of vascular smooth muscle cells by affecting mitochondrial and endoplasmic reticulum function. In this study, we demonstrate the protective role of appropriate iron supplementation in the progression of AAA. Our data further showed that iron supplementation increases the abundance of regulatory T cells (Tregs) both in the peripheral immune system and in aortic tissues, contributing to its protective effect. Moreover, iron supplementation inhibits the expression of mitochondrial uncoupling protein 2 (UCP2) in Tregs, which in turn suppresses the phosphorylation of dynamin-related protein 1 (Drp1), thereby modulating the dynamic balance between mitochondrial fusion and fission. Our findings suggest that iron supplementation may serve as a potential intervention to delay and ameliorate the progression of AAA.
    Keywords:  Abdominal aortic aneurysm; Drp1; Iron deficiency; Mitochondrial homeostasis; Treg; UCP2
    DOI:  https://doi.org/10.1016/j.intimp.2026.116704
  34. Biofactors. 2026 Mar-Apr;52(2):52(2): e70098
    Phytoestrogenic Isoflavone Formononetin Attenuates Motor Deficits and Mitochondrial Impairment by Regulating SIRT1/PGC-1α/NRF1/TFAM Axis in Parkinson's Disease.
    Jasleen Kaur, Saba Naqvi.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder. An essential early hallmark of PD is disrupted mitochondrial dynamics driven by impaired cellular energy homeostasis. Therapeutic interventions restoring mitochondrial function and biogenesis hold promise for neuroprotection in PD. In the present study, the neuroprotective effects of formononetin (FMN) were evaluated in both MPP+-induced SH-SY5Y cells and the MPTP-induced mouse model of Parkinson's disease, using concentrations of 5, 10, 20, and 40 μM in vitro and doses of 25 and 40 mg/kg in vivo. To evaluate its biological activity, we employed western blotting and immunofluorescence assay to quantify the expression of disease-relevant markers. Mitochondrial health was further assessed using Mitotracker, alongside reactive oxygen species (ROS) assessment. Motor behavior and molecular endpoint parameters were also measured. Our results demonstrated that FMN significantly attenuates MPP+/MPTP-induced neurotoxicity, improves motor function, and restores the expression of PGC-1α, tyrosine hydroxylase, and key mitochondrial proteins involved in mitochondrial DNA replication. Enhancement of mitochondrial fusion proteins and other transcriptional regulators was also observed in the administered groups. Flow cytometry and imaging analyses confirmed that FMN-mediated PGC-1α activation preserves mitochondrial integrity and reduces oxidative stress. Altogether, these findings provide evidence that formononetin exerts neuroprotective effects in PD by modulating the PGC-1α signaling axis.
    Keywords:  Parkinson's disease; mitochondrial biogenesis; mitochondrial dynamics; motor impairment; oxidative stress
    DOI:  https://doi.org/10.1002/biof.70098
  35. Phytother Res. 2026 Apr 22.
    Paeoniflorin Ameliorates Liver Fibrosis by Inhibiting HIF-1α-Mediated Mitophagy in Hepatic Stellate Cells.
    Chunyu He, Yang Liu, Mengchen Qin, Wenyan Jia, Weicong Chen, Weiguang Chen, Binglian Zhong, Xuemei Yang, Huishan Lin, Yuyang Zhou, Bin Wen, Haitao Sun, Songqi He.
      Paeoniflorin (PF) has exhibited significant anti-hepatic fibrosis potential, yet its precise pharmacological mechanisms and molecular targets remain to be fully elucidated. This study aims to investigate the role of PF in modulating HIF-1α-mediated mitophagy both in vivo and in vitro, thereby elucidating its impact on liver fibrosis. The rat model of hepatic toxicity and chronic inflammation was established via CCl4 injection, followed by preventive administration of PF in three dosage tiers (100, 150, 200 mg/kg/d). Additionally, HSC-T6 cells were subjected to exposure to cobalt chloride (CoCl2, 200 μM) to mimic hypoxic conditions. Lentiviral transfection was employed to establish stable cell lines with either overexpression or knockdown of HIF-1α, aiming to delineate the functional significance of HIF-1α in hepatic stellate cells (HSCs) activation. The severity of liver inflammatory response and fibrotic progression was evaluated with several pathological stainings. Levels of mRNA were detected by qPCR. Expression levels of protein were assayed with Western blot. The protein content and distribution were also visually detected through IHC and IF staining. ROS was detected by DCFH-DA, and mitochondrial membrane potential was quantitatively assessed using JC-1 staining. Our results demonstrated that PF treatment significantly reversed CCl4-induced liver fibrosis, effectively reducing hepatic inflammation and oxidative damage. PF also inhibited mitophagy by suppressing the HIF-1α pathway, thereby attenuating HSCs' activation. This study uncovers a novel mechanism involving HIF-1α-mediated mitophagy in HSCs and provides evidence that PF alleviates hepatic fibrosis by inhibiting this process, leading to reduced inflammation and oxidative damage. These findings suggest that PF could be a natural and vital medicine to treat liver fibrosis.
    Keywords:  HIF‐1α; liver fibrosis; mitophagy; oxidative stress damage; paeoniflorin
    DOI:  https://doi.org/10.1002/ptr.70226
  36. Cell Death Dis. 2026 Apr 19.
    Dual-targeting nanoparticles enhance microglial P2Y12R expression to promote neuronal mitophagy for repairing spinal cord injury.
    Zhenming Tian, Hong Li, Yunheng Jiang, Huiye Wei, Yubao Lu, Senyu Yao, Mao Pang, Xintao Shuai, Bin Liu, Limin Rong.
      Spinal cord injury (SCI) leads to severe mitochondrial dysfunction and ROS cascade, with microglia playing a dual role in both exacerbating damage and providing neuroprotection. Recent evidence has highlighted the importance of P2Y12R in microglial-neuron interactions, particularly in modulating mitochondrial quality control and mitigating oxidative stress. Here, we develop a dual-targeting nanoparticle system (P2Y-TK-Nano) to enhance P2Y12R expression in microglia and promote neuronal mitophagy, aiming to reduce mitochondrial reactive oxygen species (mtROS) and improve neuronal survival following SCI. The P2Y-TK-Nano system combines a ROS-responsive thioketal bond for injury-site targeting with an MG1 peptide to selectively target microglia. This design enables precise nanoparticle delivery to the ROS-enriched injury microenvironment, effectively restoring P2Y12R expression in microglia. Microglia treated with P2Y-TK-Nano exhibit elevated P2Y12R expression, leading to increased interaction with injured neurons, improved mitophagy, and reduced mtROS production. These combined effects significantly attenuate secondary damage and contribute to neuroprotection post-SCI. Our findings reveal a novel regulatory mechanism by which P2Y12R overexpression in microglia enhances neuronal mitophagy and mitigates oxidative stress after SCI. The dual-targeting P2Y-TK-Nano system offers a promising therapeutic approach to address microglial activation and mitochondrial dysfunction in the context of SCI.
    DOI:  https://doi.org/10.1038/s41419-026-08596-2
  37. Research (Wash D C). 2026 ;9 1251
    Lycopene Alleviates Deoxynivalenol-Induced Porcine Intestinal Epithelial Barrier Injury by Inhibiting PGAM5-Mediated Mitophagy-Dependent Ferroptosis.
    Jing Zheng, Zi-Yan Hu, Ming Lou, Xin Yao, Yue Cheng, Yi-Feng Huang, Ming-Shan Chen, Jia-Xin Wang, Fu-Wei Jiang, Yi Zhang, Zhuo-Yu Liu, Si-Tong Liu, Hong-Li Si, Qi Yu, Xiao-Yi Zhang, Jin-Long Li, Yi Zhao.
      Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, is a major and unavoidable environmental contaminant that poses serious risks to intestinal health. Lycopene (LYC), a natural carotenoid with potent antioxidant properties, has been reported to exert protective effects against oxidative stress. Phosphoglycerate mutase family member 5 (PGAM5) acts as a key signaling hub to control mitochondrial dynamics and mitophagy. This study aimed to elucidate the potential role of LYC in DON-induced intestinal damage and clarify the contribution of PGAM5. We established intestinal porcine epithelial cell models to explore the effects of DON and LYC on intestinal barrier integrity, mitochondrial function, mitophagy, and ferroptosis through assessments of cell viability, oxidative stress, iron accumulation, and autophagic activity. Mechanistic insights were validated using RNA sequencing, molecular docking, Western blotting, and immunofluorescence analyses. PGAM5 expression was modulated via plasmids and small interfering RNA. Our results demonstrated that DON disrupted barrier integrity, reduced cell motility, and induced cytoskeletal disorganization, accompanied by excessive mitophagy, lipid peroxidation, and ferrous iron accumulation, ultimately leading to ferroptosis. Notably, LYC alleviated DON-induced intestinal damage by inhibiting mitophagy and ferroptosis. Importantly, PGAM5 overexpression abolished the protective effects of LYC, indicating that PGAM5-mediated mitophagy-dependent ferroptosis plays a critical role in DON-induced intestinal damage. These findings suggest that LYC may serve as a potential therapeutic strategy for treating mycotoxin-induced intestinal disorders.
    DOI:  https://doi.org/10.34133/research.1251
  38. Free Radic Biol Med. 2026 Apr 21. pii: S0891-5849(26)00430-2. [Epub ahead of print]
    Myeloperoxidase (MPO) mediates LPS-induced mitophagy in murine macrophages through AMPK/ULK1 pathway.
    Wei Lin, Yan Zeng, Jia Li, Xinyu Zhang, Zhengyi Wang, Di Zhao, Xijing Chen, Yongjie Zhang, Chaorui Guo.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.140
  39. Zhongguo Zhong Yao Za Zhi. 2026 Mar;51(6): 1724-1735
    [Mechanism of Angelicae Pubescentis Radix-Taxilli Herba components in preventing nucleus pulposus cell apoptosis via regulating PINK1/Parkin and Nrf2 pathways based on "Qu-Zhi-Bu-Yi" theory].
    Chao-Qun Feng, Min Zhao, Mao-Yin Luo, Chuan Leng, Fei Yang, Xiao-Hong Fan.
