bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–04–12
fifty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
  2. STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
  3. Low-intensity pulsed ultrasound restores mitochondrial dynamics and function in lipopolysaccharide-stimulated astrocytes.
  4. Curcumin ameliorates hepatic insulin resistance by activating PINK1/Parkin-mediated mitophagy.
  5. Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
  6. Myricetin stabilizes PINK1 to activate mitophagy and ameliorate metabolic dysfunction-associated steatotic liver disease.
  7. Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
  8. Melatonin attenuates Drp1-mediated excessive mitochondrial fission through upregulation of SIRT1 in granulosa cells in PCOS.
  9. Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.
  10. Mitophagy in bladder cancer: a double-edged sword in tumor progression and therapy.
  11. Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
  12. Mitochondrial dynamics and cancer: mechanisms and targeted therapy.
  13. Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.
  14. USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L.
  15. Kisspeptin-10 attenuates pulmonary arterial hypertension via restoration of mitochondrial function in pulmonary artery smooth muscle cells.
  16. Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.
  17. Mitochondrial Dynamics Disorder Drives Nucleus Pulposus Cell Senescence in Lumbar Scoliosis of Aging Bipedal Rats Under Asymmetric Force.
  18. SIRT1-regulated mitophagy mitigates lipotoxicity-induced ferroptosis in diabetic kidney disease.
  19. High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.
  20. Platycodin D alleviates myocardial ischemia-reperfusion injury by suppressing aberrant mitophagy.
  21. Bergapten ameliorates osteoarthritis progression by inhibiting the PI3K/AKT/mTOR pathway to activate mitophagy and suppress pyroptosis.
  22. ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.
  23. Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
  24. PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.
  25. USP2 Attenuates Spermatogenic Cell Apoptosis Via PINK1/Parkin-Dependent Mitophagy in Varicocoele: A Functional Study.
  26. Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
  27. Targeting mitochondrial dynamics against cancer.
  28. Glucose deprivation impairs lipid tolerance related to mitophagy disorder in cardiomyocytes.
  29. In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
  30. Vps34 Knockdown Alleviated the Long-Term Effect of Nano-Alumina on Cognitive Impairment in Zebrafish When in Embryos.
  31. African swine fever virus pE199L, as a mitophagy receptor, suppresses antiviral innate immunity to promote viral replication.
  32. Interplay of Skin Aging: Mitochondrial Stress and Ultraviolet Exposure.
  33. Targeting GHSR-1α with silibinin to enhance mitophagy and prevent tubular injury in diabetic kidney disease.
  34. Suppression of Nr1d1/Bnip3-dependent mitophagy by notch signaling aggravates inflammatory response in RSV-infected mice lungs.
  35. Mitochondrial Quality Control as a Central Pharmacological Target in Aging.
  36. Microvesicle release drives cycles of mitophagy flux disruption and inflammatory amplification in sepsis-induced myocardial dysfunction.
  37. Dusp22 deficiency in cardiomyocytes exacerbates doxorubicin-induced cardiotoxicity by aggravating mitochondria-dependent apoptosis via JNK pathway.
  38. Moxibustion delays ovarian aging by regulating mitochondrial biogenesis and improving oocyte quality.
  39. From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.
  40. Echinacoside Improves Antioxidant Responses and Angiogenesis Through Parkin-MFN2-Mediated Mitophagy to Promote Diabetic Wound Healing.
  41. Maternal Insulin Resistance during Late Gestation Impairs Brown Adipose Tissue Development and Thermogenic Function in Calves.
  42. Icariin, astragaloside IV and puerarin mixture salvages synaptic loss by enhancing mitochondrial biogenesis: A multi-target strategy for Alzheimer's disease therapy.
  43. Chlorogenic acid (CGA) exerts antidepressant-like effects by regulating SIRT1/FoxO3a/PINK1/Parkin pathway in LPS-induced depressive mice.
  44. A dual-responsive CO-releasing nanogel ameliorates retinal ischemia-reperfusion injury by restoring mitochondrial homeostasis and attenuating cGAS-STING pathway activation.
  45. SARS-CoV-2 targets mitochondria, exacerbating COVID-19 pneumonia.
  46. Inhibition of ADAMTS1 and ATP citrate lyase attenuates connexin-43 degradation and HFrEF.
  47. Chitosan-gelatin hybrid hydrogel incorporating strontium-doped ceria nanoparticles for enhanced wound healing and mitochondrial function recovery.