      Based on the theory of ″Qu-Zhi-Bu-Yi″, this study aimed to investigate the optimal compatibility ratio of Angelicae Pubescentis Radix and Taxilli Herba for preventing and treating pressure-induced human nucleus pulposus(NP) cell apoptosis, and to elucidate the mechanisms. A human NP cell apoptosis model was established using abnormal mechanical pressure at 1.0 MPa. The concentration ratios of quercetin, osthole, and columbianadin were screened by the orthogonal experimental design. Cell proliferation and apoptosis were determined using the cell counting kit-8(CCK-8) assay and Annexin V-APC/PI double staining, respectively. Western blot was performed to detect apoptosis-related proteins, as well as key protein expressions in the phosphatase and tensin homolog(PTEN)-induced putative kinase 1(PINK1)/Parkin-mediated mitophagy pathway, and the nuclear factor erythroid 2-related factor 2(Nrf2)-mediated antioxidant pathway. Mitochondrial ultrastructure was observed by transmission electron microscopy(TEM). Mitochondrial membrane potential was measured using the JC-1 staining. Oxidative stress markers were evaluated by the enzyme-linked immunosorbent assay(ELISA). Energy metabolism was quantified using colorimetry. Reactive oxygen species(ROS) levels were detected using the 2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA) fluorescent probe. The Nrf2 overexpression and knockdown model construction efficacy in NP cells was validated by quantitative real-time polymerase chain reaction(qRT-PCR). Additionally, rescue experiments were designed to validate the mechanism of the above pathways. Based on the results, the optimal combination of quercetin at 50 μmol·L~(-1), osthole at 6.25 μmol·L~(-1), and columbianadin at 12.5 μmol·L~(-1) significantly promoted NP cell proliferation and inhibited apoptosis. The components enhanced mitophagy by activating the PINK1/Parkin pathway and alleviated oxidative stress by activating the Nrf2 pathway. Rescue experiments showed that the anti-apoptotic effects of the traditional Chinese medicine(TCM) components could be reversed by mitophagy inhibition and Nrf2 knockdown. In conclusion, the Angelicae Pubescentis Radix-Taxilli Herba components inhibit pressure-induced NP cell apoptosis by synergistically activating PINK1/Parkin-mediated mitophagy and Nrf2-mediated antioxidant response. These findings provide experimental evidence for intervertebral disc degeneration treatment.
    Keywords:  Qu-Zhi-Bu-Yi; apoptosis; intervertebral disc degeneration; mitophagy; traditional Chinese medicine component
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20251113.706
  40. Exp Neurol. 2026 Apr 16. pii: S0014-4886(26)00151-2. [Epub ahead of print]402 115787
    mtHsp70 overexpression enhances neuroprotection through ATF5-dependent UPRmt signaling after traumatic brain injury.
    Yuanqing Zhang, Yi Jin, Runze Han, Yucheng Shen, Zongqi Wang, Xiaoou Sun, Jiangang Liu.
      Traumatic brain injury (TBI) induces secondary neuronal damage, in which mitochondrial dysfunction plays a central role. Mitochondrial heat shock protein 70 (mtHsp70) is a key mitochondrial chaperone involved in protein folding and proteostasis, yet its role in TBI pathology remains unclear. In the present study, we investigated the neuroprotective function of mtHsp70 and its underlying mechanisms using a controlled cortical impact (CCI) mouse model. We found that CCI selectively reduced mtHsp70 levels within mitochondria, accompanied by its cytoplasmic accumulation, while total cellular mtHsp70 expression remained unchanged. Stereotactic AAV-mediated overexpression of mtHsp70 in the cortex significantly reduced neuronal apoptosis, improved motor and cognitive behavioral outcomes, and increased neuronal survival following CCI. In vitro, mtHsp70 overexpression in HT22 cells attenuated H₂O₂-induced neuronal injury, improved mitochondrial respiration (OCR), and reduced mitochondrial protein aggregation. Mechanistically, mtHsp70 overexpression increased the expression of mitochondrial unfolded protein response (UPRmt)-related proteins, including HSP60 and Lonp1, and restored mitochondrial membrane potential. Importantly, ATF5 knockdown attenuated mtHsp70-induced upregulation of UPRmt-associated proteins and diminished mitochondrial respiratory improvement, suggesting that mtHsp70-mediated protection is dependent on ATF5-associated UPRmt signaling. Together, these findings indicate that mitochondrial mtHsp70 deficiency contributes to neuronal injury after CCI, whereas restoration of mtHsp70 improves mitochondrial proteostasis and neuronal survival. Targeting the mtHsp70-UPRmt pathway may represent a potential therapeutic strategy for TBI.
    Keywords:  DNAJA3; Mitochondrial proteostasis; Mitochondrial unfolded protein response; Neuroprotection; Traumatic brain injury; mtHsp70
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115787
  41. J Virol. 2026 Apr 20. e0180025
    Coronavirus infectious bronchitis virus spike protein inhibits FUNDC1-mediated mitophagy to prevent nucleocapsid protein degradation.
    Jun Zhao, Jiaxin Tian, Liwei Zhang, Yingfei Li, Lihua Tang, Qila Sa, Ruotong Li, Jing Zhao, Ye Zhao, Guozhong Zhang.
      Autophagy is involved in various stages of the viral life cycle and modulates viral replication. Coronaviruses have developed several strategies to exploit autophagy for their benefit. Nevertheless, the exact mechanisms through which the infectious bronchitis virus (IBV) influences autophagy remain inadequately understood. Here, we demonstrate that IBV infection of chicken embryonic kidney (CEK) cells activates the AKT-mTOR signaling pathway to suppress autophagosome formation and mitophagy. Further investigation reveals that the viral spike protein (S) inhibits cellular autophagy by interacting with the mitophagy receptor FUNDC1. However, FUNDC1-mediated mitophagy promotes degradation of the viral nucleocapsid (N) protein and restricts IBV replication. To counteract this host defense mechanism, the S protein competitively binds to the LC3-interacting region (LIR) motif of FUNDC1, thereby disrupting its interaction with LC3 and ultimately suppressing mitophagy. Molecular docking analysis revealed that a conserved asparagine residue at position 240 (N240) in the S1 subunit of the IBV S protein is essential for binding to FUNDC1. Furthermore, reverse genetics demonstrated that an IBV mutant with an N240A substitution exhibited reduced pathogenicity in the kidneys, trachea, and lungs of specific-pathogen-free (SPF) chickens compared to the wild-type virus. Collectively, these findings unveil a novel mechanism by which IBV antagonizes host mitophagy and provide new insights into the host-virus interplay within the context of autophagic regulation.IMPORTANCEIBV has evolved a mechanism to counteract the host's antiviral defense. Specifically, the viral spike (S) protein blocks a form of autophagy called mitophagy by binding to the mitochondrial receptor FUNDC1. Normally, FUNDC1 helps cells eliminate damaged mitochondria and restricts IBV replication by promoting the degradation of the viral nucleocapsid protein. By interfering with this process, the S protein enhances viral survival. We further identified a single conserved amino acid in the S protein that is critical for this function, and mutation of this residue weakened IBV in chickens. These findings reveal how IBV manipulates host defenses and suggest new strategies for controlling coronavirus infections.
    Keywords:  FUNDC1; IBV; host-virus; mitophagy; spike protein
    DOI:  https://doi.org/10.1128/jvi.01800-25
  42. PLoS One. 2026 ;21(4): e0346974
    Integrated RNA-seq and scRNA-seq to explore the biological mechanisms of mitophagy-related genes in ulcerative colitis.
    Jianguo Ma, Rongyi Xu, Yunfei Liu, Junli Shao, Jing Xu, Yan Qi.
      Mitophagy's role in ulcerative colitis (UC) is not fully understood. This study explores mitophagy's impact on UC and aims to create a diagnostic model. The transcriptomic datasets of patients with UC and healthy controls were obtained from the Gene Expression Omnibus database. The mitophagy-related differentially expressed genes (MRDEGs) and hub genes were identified by weighted gene co-expression network and protein-protein interaction (PPI) network analysis. Networks of mRNA-miRNA and mRNA-TF were established to detect pertinent mechanisms. CIBERSORT was used to evaluate association between immune cells with hub genes. A diagnostic model was developed utilizing logistic regression. Single-cell RNA sequencing was used to characterize the expression of hub genes in specific cell clusters and the results of the differential analysis were annotated with the hub genes identified in the logistic model. Finally, a mice model of colitis was established, and the results were verified using qRT-PCR and western blot. The study identified 28 MRDEGs and 20 hub genes. A significant link was found between immune cell infiltration and hub genes, highlighting mitophagy's interaction with the immune response. A diagnostic model with 13 potential markers was developed, achieving high accuracy. Single-cell RNA sequencing delineated key cell types and confirmed varied hub gene expression, with validation through RT-qPCR and western blot. These findings not only deepens our understanding of mitochondrial autophagy in UC but also establishe a robust diagnostic model through interdisciplinary approaches, laying the groundwork for the development of targeted diagnostic and therapeutic strategies that warrant further research for clinical application.
    DOI:  https://doi.org/10.1371/journal.pone.0346974
  43. IBRO Neurosci Rep. 2026 Jun;20 577-586
    EGR2 affects mixed stroke repair through BNIP3L-mediated microglial mitophagy.
    Xiujun Zhang, Bensi Zhang, Chun Shi, Natnicha Kampan, Waleephan Treebupachatsakul, Rungusa Pantan, Suteera Narakornsak, Manussabhorn Phatsara.
      Mixed stroke, also known as hemorrhagic infarction or infarction with hemorrhage, presents as a cerebral infarction combined with intracerebral hemorrhage (ICH) on computed tomography (CT) brain scans. ICH is a brain parenchymal hemorrhage caused by the loss of vascular integrity, which can lead to permanent disability or death. The early growth response 2 (EGR2) gene has been studied in a variety of brain diseases. However, effective treatments are still lacking.
    METHODS: In this study, a cell model was constructed using oxyhemoglobin (OxyHb), and cell viability was detected using CCK-8. The mitochondrial membrane potential was measured using a mitochondrial membrane potential detection kit. Protein stress was used to assess the expression of EGR2, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like‌ (BNIP3L or BNIP3L/NIX), and autophagy-related proteins. RT-qPCR detected the expression of EGR2 and BNIP3L mRNA. Microtubule-associated protein 1 A/1B-light chain 3 (LC3) expression was detected by immunofluorescence.
    RESULTS: This study found that OxyHb reduced microglial viability in a concentration-dependent manner, and 20 μM OxyHb produced the most robust effect and was selected for subsequent experiments. In the cell model, the membrane potential of microglia decreased, and the fluorescence intensities of autophagy-related proteins (ATG7, LC3 II/LC3 I, and P62) and LC3 were inhibited. Over-expression-EGR2 (oe-EGR2) can increase the membrane potential of microglia and promote the fluorescence intensity of autophagy-related proteins (ATG7, LC3 II/LC3 I, and P62) and LC3. Mitochondrial division inhibitor-1 (Mdivi-1) and sh-BNIP3L could reverse the effect of oe-EGR2.
    CONCLUSION: EGR2 promotes microglial mitophagy by upregulating BNIP3L, thereby alleviating ICH.
    Keywords:  BNIP3L; EGR2; Intracerebral hemorrhage; Mitophagy; Mixed stroke
    DOI:  https://doi.org/10.1016/j.ibneur.2026.04.002
  44. Biol Res. 2026 Apr 24.
    Effects of MICT and HIIT on mitochondrial dynamics-related proteins in visceral adipose tissue of type 2 diabetic rats.
    Mohammad Rahman Rahimi, Ian G Davies, Hadi Golpasandi, Narges Fatahi.
      
    Keywords:  HIIT; Insulin resistance; MICT; Mitochondrial dynamics; Type 2 diabetes
    DOI:  https://doi.org/10.1186/s40659-026-00694-x
  45. Exp Eye Res. 2026 Apr 21. pii: S0014-4835(26)00191-0. [Epub ahead of print] 111035
    TARGETING DRP1 ATTENUATES FERROPTOSIS AND DELAYS THE PROGRESSION OF DIABETIC RETINOPATHY.
    Simin Xu, Yunxiang Chao, Shuyu Sun, Wen Yang, Yuling Zou.
      Diabetic retinopathy (DR), the leading cause of blindness among working-age adults, is driven by largely undefined modes of retinal microvascular cell death. We asked whether the mitochondrial fission GTPase dynamin-related protein 1 (DRP1) governs ferroptotic injury in this setting. In cultured human retinal microvascular endothelial cells (HRMECs) exposed to high glucose (40 mM) or to the ferroptosis agonist RSL3, DRP1 expression rose in parallel with ferroptotic signaling: ACSL4 and PBP1 were up-regulated, SLC7A11 and GPX4 were down-regulated, intracellular ROS and Fe2+ accumulated, glutathione plummeted, and mitochondria became swollen with fragmented cristae. Lentiviral DRP1 knock-down reversed each of these alterations. In streptozotocin-diabetic Sprague-Dawley rats, retinal endothelial cells displayed similar ferroptotic activation, whereas daily administration of the DRP1 inhibitor Mdivi-1 restored antioxidant indices and preserved mitochondrial ultrastructure. Collectively, the data identify DRP1-mediated ferroptosis as a critical driver of microvascular injury in DR and position DRP1 inhibition as a plausible therapeutic strategy for the disease.
    Keywords:  DRP1; Diabetic retinopathy; Ferroptosis; Retinal microvascular endothelial cells
    DOI:  https://doi.org/10.1016/j.exer.2026.111035
  46. Stem Cells. 2026 Apr 22. pii: sxag021. [Epub ahead of print]
    Exosomes secreted by ADMSCs preserve cartilage integrity in knee osteoarthritis via AMPK-mediated mitochondrial dynamics and apoptosis.
    Jinliang He, Yang Liu, Lu Zhang, Nan Nan, Te Ba, Yanfang Gao, Junfeng Kang, Huiqin Hao.
      Adipose-derived mesenchymal stem cell (ADMSC) exosomes have emerged as promising therapeutic agents for degenerative joint diseases, yet their molecular actions in knee osteoarthritis (KOA) remain inadequately defined. In this study, exosomes were isolated from ADMSCs under both physiological and IL-1β-induced inflammatory conditions and comprehensively characterized by NTA, TEM, and exosome marker expression. Both types of exosomes were efficiently internalized by chondrocytes, with uptake reaching saturation after 12 hours regardless of inflammatory status. Functional assays revealed that while exosomes from healthy ADMSCs (EXOs) significantly enhanced levels of mitochondrial fusion proteins and decreased fission marker in IL-1β-induced chondrocytes after 24 hours, these beneficial effects were absent in exosomes derived from inflamed ADMSCs (IL-1β EXOs). Notably, EXO treatment reduced intracellular ROS accumulation, boosted SOD2 levels, and diminished apoptotic cell rates in chondrocytes. In vivo, administration of EXOs to rats with ACLT-induced KOA markedly alleviated cartilage degeneration, restoration of mitochondrial dynamics, and suppression of inflammatory and matrix-degrading mediators. Transcriptomic analysis showed that EXOs activated gene expression programs related to fatty acid metabolism, oxidative phosphorylation, and AMPK signaling, while IL-1β EXOs enriched inflammatory and apoptotic pathways. Importantly, both genetic knockdown and pharmacological inhibition of AMPK abolished the restorative effects of EXOs on mitochondrial dynamics and on the reduction of apoptotic markers both ex vivo and in vivo. These findings demonstrate that exosomes secreted by ADMSCs preserve cartilage integrity in KOA via AMPK-mediated mitochondrial dynamics. This work supports AMPK-targeted modulation of mitochondrial dynamics by stem cell exosomes as a promising disease-modifying strategy for KOA.
    Keywords:  AMPK; DRP; MFN; OPA; adipose-derived mesenchymal stem cells; exosomes; knee osteoarthritis; mitochondrial dynamics
    DOI:  https://doi.org/10.1093/stmcls/sxag021
  47. Environ Int. 2026 Apr 15. pii: S0160-4120(26)00220-5. [Epub ahead of print]211 110262
    Trimethyltin chloride triggers ferroptosis in myocardial injury: mitochondria-dependent protection by luteolin.
    Pengyu Wang, Xia Zhang, Ning Ding, Aimei Liu, Shuo Zhang, Yan Song, Leiming Yang, Huiting He, Mi Chen, Xiying Guo, Youzhi Zhang.
      Trimethyltin chloride (TMT), a poison from water and soil, has been linked to bradycardia. Ferroptosis, an iron-driven type of regulated cell death, is critically involved in cardiovascular diseases. However, the mechanism of TMT-induced myocardial injury remains unclear. This study aims to investigate the toxicological mechanism of TMT-induced myocardial injury and evaluate the protective effect of Lut. In this study, RNA sequencing identified Gpx4 as the key ferroptosis-related gene of TMT-induced cardiomyopathy. In vitro, TMT induced ferroptosis, which was reversed by Ferrostatin-1. Notably, TMT also suppressed mitophagy, co-treatment with chloroquine (CQ) aggravated TMT-induced ferroptosis, whereas Urolithin A reversed this effect. In vivo and in vitro, TMT caused bradycardia and myocardial ferroptosis, while Luteolin (Lut) exerted anti-ferroptosis effects. Furthermore, TMT increased DRP1 phosphorylation and reduced the expression of mitochondrial fusion and mitophagy proteins, which were restored by Lut. And the anti-ferroptosis effect of Lut was abolished by CQ. Collectively, it revealed that TMT induced ferroptosis in vitro and in vivo, while Lut alleviated TMT-induced myocardial injury by activating mitophagy, inhibiting ferroptosis, then restoring mitochondrial function.
    Keywords:  Ferroptosis; Luteolin; Mitophagy; Myocardial injury; Trimethyltin chloride
    DOI:  https://doi.org/10.1016/j.envint.2026.110262
  48. J Ethnopharmacol. 2026 Apr 17. pii: S0378-8741(26)00548-9. [Epub ahead of print] 121697
    Anmei Decoction alleviates myocardial injury in sleep-deprived rats by PI3K/Akt/mTOR/HIF-1 pathway.
    Bo Xu, Miao Zhu, Kang Sun, Qi-Qi Feng, Zhi Zhang, Jing Xia, Guang-Jing Xie, Yuan Liu, Lin-Lin Chen, Ping Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Sleep deprivation (SD) has become a major public health concern in modern society and is closely associated with an increased risk of myocardial injury. However, current therapeutic strategies are often limited by high costs and notable adverse effects. Anmei Decoction (AMD), a classical traditional Chinese medicine formula, has shown promising clinical efficacy in alleviating SD-induced myocardial injury, yet the underlying mechanisms of its cardioprotective effects remain to be fully elucidated.
    OBJECTIVE: This study aims to systematically elucidate the underlying mechanisms by which AMD alleviates SD-induced myocardial injury through integrating behavioral tests, morphological assessments, multi-omics analysis, and molecular biology techniques.
    METHODS: In this study, UPLC-MS/MS is employed for the analysis of the effective components and quantitative profiling of AMD. An in vivo SD rat model is established using a modified multi-platform aquatic environment method. Electrocardiography, echocardiography, and myocardial pathological staining are utilized to assess the extent of myocardial injury. To investigate the underlying mechanisms, transcriptomics, proteomics, immunofluorescence, real-time quantitative PCR (RT-QPCR,), and Western blotting (WB) are applied for comprehensive evaluation.
    RESULTS: Thirty-six components of the AMD extract were quantified using UPLC-MS/MS. AMD significantly improved impaired myocardial function by reducing HW/BW ratios, restoring normal ECG rhythms, and normalizing EF, LVFS, LVEDs, and LVEDd values. It markedly reversed myocardial pathological damage by attenuating fibrosis and collagen deposition, reducing cell apoptosis and hypertrophy, and modulating mitophagy. Transcriptomic and proteomic analyses revealed that AMD alleviates myocardial injury by regulating autophagy, apoptosis, and mitophagy via the PI3K-Akt, mTOR, and HIF-1 signaling pathways. Specifically, AMD treatment significantly upregulated PI3K, Akt, mTOR, and p62 protein and mRNA levels, while downregulating HIF-1α, LC3, BNIP3, and Beclin-1, indicating that AMD mitigates myocardial injury by modulating mitophagy through the PI3K/Akt/mTOR/HIF-1 pathway.
    CONCLUSION: This study demonstrates that AMD alleviates SD-induced myocardial fibrosis, hypertrophy, and apoptosis by modulating mitophagy via the PI3K/Akt/mTOR/HIF-1 signaling cascade, thereby improving myocardial functional impairment.
    Keywords:  Anmei Decoction; Mitophagy; Myocardial Injury; PI3K/Akt/mTOR/HIF-1; Sleep deprivation
    DOI:  https://doi.org/10.1016/j.jep.2026.121697
  49. Food Sci Nutr. 2026 Apr;14(4): e71778
    Protective Effects of Agrimonia pilosa Ledeb. In Myocardial Fibrosis: Inhibition of Mitophagy Mediated by the FOXO Signaling Pathway.
    Jian Chen, Zhixiang Wei, Jiaqi An, Dantong Li, Ying Gu, Yixin Zhang, Muqing Zhang.