  48. Vitamin B3 rescues mitochondrial homeostasis in dexamethasone-induced skeletal muscle atrophy by reducing oxidative stress.
  49. Chloride intracellular channel 4 contributes to Aβ-induced cognitive impairment in mice through the regulation of mitochondrial fission. CLIC4 promotes mitochondrial fission.
  50. GL-V9 disrupts the mitochondrial homeostasis and triggers the integrated stress response by promoting the binding of cytosolic MDM2 with NDUFS1 in colorectal cancer.
  51. mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.
  52. Exogenous lactate administration alleviates post-cardiac arrest brain injury by coordinating metabolic reprogramming and pathological mitophagy suppression.
  53. DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
  54. Proteostasis regulation in T cell dysfunction: dual regulation by KLHL6.
  55. Diffusive spreading across dynamic mitochondrial network architectures.
  56. A single-nucleus RNA-seq dataset of the colon in Pink1-deficient and wild-type mice.
  57. Extracellular biogenic nanoscale mitochondria reprogram the wound microenvironment via ROS scavenging independent of cellular uptake.
  58. Impaired Endosomal Recycling of Signaling Receptors Activates an Extracellular UPR.
  59. β1/β2 adrenergic dysregulation: a missing link between mitochondrial fission/fusion in the failing heart.
  1. Nat Commun. 2026 Apr 09.
    The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-71630-6
  2. Autophagy. 2026 Apr 11.
    STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
    Jin-Yi Lin, Ze-Bo Huang, Evandro F Fang, Guang Lu.
      PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.
    Keywords:  Alzheimer disease; PINK1; PRKN; STUB1; VCP/p97; memory; mitochondrial homeostasis; mitophagy; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2026.2658848
  3. Ups J Med Sci. 2026 ;131
    Low-intensity pulsed ultrasound restores mitochondrial dynamics and function in lipopolysaccharide-stimulated astrocytes.
    Umut Kerem Kolac, Aysegul Turkkol, Mahmut Alp Kılıc, Gizem Donmez Yalcın, Abdullah Yalcın, Mehmet Dincer Bılgın.
       Background: Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapeutic modality with growing potential in the treatment of neurodegenerative diseases. However, its mechanistic role in regulating mitochondrial homeostasis in astrocytes under inflammatory stress remains poorly understood. This study aimed to investigate the effects of LIPUS on mitochondrial dynamics, morphology, oxidative stress, mitochondrial membrane potential, and mitochondrial stress response in an in vitro model of neuroinflammation.
    Methods: Normal Human Astrocytes (NHA) were stimulated with lipopolysaccharide (LPS; 0.5 µg/mL, 24 h) and subsequently treated with LIPUS (1 MHz, 50% duty cycle, 100 Hz, 15 min) at intensities of 100, 300, or 500 mW/cm2. The expression of mitochondrial fusion (MFN1, MFN2, OPA1) and fission (DRP1, FIS1) markers was analyzed using qPCR. Mitochondrial morphology was evaluated by confocal microscopy, while reactive oxygen species (ROS) levels and mitochondrial membrane potential (ΔΨm) were measured using specific fluorescent probes. Expression of mitochondrial stress-related genes (PGC1α, CLPP, HSP60, LONP1) was also assessed.
    Results: LIPUS treatment, particularly at 300 mW/cm2, significantly enhanced the expression of mitochondrial fusion markers while suppressing fission markers in a dose- and time-dependent manner, with peak effects observed 4 h post-treatment. Confocal imaging revealed that LIPUS mitigated LPS-induced mitochondrial fragmentation. Additionally, LIPUS reduced ROS accumulation, preserved ΔΨm, and attenuated the LPS-induced upregulation of mitochondrial stress-related genes, suggesting modulation of both stress response and biogenesis.
    Conclusion: LIPUS ameliorates mitochondrial dysfunction in inflamed astrocytes by restoring mitochondrial dynamics and reducing stress signaling, supporting its potential as a therapeutic strategy for neuroinflammation-associated neurodegenerative disorders.