      Agrimonia pilosa Ledeb. (APL) is an edible and medicinal plant, which has a favorable cardioprotective effect. Myocardial fibrosis (MF) is a hallmark pathological feature of various cardiovascular diseases. This study aims to evaluate its protective effects against isoproterenol (ISO)-induced MF and investigate the underlying mechanisms. HPLC was employed to analyze the main active ingredients in APL. Network pharmacology methods, combined with experimental validation, elucidated the mechanism by which APL modulates mitophagy to alleviate MF. HPLC analysis showed that six ingredients were identified. We demonstrated that APL significantly attenuated myocardial injury, enhanced cardiac function, inhibited oxidative stress and apoptosis, and effectively ameliorated MF progression. Network pharmacological predictions and in vivo experimental validation demonstrated that APL exerts its therapeutic effects through regulation of the FOXO signaling pathway and suppression of excessive mitophagy. Furthermore, we artificially elevated FOXO1 expression in vitro, which reversed the effects of APL, as evidenced by increased expression of mitophagy and fibrosis-related proteins. Consistent results from both in vivo and in vitro experiments demonstrated that APL attenuates ISO-induced MF and suppresses mitophagy mediated by the FOXO signaling pathway.
    Keywords:  Agrimonia pilosa Ledeb; FOXO signaling pathway; apoptosis; functional food; inflammatory response; mitophagy; myocardial fibrosis; oxidative stress
    DOI:  https://doi.org/10.1002/fsn3.71778
  50. Phytomedicine. 2026 Apr 10. pii: S0944-7113(26)00408-3. [Epub ahead of print]155 158174
    Spermidine alleviates sepsis-induced cardiomyopathy by improving mitochondrial quality and quantity via a Metallothionein 1-dependent antioxidant pathway.
    Shiyun Long, Jiaxin Sun, Yaguang Wu, Jia Yi, Shuang Ren, Xiaoping Ran, Xiaofeng Li, Gautam Sethi, Zhenchun Luo, Chenyang Duan.
       BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is characterized by mitochondrial dysfunction, impaired mitophagic flux, and overwhelming oxidative stress. Spermidine (SPD), a natural polyamine known to enhance autophagy and preserve cardiac function in aging and metabolic disorders, has not been systematically evaluated in the context of septic cardiomyopathy.
    PURPOSE: To determine the therapeutic potential and mechanistic basis of SPD in septic cardiac dysfunction.
    METHODS: Network pharmacology, RNA sequencing, a cecal ligation and puncture (CLP) mouse model, and multiple cellular assays were integrated to assess the protective actions of SPD. Mitochondrial function, mitophagy flux, and oxidative stress were evaluated using transmission electron microscopy (TEM), immunohistochemistry (IHC), Western blotting, structured illumination microscopy (SIM), mitochondrial membrane potential assays, oxygen consumption rate (OCR) analysis, and mitochondrial DNA (mtDNA) quantification. Transcriptomic clustering and pathway enrichment identified molecular targets, which were validated through siRNA-mediated gene silencing.
    RESULTS: SPD markedly attenuated SICM in vivo and in vitro by improving both mitochondrial quantity and quality. It restored sepsis-impaired mitophagy by upregulating LC3B and ATG7, promoting autophagosome maturation, and enhancing cellular ubiquitination. Transcriptomic profiling highlighted metallothionein-1 (MT1) as a key node in metal-ion response pathways. SPD activated the NRF2-MT1-SOD2 antioxidant axis, reduced mitochondrial reactive oxygen species (mtROS) under lipopolysaccharide (LPS) stimulation, and reversed sepsis-induced suppression of SOD2. MT1 knockdown abolished SPD-mediated SOD2 stabilization and mtROS clearance, confirming its essential role in SPD's cardioprotective effects.
    CONCLUSION: SPD mitigates SICM by orchestrating the restoration of mitochondrial quality control, normalization of mitophagic flux, and stabilization of cellular redox homeostasis. These findings support SPD as a promising therapeutic candidate for septic cardiomyopathy.
    Keywords:  Autophagy; MT1; Mitochondria; ROS; Sepsis; Spermidine
    DOI:  https://doi.org/10.1016/j.phymed.2026.158174
  51. Mater Today Bio. 2026 Jun;38 103091
    Targeted biohybrid nanoplatform for spinal cord injury treatment: Restoring microglial mitophagy and alleviating oxidative stress.
    Yu Deng, Haosen Zhao, Mina Huang, Yue Guo, Feng Jin, Baofeng Zhao, Hongkai Yang, Dongyang Li, Xifan Mei, Sen Lin, Zhanpeng Guo.
      Spinal cord injury (SCI) remains refractory because oxidative stress, impaired mitochondrial quality control, and maladaptive microglial activation form an interdependent cascade that sustains secondary degeneration. Here, we develop a modular biomimetic nanozyme platform (PM-Lipo@PB NPs) by integrating distinct functional components into a unified system. Platelet-derived membrane vesicles (PMVs) and M2 macrophage-derived extracellular vesicles (M2EVs) are fused to form a hybrid membrane (PM-Lipo) that mediates lesion-associated accumulation and provides immunoregulatory cues, while a Prussian blue (PB) nanozyme shell is grown in situ to confer catalytic redox activity. This design enables concurrent vascular injury-associated enrichment, interaction with activated microglia, and localized ROS scavenging within the lesion microenvironment. PM-Lipo@PB NPs accumulate at the injury site and reduce oxidative burden, thereby contributing to the recovery of mitochondrial function and cellular homeostasis. These effects are accompanied by modulation of PI3K/AKT/mTOR signaling and restoration of mitophagic flux, together with a shift of microglia toward a reparative phenotype. In cellular and murine SCI models, the platform exhibits lesion-preferential accumulation, effective ROS clearance, reduced inflammatory activation, and improved tissue preservation and motor function. Taken together, this study establishes a modular strategy that couples membrane-derived biological functionality with nanozyme-based redox regulation, providing a basis for microenvironment-directed therapy in SCI and related neuroinflammatory conditions.
    Keywords:  Biomimetic nanoplatform; Microglial polarization; Mitophagy; Prussian blue nanozyme; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103091
  52. Drug Dev Res. 2026 May;87(3): e70287
    PKCδ-Drp1 Axis Mediates VIP-Induced Mitochondrial Fragmentation and Metabolic Crisis in Nasopharyngeal Carcinoma.
    Jingda Xu, Guanzheng Wu, Min Chen, Gang Chen.
      In nasopharyngeal carcinoma, mitochondria often function abnormally. However, the precise signals that cause excessive mitochondrial division are still undefined. Levels of the neuropeptide Vasoactive Intestinal Peptide are altered in NPC tissues. How VIP influences the metabolic behavior of cancer cells is not well established. Our experiments utilized established NPC cell lines. We tested how physiological concentrations (10-100 nM) of VIP exposure affect survival and mitochondrial integrity. Morphology was analyzed using fluorescence staining. We measured functional outputs, including reactive oxygen species, ATP levels, and membrane potential. Immunoblotting and activity assays helped trace the involved molecular events. Both genetic knockdown and a highly selective pharmacological inhibitor confirmed the proposed mechanism. To address pathway generality, experiments were repeated in an additional NPC line (NPC‑TW02). Receptor identity was probed using siRNA against VPAC1 and VPAC2. Selectivity for cancer cells was tested in normal nasopharyngeal epithelial NP69 cells. Administering VIP at 10-100 nM increased oxidative stress within mitochondria in a concentration-dependent manner. The transmembrane potential collapsed. Activity of the electron transport chain's Complex IV was suppressed, and cellular ATP content diminished. These failures led to pronounced mitochondrial fragmentation. VIP treatment (100 nM) rapidly activated the kinase PKCδ. PKCδ then phosphorylated the fission protein Drp1 at serine 616, causing Drp1 to accumulate at mitochondria. When we applied the compound Rottlerin to inhibit PKCδ, it effectively blocked Drp1 modification and recruitment. Consequently, mitochondrial fragmentation was prevented and energy metabolism recovered. These findings were confirmed in NPC‑TW02 cells. VPAC1 silencing, but not VPAC2 silencing, blocked VIP effects in C666-1 cells. Normal NP69 cells showed no significant response to VIP under the tested conditions. This work defines a previously unrecognized VIP-PKCδ-Drp1 pathway that operates at physiologically relevant VIP concentrations and controls mitochondrial division and fitness in NPC cells. This signaling axis highlights a specific metabolic weak point in these tumors. Our results suggest PKCδ could be investigated as a candidate target for therapies designed to correct mitochondrial dysfunction in nasopharyngeal carcinoma.
    Keywords:  Drp1; PKCδ; mitochondrial fission; nasopharyngeal carcinoma; vasoactive intestinal peptide (VIP)
    DOI:  https://doi.org/10.1002/ddr.70287
  53. PLoS One. 2026 ;21(4): e0347845
    Biomarkers of mitochondrial dynamics in idiopathic pulmonary fibrosis: Identification and validation through transcriptomic and single-cell analyses.
    Yongbin Wang, Peng Cheng, Zixiang Meng, Ying Zhang, Yan Li, Feifei Feng.
       BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that has increasingly been associated with dysregulated mitochondrial quality control and dynamics. However, the molecular mechanisms underlying these alterations remain incompletely understood. This study aimed to systematically identify and validate candidate biomarkers related to mitochondrial dynamics in IPF and to characterize their cell-type specificity and putative regulatory relationships.
    METHODS: We integrated bulk transcriptomic datasets from the Gene Expression Omnibus (GEO), single-cell RNA sequencing (scRNA-seq) data, and literature-derived mitochondrial dynamics gene sets. Candidate genes were identified through differential expression analysis and consensus clustering, followed by functional enrichment and protein-protein interaction (PPI) network analyses. A total of 101 machine-learning model combinations-including random forest, LASSO, and support vector machine-were constructed to select optimal feature genes. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis and further evaluated with artificial neural network (ANN) modeling. Additional analyses included chromosomal localization, immune infiltration profiling, multilayer regulatory network construction (transcription factors, lncRNAs, circRNAs), molecular docking prediction, and single-cell expression and pseudotime trajectory analysis. Key biomarkers were further evaluated by RT-qPCR in an independent clinical cohort.
    RESULTS: Integrated multi-omics and machine-learning analyses identified CD247, IL7R, and RETN as candidate biomarkers related to mitochondrial dynamics-associated pathways in IPF. Across independent transcriptomic datasets, RETN was upregulated, whereas CD247 and IL7R were downregulated, and each showed diagnostic value (single-gene AUC > 0.7). The ANN model based on these genes achieved encouraging discriminative performance (training AUC = 0.91; validation AUC = 0.82), and expression differences were confirmed by RT-qPCR in a modest independent cohort. Enrichment analyses indicated convergence on spliceosome-related pathways, and regulatory-network analysis highlighted interactions involving transcription factors and non-coding RNAs, including circRNA CDR1as. Molecular docking suggested putative interactions with selected compounds. Single-cell analyses suggested that dysregulation was most evident in monocyte-associated compartments in one publicly available scRNA-seq dataset, and pseudotime analysis indicated dynamic expression patterns, with early transient increases in CD247 and IL7R and progressive elevation of RETN.
    CONCLUSION: Through multi-omics integration and machine-learning approaches, we identified and preliminarily validated CD247, IL7R, and RETN as candidate biomarkers related to mitochondrial dynamics-associated pathways in IPF. These findings provide transcriptomic and cell-type-specific evidence suggesting potential immune-mitochondrial associations in IPF and may inform future biomarker validation and mechanistic hypothesis generation.
    DOI:  https://doi.org/10.1371/journal.pone.0347845
  54. Protein Sci. 2026 May;35(5): e70587
    Proteostasis at the mitochondrial outer membrane: Quality control of mitochondrial protein transport.
    Shunsuke Matsumoto, Suzuka Ono, Toshiya Endo.
      Mitochondria are enclosed by a double-membrane structure composed of the outer and inner membranes, and this architectural organization underlies their diverse cellular functions. In particular, the mitochondrial outer membrane serves as an essential interface between the cytosol and the mitochondrial interior, regulating the flux of proteins, lipids, small molecules, and ions through the coordinated activities of its resident proteome. Consequently, structural and functional defects of outer membrane proteins are subject to continuous surveillance, and aberrant proteins are rapidly recognized and degraded. Defects in precursor translocation or translation can lead to the stalling of precursor proteins at the primary protein import gate, the TOM complex. Such situations are resolved by multiple quality control systems operating across both the mitochondria and the cytosol. In addition, proteins normally destined for the endoplasmic reticulum or peroxisomes may be mistargeted to mitochondria, and these mislocalized proteins are likewise managed through dedicated mechanisms that promote their degradation or re-targeting. In this review, we summarize current insights into the molecular factors and mechanisms that maintain proteostasis at the mitochondrial outer membrane.
    Keywords:  mitochondria; outer membrane; protein degradation; quality control; re‐targeting
    DOI:  https://doi.org/10.1002/pro.70587
  55. Protein Sci. 2026 May;35(5): e70553
    Proteolytic control of mitochondrial protein translocases.
    Lara Kroczek, Thomas Langer.
      Mitochondria are essential organelles that drive numerous cellular processes, including energy metabolism, ion homeostasis, and programmed cell death. This functional versatility relies on a highly dynamic proteome whose composition is continuously remodeled to meet changing cellular and environmental demands. Central to this remodeling are mitochondrial proteases (termed mitoproteases), which maintain protein quality and regulate mitochondrial function through selective processing and degradation events. Their activity ensures rapid degradation of regulatory proteins and dynamically adjusts components of multiprotein complexes. Among their most critical targets are elements of the mitochondrial protein import machinery. By modulating translocase stability and by processing preproteins during translocation, mitoproteases enable precise control over the organelle's proteome, aligning mitochondrial function with the cell's metabolic state. This review discusses how mitoproteases maintain translocase integrity and dynamically regulate mitochondrial protein import and the mitochondrial proteome.
    Keywords:  mitochondrial proteases; mitochondrial protein import; mitochondrial remodeling; protein quality control
    DOI:  https://doi.org/10.1002/pro.70553
  56. J Ethnopharmacol. 2026 Apr 20. pii: S0378-8741(26)00593-3. [Epub ahead of print] 121741
    Mitochondrial Homeostasis Regulation in the Prefrontal Cortex: A Key Mechanism for Emodin-Mediated Attenuation of Insomnia.
    Zhen Zhang, Xinyue Che, Ren Zhang, Laishiqi Wan, Chunmei Ma, Juntao Zou, Xiaowu Xu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Insomnia represents a prevalent sleep disorder with neurobiological underpinnings that are not yet fully elucidated. Emerging research indicates that mitochondrial homeostasis plays a pivotal role in the regulation of sleep. Emodin (EMD), the principal bioactive constituent of the traditional Chinese medicinal herb Polygonum multiflorum, has been reported to exert antioxidant properties and promote sleep. Nevertheless, the precise mechanisms underlying its effects remain to be clarified.
    AIM OF THE STUDY: The present study seeks to investigate whether EMD ameliorates insomnia and associated anxiety-like behaviors through the restoration of mitochondrial homeostasis within the prefrontal cortex (PFC).
    MATERIALS AND METHODS: An insomnia model was induced in mice via intraperitoneal administration of p-chlorophenylalanine (PCPA). Behavioral assessments, including the open field test (OFT), elevated plus maze (EPM), and loss of righting reflex (LORR) test, were employed to evaluate the impact of EMD on insomnia and concomitant anxiety-like phenotypes. After behavioral testing, PFC tissues were harvested for comprehensive analyses. Mitochondrial morphology and ultrastructure were examined using Janus green B (JG-B) staining and transmission electron microscopy (TEM), respectively. Mitochondrial respiratory function and ATP synthesis capacity were quantified utilizing a Seahorse XF Analyzer. Oxidative stress parameters were assessed by measuring reactive oxygen species (ROS), malondialdehyde (MDA) concentrations, superoxide dismutase (SOD) activity, and the enzymatic activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase. Additional evaluations included the assessment of mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (ΔΨm), expression levels of cytochrome c oxidase (COX) mRNA and protein, and mitochondrial DNA (mtDNA) copy number.
    RESULTS: EMD significantly alleviated insomnia and the accompanying anxiety-like behaviors in mice. In the PFC, it increased the number of mitochondria, alleviated ultrastructural damage, and attenuated OS, as evidenced by increased activities of Na+-K+-ATPase, Ca2+-Mg2+-ATPase, and SOD, along with reduced levels of ROS and MDA. Moreover, EMD elevated mtDNA copy number and upregulated COX mRNA and protein expression. It also inhibited mPTP opening and increased the ΔΨm, collectively contributing to the restoration of mitochondrial homeostasis and promoting ATP production.
    CONCLUSION: EMD mitigates oxidative stress-induced damage by modulating the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in PFC neuronal membranes. This regulation facilitates the restoration of mitochondrial homeostasis, thereby preserving mitochondrial structural integrity and function, which in turn ameliorates insomnia and related anxiety-like manifestations. These findings offer novel insights into the pathophysiology of sleep disorders and underscore the therapeutic potential of mitochondria-targeted interventions aimed at modulating cellular energy metabolism.
    Keywords:  Emodin; Insomnia; Mitochondrial DNA; Oxidative Phosphorylation; Respiratory Chain
    DOI:  https://doi.org/10.1016/j.jep.2026.121741
  57. Cell Signal. 2026 Apr 21. pii: S0898-6568(26)00197-X. [Epub ahead of print] 112545
    Reactivating mitochondrial quality control via the Nrf2 pathway to combat metabolic stress in diabetic osteoarthritis.
    Yang Chen, Juan Xiao, Yanmin Yu, Hai-Bo Si.
      The intersection of diabetes mellitus (DM) and osteoarthritis (OA) defines a distinct metabolic phenotype, commonly termed diabetic osteoarthritis (DOA), in which systemic metabolic toxicity independently accelerates articular degeneration. In addition to shared risk factors, this review delineates the molecular framework of DOA, detailing how persistent hyperglycemia initiates oxidative stress, chronic inflammation, and the accumulation of advanced glycation end products (AGEs), disrupting chondrocyte bioenergetic homeostasis. A pivotal event in this process is the dysregulation of mitochondrial quality control (MQC), a central regulatory mechanism that maintains cellular viability under metabolic stress. We further emphasize the dysregulation of the Nrf2 signaling pathway as a critical upstream determinant of mitochondrial dysfunction. By integrating epidemiological findings with mechanistic evidence, we propose that therapeutic restoration of the Nrf2-MQC axis may offer a rational strategy to preserve mitochondrial integrity and slow the progression of diabetes-associated joint degeneration.
    Keywords:  Chondrocyte bioenergetics; Diabetic osteoarthritis; Metabolic stress; Mitochondrial quality control; Nrf2 signaling; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112545
  58. Zhen Ci Yan Jiu. 2026 Apr 25. pii: 1000-0607(2026)04-0437-10. [Epub ahead of print]51(4): 437-446
    [Effect of moxibustion on endothelial cell apoptosis in ApoE-/- atherosclerotic mice via PINK1/Parkin signaling pathway].
    Li Pan, Qi-Biao Wu, Zhou Zhu, Jiao-Jiao Xiong, Zhao-Bo Yan, Ning Zhang, Zhi-Hong Yang, Xiao-Fang Yang.
       OBJECTIVES: To observe the effect of moxibustion on the lipid metabolism, aortic arch and mitochondrial structure, PTEN-induced kinase 1 (PINK1)/Parkin signaling pathway, and the expressions of apoptosis-related proteins in atherosclerotic (AS) mice, so as to explore its potential mechanisms underlying prevention and treatment of AS.
    METHODS: Ten C57BL/6J mice were fed with normal chow and used as the control group. Thirty ApoE-/- mice were fed with high-fat chow to establish the AS model, and randomly divided into model, moxibustion, and moxibustion+Mdivi-1(mitochondrial fission inhibitor) groups, with 10 mice in each group. For mice in the moxibustion group, moxibustion was applied to "Danzhong"(CV17), "Shenque"(CV8), and bilateral "Neiguan"(PC6) and "Xuehai"(SP10) for 30 min. The mice in the moxibustion + Mdivi-1 group received intraperitoneal injection of Mdivi-1 (1.2 mg·kg-1·d-1) 30 min before each session of moxibustion, and those of the control, model and moxibustion groups received equal volume of lysosomal injection. The intervention was conducted once daily, 5 d a week for 12 consecutive weeks. The contents of serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were measured by using an automatic biochemical analyzer. Histopathologial changes of the aorta arch were observed by H.E. staining, and the mitochondrial structure of the aorta was observed using a transmission electron microscopy. The expression levels of PINK1, Parkin, Bax, Bcl-2, and Caspase3 protein in the aortic tissue were detected using Western blot, and the immunoactivity of mitochondrial cytochrome C (Cyt C) in the aortic tissue was determined using immunofluorescence staining.
    RESULTS: Compared with the control group, the contents of serum TC, TG and LDL-C, expression levels of PINK1, Parkin, Bax and Caspase3 protein, and the immunoactivity of Parkin and Cyt C were significantly increased (P<0.01, P<0.05), while the content of serum HDL-C level and the expression of Bcl-2 protein notably decreased (P<0.01) in the model group. In comparison with the model group, the moxibustion group showed a significant decrease in the contents of serum TC, TG and LDL-C, expression levels of Bax and Caspase3, and immunoactivity of Cyt C (P<0.01, P<0.05), and a striking increase in the expressions of PINK1, Parkin, and Bcl-2 protein and immunoactivity of Parkin(P<0.01). After intraperitoneal injection of Mdivi-1, the effects of moxibustion disappeared in lowering the levels of TC, TG and LDL-C, the expressions of Bax, Caspase3 and the immunoactivity of Cyt C and in up-regulating the expressions of PINK1, Parkin, Bcl-2 and the immunoactivity of Parkin. Morphological observation showed uneven intima of the aortic arch in the model group, with plaque proliferation, hyperplasia of fibrous tissue or smooth muscle tissue, swollen mitochondria with matrix dissolution, and reduction in the number of cristae accompanied by vacuoles, etc;while in the moxibustion group, morphological observation showed relatively regular lumen of the aortic arch, with less endometrial degeneration and fewer swelling endothelial cells, and a smaller amount of plaque formation and some foam cells, slightly swollen mitochondria with partially dissolved matrix and secondary lysosomes;and the morphological observation showed shedding of local endothelial cells of the aortic arch, with thickened intima, proliferated smooth muscle tissue, and foam cells within the plaque;slightly swollen mitochondria, reduction in the number of cristae, and partially dissolved matrix in the moxibustion + Mdivi-1 group.
    CONCLUSIONS: Moxibustion can improve the lipid metabolism level, relieve pathological injury of the thoracic aorta, restore mitochondrial structure and function in ApoE-/- AS mice, which may be related to its functions in reducing Cyt C metastasis, and inhibiting apoptosis by regulating PINK1/Parkin signaling pathway.
    Keywords:  Apoptosis; Atherosclerosis; Mitochondria; Moxibustion; PINK1/Parkin signaling pathway
    DOI:  https://doi.org/10.13702/j.1000-0607.20250472
  59. Autophagy. 2026 Apr 21. 1-2
    Getting a handle on RAB1: from Golgi trafficking to mitophagy.
    Alexander R van Vliet.
      The small GTPase RAB1 is essential for life. A knockout of RAB1 is not only embryonically lethal, but even triggers cell death in a cultured cell line, underscoring its importance for cellular homeostasis. Previous work has shown that RAB1 plays a key role in protein and membrane trafficking as a player in the ER-to-Golgi trafficking pathway. Here, RAB1 has been shown to interact with COPII vesicles that have left the ER and are arriving at the Golgi. In addition, RAB1 is an essential part of autophagy initiation, where loss of RAB1 leads to defects very early in the pathway. To complicate matters further, there is a non-trivial overlap in phenotype between a Golgi trafficking defect and an autophagy initiation problem, as ATG9A vesicle trafficking and the general importance of the Golgi in autophagy illustrates. Given these hurdles, how would one get a handle on the molecular mechanism of RAB1? In this Punctum, I discuss our recent mapping of a new RAB1 interactome that provides fresh insights into its multifaceted functions.
    Keywords:  BioID; Golgi; Membrane trafficking; autophagy; interactomics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2657541
  60. Heart Rhythm. 2026 Apr 20. pii: S1547-5271(26)02280-0. [Epub ahead of print]
    Cardiac STIM1 deficiency triggers mitochondrial fission to impair electrophysiological function and exacerbate post-MI remodeling.
    Marine Cacheux, Juan Velasco, Jonathan M Granger, Xiaohong Wu, Benjamin Strauss, Fadi G Akar.
       BACKGROUND: STIM1 (stromal-interaction-molecule-1) is a sarcoplasmic reticulum Ca2+ sensor that links intracellular Ca2+ signaling to pathways governing cellular stress adaptation.
    HYPOTHESIS: We hypothesized that cardiac STIM1 is a critical regulator of basal electromechanical function in the heart, and that its depletion exacerbates post-MI left ventricular (LV) dysfunction and electrophysiological (EP) remodeling.
    METHODS: Mice received cardiotropic AAV9-mediated delivery of shRNA targeting STIM1 or control. Four weeks later, cardiac function was assessed in-vivo by echocardiography followed by ex-vivo optical action potential (AP) mapping. Complementary studies in isolated myocytes were used to assess contractility, action potentials, and Ca2+ transients in-vitro. Mitochondrial ultrastructure was assessed by electron microscopy and mitochondrial dynamics protein expression was determined by immunoblotting. In a separate cohort, mice underwent in vivo ischemia-reperfusion injury, followed by comprehensive post-MI assessment of ventricular function and EP remodeling.
    RESULTS: Cardiac STIM1 knockdown reduced ventricular systolic function and impaired intrinsic myocyte contractility. At the tissue level, hearts exhibited slowed conduction, reduced connexin-43 expression, and pacing-induced EP instability. These abnormalities were accompanied by pronounced remodeling of mitochondrial architecture and dynamics, consistent with a shift toward enhanced fission. Functionally, STIM1-deficient myocytes displayed a marked reduction in mitochondria-enriched Rhod-2 AM Ca2+ transient amplitude, indicating impaired mitochondrial Ca2+. Following ischemia-reperfusion injury, STIM1-deficient hearts developed more severe ventricular dysfunction and adverse EP remodeling, including the genesis of spatially-discordant alternans.
    CONCLUSIONS: STIM1 is a central regulator of mitochondrial function and electromechanical stability. Its loss impairs mitochondrial Ca2+ handling, disrupts EP function, and accelerates adverse post-MI remodeling.
    Keywords:  Alternans; Arrhythmia; Calcium; Myocardial Infarction; Stromal Interaction Molecule 1
    DOI:  https://doi.org/10.1016/j.hrthm.2026.04.030
  61. Int Immunopharmacol. 2026 Apr 22. pii: S1567-5769(26)00552-7. [Epub ahead of print]180 116706
    Sakuranin attenuates UVB-induced skin damage by preserving mitochondria-ER coupling and restoring redox-organelle homeostasis.
    Jayasingha Arachchige Chathuranga Chanaka Jayasingha, Wisurumuni Arachchilage Hasitha Maduranga Karunarathne, Sang Rul Park, Chang Soo Lee, Cheng-Yun Jin, Yung Hyun Choi, Kyoung Tae Lee, Gi-Young Kim.
      Ultraviolet B (UVB) irradiation elicits complex intracellular stress responses that drive keratinocyte injury and skin photoaging through coordinated disruption of redox homeostasis, mitochondrial dynamics, and endoplasmic reticulum (ER) stress signaling at mitochondria-ER contact sites. This study investigated whether sakuranin (SKR), a naturally occurring flavanone glycoside, exerts photoprotective effects by modulating mitochondria-ER networks under UVB exposure. SKR displayed no cytotoxicity at concentrations up to 100 μM, when administered as a pre-treatment, significantly reduced UVB-induced apoptotic cell death by suppressing cytosolic and mitochondrial reactive oxygen species accumulation, preserving mitochondrial membrane potential, and restoring the balance between DRP1-driven fission and OPA1-mediated fusion. In parallel, SKR markedly attenuated ER stress responses, as evidenced by reduced eIF2α phosphorylation and downregulation of GRP78 and CHOP expression, while live-cell imaging confirmed the preservation of mitochondria-ER contact integrity disrupted by UVB exposure. These protective effects were consistently reproduced in UVB-exposed zebrafish larvae, in which SKR significantly alleviated oxidative stress and ER stress responses. Collectively, these findings demonstrate that SKR provides robust photoprotection by coordinately regulating oxidative stress, mitochondrial dynamics, ER stress signaling, and mitochondria-ER communication, thereby mitigating UVB-induced apoptotic injury and supporting its potential as a natural therapeutic candidate for preventing photoaging and UVB-associated skin disorders.
    Keywords:  ER stress; Mitochondrial dynamics; Mitochondria–ER coupling; Oxidative stress; Sakuranin; UVB
    DOI:  https://doi.org/10.1016/j.intimp.2026.116706
  62. J Biol Chem. 2026 Apr 16. pii: S0021-9258(26)00327-3. [Epub ahead of print] 111455
    Role of mitochondrial translation in modulating inflammatory disease outcome: current knowledge and future perspectives.
    Swarnali Basu, Rukshar Khan, Shiva Sharma, Priyanka Prajapati, Veena Ammanathan, Sumit Rungta, Amit Lahiri.
      Mitochondrial translation is crucial for maintaining cellular respiration, energy balance, calcium signaling, apoptosis, immune surveillance, and the regulation of inflammatory responses. This specialized process, involving mitochondrial rRNAs, tRNAs, mitoribosomes, and nuclear-encoded translation factors, ensures the synthesis of mitochondrially encoded proteins that support oxidative phosphorylation. The mitochondrial translation cycle is tightly regulated by RNA-binding proteins, mitochondrial unfolded protein response, and stress-responsive pathways such as mTOR, particularly during metabolic shifts and immune activation. Emerging evidence highlights mitochondrial translation as a critical modulator of inflammation. In this review, we describe the alteration in mitochondrial-specific translation dynamics in immune cells, its adaptation to stress, and its interplay with organelle-wide signaling via mito-nuclear and mito-cytosolic communication. We focus on the alterations in mitochondrial translation machinery including mitoribosomal proteins, rRNA, tRNA synthetases or other regulatory factors linked to inflammatory diseases, including neurodegeneration, IBD, metabolic and cardiovascular disorders. We further examine how mitochondrial translation influences immune responses through mitochondrial DNA/RNA release, activation of mitochondrial damage-associated molecular patterns, and inflammasomes such as NLRP3. Collectively, mitochondrial translation functions as an immune centric-checkpoint that presents promising therapeutic target for intervention in inflammation-driven diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2026.111455
  63. CNS Neurosci Ther. 2026 Apr;32(4): e70881
    Inhibition of Microglial TRPV1 Ameliorates Brain Injury After Intracerebral Hemorrhage by Suppressing AMPK/PINK1-Mediated Mitophagy.
    Kezhu Chen, Xiangyang Deng, Jun Zeng, Baoye Sun, Jingyu Yu, Tianwen Li, Junjie Zhong, Pengjie Hong, Peng Wang, Fengshi Li, Quan Zhang, Junwei Ren, Qisheng Tang, Tongming Zhu, Jianhong Zhu.
       BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) is a cation channel implicated in neurological disorders. Although TRPV1 activation contributes to intracerebral hemorrhage (ICH) pathology, its microglia-specific role and underlying mechanisms remain poorly defined. This study investigates how microglial TRPV1 influences ICH injury.
    METHODS: We utilized a mouse ICH model alongside microglia-specific TRPV1 knockout mice, BV2 cells, and primary microglial cultures. Interventions included TRPV1 antagonist capsazepine (CPZ), agonist capsaicin (CAP), microglial depletion agent PLX5622, and TRPV1 knockdown. Outcomes were assessed using immunofluorescence, behavioral tests, Western blot, magnetic resonance imaging (MRI), and transmission electron microscopy (TEM).
    RESULTS: TRPV1 expression was significantly upregulated post-ICH, primarily in microglia. TRPV1 blockade with CPZ treatment reduced hematoma volume, brain edema, neuronal apoptosis, and improved neurological function, whereas CAP exacerbated injury. These benefits were replicated in microglia-specific TRPV1 knockout mice. Mechanistically, CPZ shifted microglia from a pro-inflammatory (iNOS+) to a regulatory (Arg1+) phenotype and suppressed excessive mitophagy via the Ca2+-AMPK-PINK1 pathway.
    CONCLUSION: TRPV1 activation in microglia exacerbates ICH injury by promoting inflammation and disruptive mitophagy. Targeted inhibition of microglial TRPV1 represents a promising therapeutic strategy for ICH.
    Keywords:  TRPV1; capsaicin; capsazepine; intracerebral hemorrhage; mitophagy
    DOI:  https://doi.org/10.1002/cns.70881
  64. Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00185-0. [Epub ahead of print] 102768
    Macrophage-mimetic photothermal nanotherapeutics regulate mitochondrial homeostasis and inflammatory cascades in lung ischemia-reperfusion injury.
    Haoxiang Yuan, Bo Zeng, Pu Shen, Jiancheng Deng, Ying Chen, Meiyu Huang, Wentao Wu, Xin Xu, Xuanlin Zhang, Xue Liu, Xudong Zhang, Zhijin Fan, Jianxing He.
      Pulmonary ischemia-reperfusion injury is a major cause of acute lung injury and primary graft dysfunction after lung transplantation, with few effective treatments available. In this study, we develop a macrophage-membrane-coated mesoporous polydopamine nanoparticle system loaded with ginsenoside Rg3 (Rg3@PACVs) and activated by near-infrared irradiation. This design enables precise targeting of injured lung tissue via chemokine-receptor- and integrin-mediated pathways, while allowing controllable, on-demand drug release. In vitro hypoxia-reoxygenation models and a rat pulmonary ischemia-reperfusion model demonstrate that Rg3@PACVs with mild photothermal therapy reduce reactive oxygen species accumulation, suppress inflammatory cytokines, preserve mitochondrial structure and tricarboxylic acid cycle metabolism, and alleviate tissue injury. The approach combines targeted delivery, multimodal protection against oxidative and inflammatory damage, and mitochondrial restoration. These findings suggest a promising therapeutic strategy for mitigating lung ischemia-reperfusion injury and potentially for other inflammation- and oxidative-stress-driven pulmonary diseases.
    Keywords:  ginsenoside Rg3; ischemia-reperfusion injury; macrophage membrane; mesoporous polydopamine; mild thermotherapy; mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102768
  65. J Transl Med. 2026 Apr 24.
    m6A-Mediated epitranscriptional reprogramming drives cardiac fibrosis by suppressing PGC-1α and boosting mitochondrial fission.
    Xiao-Ying Cao, Bin Tu, Zhen-Rui Cao, Fei Liu, Ge Yan, Jun Dong, Quan-Wei Huang, Zhi-Jie Li, Qi-Yi Liu, Jia-Jie Leng, Wen-Cai Yu, Meng-Jun Bie, Xiao-Wen Wang, Ying-Jiu Jiang.
      
    Keywords:  Cardiac fibrosis; Epigenetic modification; M6A; Mitochondrial fission; PGC1α
    DOI:  https://doi.org/10.1186/s12967-026-08163-5
  66. Cell Death Dis. 2026 Apr 23.
    Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.
    Yinong Wang, Bingzhi Wang, Yu Liu, Cheng Zhou, Junhu Yuan, Fanyu Zhang, Ling Ma, Yiming Ma, Hongying Wang.
      Glutamine addiction is a key metabolic vulnerability in cancer. However, the mechanisms governing the limited efficacy of glutamine metabolism inhibitor (GMI) monotherapy require further investigation. Via single-cell monitoring using a caspase-3 activity indicator, we identified SLC25A6 as a key mediator of GMI-induced apoptosis in colorectal cancer cells. SLC25A6 overexpression enhanced apoptosis both in vitro and in vivo. SLC25A6 promoted mitochondrial fragmentation and dysfunction and upregulated the expression of mitochondrial fission markers. Notably, mitofission inhibitors largely abolished SLC25A6-related mitochondrial dysfunction and intrinsic apoptosis. Mechanistically, SLC25A6 directly interacted with MIC60, competitively inhibiting MIC19 binding; both MIC60 and MIC19 are key components of the mitochondrial contact site and cristae organizing system (MICOS). The SLC25A6 T126A mutant failed to bind MIC60 and lost its ability to destabilize the MICOS complex and facilitate mitofission. Upregulation of SLC25A6 expression induced by the glutaminase inhibitor CB-839 sensitized cancer cells to the Bcl-2 inhibitor ABT-199. Combined CB-839 and ABT-199 treatment showed strong synergistic antitumor effects in colorectal cancer xenograft models. Our findings reveal a novel function of SLC25A6 that links metabolic stress to mitochondrial apoptosis via disruption of the MICOS complex. Combination treatments with mitochondrial apoptotic inducers represent a promising avenue for maximizing the efficacy of GMIs in cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-026-08754-6
  67. J Pharmacol Exp Ther. 2026 Mar 23. pii: S0022-3565(26)00520-3. [Epub ahead of print]393(5): 104321
    5-Hydroxytryptamine 2B receptor antagonism restores ATP and reduces tubulointerstitial fibrosis in the renal cortices of aged mice.
    Kai W McAlister, Natalie E Scholpa, Austin D Thompson, Jaroslav Janda, Ishika Girdhar, Kristian P Doyle, George L Sutphin, Rick G Schnellmann.
      Age is a prominent risk factor for the development of kidney disease, emphasizing the importance of understanding and mitigating the mechanisms underlying renal aging. Aging mitochondria in tubular cells become increasingly dysfunctional, reducing ATP production, and increasing reactive oxygen species, which drives inflammation. Pharmacological induction of mitochondrial biogenesis, the generation of new and functional mitochondria, restores renal function in mouse models of kidney disease, including acute kidney injury and diabetic kidney disease. The potential of this therapy in age-related renal decline remains unknown. 2,4,6-trifluoro-N-(6-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)benzamide (MARY1) is a novel, selective serotonin 2B receptor antagonist that induces mitochondrial biogenesis and improves recovery after acute kidney injury in vivo. Young (12-week-old) and aged (104-week-old) male mice were treated with MARY1 (0.3 mg/kg, i.p.) or vehicle daily for 3 weeks. Mice were euthanized at 15- and 107-weeks, respectively, and the kidneys collected for analyses. Aged 107-week-old mice exhibited increased phosphorylation of mammalian target of rapamycin, decreased AMP-activated protein kinase phosphorylation, decreased ATP, and increased inflammation and fibrosis in the renal cortex compared with young controls. MARY1 treatment restored AMP-activated protein kinase phosphorylation, and increased protein kinase B activity and ATP content. MARY1 decreased the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 and reduced markers of renal inflammation and fibrosis in the aged kidney, including vascular cell adhesion molecule 1, collagen-1, and collagen deposition. These findings suggest that MARY1 treatment restores mitochondrial metabolism and ameliorates age-related renal inflammation and fibrosis in mice, supporting its potential as a therapeutic strategy to preserve renal function during aging. SIGNIFICANCE STATEMENT: Age-related kidney dysfunction is driven in part by declining mitochondrial metabolism and chronic inflammation. This study reveals that the novel selective serotonin 2B receptor antagonist 2,4,6-trifluoro-N-(6-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)benzamide restores mitochondrial metabolism and reduces renal inflammation and fibrosis in aged mice, supporting pharmacological induction of mitochondrial biogenesis and 2,4,6-trifluoro-N-(6-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)benzamide as a promising strategy to preserve kidney function during aging.
    Keywords:  Aging; Fibrosis; Mitochondrial biogenesis; Renal pharmacology
    DOI:  https://doi.org/10.1016/j.jpet.2026.104321
  68. J Radiat Res. 2026 Apr 22. pii: rrag025. [Epub ahead of print]
    Quantitative analysis of autophagic flux reveals radiation-induced activation of SQSTM1-mediated degradation of protein aggregates and ER-phagy.
    Takahito Moriwaki, Tsuyoshi Masuda.
      Autophagy is an evolutionarily conserved process that degrades and recycles intracellular components through lysosomes, thereby maintaining cellular homeostasis under stress conditions. Although radiation is known to influence autophagy, most previous studies have relied on static marker expression rather than quantitative evaluation of autophagic flux. In the present study, we quantitatively analyzed autophagic flux in hTERT/RPE-1 cells exposed to γ-rays (0.5-4 Gy) using both bafilomycin A1-based assays and HaloTag reporter systems that visualize lysosomal degradation. LC3-based total autophagic flux remained unchanged even at 4 Gy, indicating that lysosomal function is preserved after irradiation. In contrast, SQSTM1-dependent selective autophagy increased significantly at doses of 2 Gy or higher, suggesting enhanced clearance of radiation-induced protein aggregates. HaloTag-based analyses further revealed that γ-irradiation induced mitophagy and ER-phagy in a dose-dependent manner, consistent with activation of oxidative stress and unfolded protein response pathways. These findings demonstrate that ionizing radiation does not globally suppress autophagy but selectively activates organelle-specific autophagy, particularly SQSTM1-mediated ER-phagy. The selective activation of these quality-control pathways likely contributes to maintaining cellular integrity and stress adaptation following irradiation. Quantitative flux analysis thus provides new insight into the hierarchical regulation of autophagy and its role in cellular survival and repair mechanisms after radiation exposure.
    Keywords:  ER-phagy; aggrephagy; autophagy; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1093/jrr/rrag025
  69. Gut Microbes. 2026 Dec 31. 18(1): 2661411
    IL-10-STAT3 axis preserves epithelial mitochondrial homeostasis during bacterial challenge.
    Saranya Navaneetha Krishnan, Amit Jaiswal, Armaan Mohan, Arthur Wang, Timothy E Shutt, Derek M McKay.
      Increasing evidence implicates mitochondrial dysfunction in the pathogenesis of inflammatory bowel disease (IBD), with the IBD-associated pathobiont adherent-invasive E. coli-LF82 (AIEC) promoting epithelial mitochondrial depolarization and fragmentation and a concomitant reduction in barrier function. We hypothesized that the anti-inflammatory cytokine interleukin-10 (IL-10), essential for enteric homeostasis, would protect against AIEC-induced mitochondrial disruption. Mitochondrial fragmentation in colonic organoids following infection with E. coli-LF82 was reduced by IL-10 pretreatment + cotreatment. IL-10 significantly reduced the E. coli-LF82 induced mitochondrial dysfunction in the human colon-derived T84 epithelial cell line as measured by mitochondrial network analysis, membrane potential, permeability transition pore opening, oxidative phosphorylation (via oxygen consumption rate), and epithelial barrier integrity. IL-10-treated T84 cells and organoids exhibited increased phosphorylation of STAT3 at serine 727 (a requirement for STAT3 activity at mitochondria), which was abrogated by pharmacological inhibition of ERK (but not JAK) activation, leading to loss of protection against E. coli-LF82-induced mitochondrial dysfunction. Re-expression of wild-type STAT3, but not the S727A mutant, in HT-29 (human colon epithelial cell line) STAT3 knockout cells restored mitochondrial depolarization and ATP levels, underscoring the role of ERK-driven STAT3S727 phosphorylation in IL-10's protective mechanism. In contrast, IL-22, which primarily activates STAT3Y705 and not STAT3S727, failed to prevent AIEC-induced mitochondrial dysfunction. Thus, in the context of exposure to an E. coli pathobiont, IL-10 supports gut epithelial homeostasis via ERK-dependent STAT3S727 maintenance of mitochondrial integrity, contributing to preservation of epithelial barrier function.
    Keywords:  E. coli-LF82; Mitochondrial network; bacterial pathobiont; barrier function; colonic organoid; epithelium; interleukin (IL)-10; mitochondrial dysfunction; mtSTAT-3
    DOI:  https://doi.org/10.1080/19490976.2026.2661411
  70. Int J Biol Macromol. 2026 Apr 20. pii: S0141-8130(26)02053-2. [Epub ahead of print] 152127
    Melatonin attenuates mitochondrial apoptosis and improves mitochondrial quality by activating the AKT/BAD/BCL-XL signaling pathway, promoting oxidative muscle fiber formation.
    Pengkang Song, Liwei Huang, Tianye Gong, Guoqing Zhao, Xiaolong Pan, Juan Xiong, Sirong Cheng, Ruigao Song, Xi Wang, Hongxia Li.
      Skeletal muscle fiber-type plasticity is crucial for systemic metabolic health and exercise capacity. While melatonin has been reported to possess various metabolic regulatory functions, whether and how it directly regulates muscle fiber-type transformation through specific molecular pathways remains unclear. This study aimed to investigate the effects of melatonin on skeletal muscle fiber type and to elucidate the underlying signaling pathways and molecular mechanisms. In vivo, mice were chronically supplemented with melatonin, and their exercise performance was assessed. Histological analysis, transmission electron microscopy for mitochondrial ultrastructure, measurement of key mitochondrial function indicators, and marker gene levels were performed. RNA-Seq was used to screen key target genes, and molecular mechanism validation was carried out using qPCR, Western blot, siRNA gene silencing, and the AKT inhibitor (AZD5363). The results showed that melatonin treatment did not alter mouse body weight but significantly enhanced their exercise endurance, accompanied by an increased proportion of oxidative muscle fibers and comprehensive enhancement of mitochondrial biogenesis and function. Transcriptomics and molecular validation identified BCL2L1 (encoding the BCL-XL protein) as a key downstream target of melatonin. Mechanistically, melatonin activated AKT, leading to phosphorylation of BAD, thereby relieving its inhibition on BCL-XL. The upregulated BCL-XL not only effectively suppressed the mitochondrial apoptotic pathway but also synergistically improved mitochondrial function. Both AKT inhibition and BCL-XL siRNA completely abolished all the beneficial effects induced by melatonin. In summary, this study reveals that melatonin suppresses mitochondrial apoptosis, enhances mitochondrial function, and promotes oxidative myofiber generation through the AKT/BAD/BCL-XL signaling pathway.
    Keywords:  Apoptosis; BCL-XL, mitochondrial; Melatonin; Muscle fiber-type
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152127
  71. Chin J Nat Med. 2026 Apr;pii: S1875-5364(26)61171-5. [Epub ahead of print]24(4): 385-401
    Zishen Huoxue Decoction alleviates myocardial ischemia-reperfusion injury through dysregulation of endoplasmic reticulum-mitochondria homeostasis mediated by DUSP1-NDUFS4.
    Xiangyi Pu, Qin Zhang, Zhaoqi Yan, Siyuan Zhou, Qiaomin Wu, Xinai Zhang, Yongyuan Cai, Zhiming Liu, Ruxiu Liu, Xing Chang.
      Zishen Huoxue (ZSHX) Decoction can ameliorate myocardial ischaemia by regulating the mitochondrial quality control network. However, the identification of new molecular targets is necessary for ZSHX's control of mitochondrial protein homeostasis and metabolic activities. Utilizing animal and cellular models with NDUFS4CKO or DUSP1CKO, along with single-cell sequencing, metabolomics, network pharmacology, and in vivo/in vitro interventions, the study found that ischemia-reperfusion (I/R) injury triggers endoplasmic reticulum stress and mitochondrial metabolic reprogramming, accompanied by downregulation of DUSP1 and NDUFS4. Network pharmacology suggested ZSHX's role in regulating mitochondrial activity during inflammatory damage, while metabolomics confirmed that ZSHX alters metabolite composition and expression in I/R-affected tissues. Single-cell sequencing further linked I/R to disrupted mitochondrial energy metabolism and cell death, and in vitro experiments demonstrated that ZSHX preserves mitochondrial proteostasis, inhibits endoplasmic reticulum stress, restores calcium balance, upregulates DUSP1/NDUFS4 expression, and controls metabolic reprogramming to reduce myocardial inflammatory injury. Kaempferol, the primary active component of ZSHX, drives these protective effects by enhancing DUSP1/NDUFS4 expression, thereby preventing endoplasmic reticulum stress and inflammatory bursts, preserving mitochondrial function, and re-encoding mitochondrial metabolic processes post-I/R injury.
    Keywords:  DUSP1; Endoplasmic reticulum stress; Mitochondrial metabolic reprogramming; NDUFS4; Zishen Huoxue Decoction
    DOI:  https://doi.org/10.1016/S1875-5364(26)61171-5
  72. J Neuroinflammation. 2026 Apr 22.
    Parkin regulates NLRP3 degradation through chaperone-mediated autophagy to suppress PANoptosis and protect dopaminergic neurons in Parkinson's disease.
    Dongyan Zheng, He Zhang, Ailun Xie, Huilin Xiao, Duanqin Guan, Zhefan Xie, Jiankun Luo, Jianwei Cao, Tianji Lin, Lifei Xing, TingTing Xia, Fei Zou, Jialong Chen.
      Parkinson's Disease (PD) is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PANoptosis, a programmed inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, contributes to DA neuron degeneration in PD. The E3 ubiquitin ligase Parkin and the inflammasome sensor NOD-like receptor protein 3 (NLRP3) are known to play critical regulatory roles in DA neuron degeneration. However, whether Parkin modulated NLRP3 via chaperone-mediated autophagy (CMA) to inhibit PANoptosis remained unclear. To verify the above hypothesis, SN4741 cells and C57BL/6 mice were treated with rotenone to establish PD models. PANoptosis activation and DA neurons degeneration were observed in PD models, and these pathological manifestations were mitigated by the NLRP3 inhibitor MCC950. Besides, Parkin interacted with NLRP3, ubiquitinated its K353 residue, and then promoted NLRP3 degradation via CMA. Parkin overexpression or CMA activation alleviated DA neuron damage and PANoptosis, while K353R mutation abolished these effects. It was revealed that Parkin mediated CMA-dependent degradation of NLRP3 (targeting K353) to suppress PANoptosis and protect DA neurons in PD. CMA activators or NLRP3 inhibitors may serve as disease-modifying therapies for PD.
    Keywords:  Chaperone-mediated autophagy; Dopaminergic neuron; NLRP3; PANoptosis; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s12974-026-03814-2
  73. Cell Rep. 2026 Apr 16. pii: S2211-1247(26)00331-1. [Epub ahead of print]45(4): 117253
    NSUN2-mediated GATM m5C methylation regulates creatine metabolism to drive mitochondrial fission and promote renal fibrosis.
    Xiaoguo Suo, Mengmeng Zhang, Qi Zhu, Qichao Luo, Fang Wang, Qinglin Ge, Lijin Peng, Jutao Yu, Jie Wei, Chao Hou, Minglu Ji, Danfeng Zhang, Linhui Wu, Zhijuan Wang, Chao Li, Xin Chen, Sai Zhu, Shuaishuai Xie, Yu-Hang Dong, Peng Chen, Chen Yang, Juan Jin, FeiXavier Chen, Jianan Wang, Xiaoming Meng.
      Chronic kidney disease (CKD) is increasing globally, presenting a critical health challenge. Renal fibrosis, the main pathological feature of CKD, is poorly understood and lacks targeted therapies. Here, we reveal that 5-methylcytosine (m5C) RNA methylation, primarily mediated by methyltransferase NSUN2, is significantly upregulated in renal fibrosis. Reduction of m5C RNA methylation levels upon NSUN2 loss attenuates fibrosis responses in cells, and specific knockout of NSUN2 in renal tubular epithelial cells alleviates renal fibrosis in several disease models. Mechanistically, NSUN2 methylates and stabilizes glycine amidinetransferase (GATM) mRNA. GATM exacerbates mitochondrial fission not only by directly binding to Drp1 but also through its product creatine, collectively driving the progression of renal fibrosis. We subsequently identify an inhibitor of NSUN2 that mitigates the progression of renal fibrosis. Collectively, our study demonstrates that targeting NSUN2-mediated m5C methylation of GATM mRNA therapeutically offers a promising strategy to slow the progression of CKD.
    Keywords:  CP: cell biology; CP: metabolism; GATM; NSUN2; creatine; m5C; renal fibrosis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117253
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