    Keywords:  LIPUS; astrocyte; lipopolysaccharide; mitochondrial dynamics
    DOI:  https://doi.org/10.48101/ujms.v131.13678
  4. Sci Rep. 2026 Apr 08.
    Curcumin ameliorates hepatic insulin resistance by activating PINK1/Parkin-mediated mitophagy.
    Zhanhong Guo, Huan Zhang, Yinghong Kong.
      
    Keywords:  Curcumin; HepG2 cells; Insulin resistance; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1038/s41598-026-47924-6
  5. Chem Commun (Camb). 2026 Apr 07.
    Silicon rhodamine-based fluorescent probes for monitoring mitochondrial viscosity dynamics during mitophagy.
    Zixuan Zhao, Hongling Li, Lijun Li, Jinping Liu, Qi Ai, Xin Wen, Baoxiang Gao.
      Mitochondrial autophagy (mitophagy) is pivotal for mitochondrial quality control and intracellular homeostasis. However, real-time visualization of mitochondrial inner membrane viscosity - a key biophysical parameter of mitophagy - remains challenging. To address this, a silicon rhodamine (SiR)-based dual-modal imaging probe was developed, enabling reliable real-time monitoring of mitophagic processes and providing novel insights into mitochondrial remodeling during autophagy.
    DOI:  https://doi.org/10.1039/d6cc00586a
  6. Phytomedicine. 2026 Feb 23. pii: S0944-7113(26)00246-1. [Epub ahead of print]155 158009
    Myricetin stabilizes PINK1 to activate mitophagy and ameliorate metabolic dysfunction-associated steatotic liver disease.
    Weilong Xu, Lijuan Nie, Jing Cao, Chuchu Shan, Yutian Cao, Jialin Yu, Pengxu Tuo, Jiangyi Yu, Hideki Fujii, Le Thi Thanh Thuy, Fei Li, Xiqiao Zhou.
       BACKGROUND: Myricetin, a bioactive flavonoid from Abelmoschus manihot, has demonstrated therapeutic potential for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). However, its precise mechanisms, particularly concerning mitochondrial homeostasis, remain inadequately elucidated.
    OBJECTIVES: The present study evaluated the therapeutic efficacy of myricetin in alleviating hepatic steatosis, inflammation, fibrosis, and insulin resistance associated with MASLD/MASH, with a specific focus on unraveling the role of mitophagy regulation.
    METHODS: MASLD and MASH models were established in mice using a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet, followed by myricetin treatment. Systemic metabolism, liver injury, histology, and insulin sensitivity were assessed. Transcriptomic profiling was performed to analyze metabolic pathways. Molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation, and immunofluorescence were used to study the interaction between myricetin and PINK1 and its impact on PINK1/Parkin-mediated mitophagy. Finally, in vitro loss-of-function experiments using shPINK1 were conducted to validate the mechanism.
    RESULTS: Myricetin significantly ameliorated hepatic steatosis, inflammation, fibrosis, and systemic insulin resistance in MASLD/MASH mice. Transcriptomics revealed enhanced fatty acid β-oxidation and mitochondrial function. Mechanistically, myricetin directly bound to PINK1, inhibiting its mitochondrial import through the TOM complex (TOM40) and subsequent cleavage by the PARL protease, thereby stabilizing PINK1 on the outer mitochondrial membrane. This stabilization activated PINK1/Parkin-dependent mitophagy, restoring mitochondrial integrity. Notably, the myricetin-mediated improvements in mitophagy and mitochondrial function were negated by PINK1 silencing.
    CONCLUSION: Myricetin mitigates MASLD/MASH progression by acting as a novel PINK1 stabilizer, augmenting PINK1/Parkin-dependent mitophagy to enhance mitochondrial quality. This study highlights myricetin as a potent intervention targeting mitochondria to combat metabolic liver diseases.
    Keywords:  Metabolic dysfunction-associated steatotic liver disease; Mitochondrial function; Mitophagy; Myricetin; PINK1 stability
    DOI:  https://doi.org/10.1016/j.phymed.2026.158009
  7. bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]
    Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
    Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.
      Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.
    DOI:  https://doi.org/10.64898/2026.03.29.715103
  8. Reproduction. 2026 Apr 06. pii: xaag041. [Epub ahead of print]
    Melatonin attenuates Drp1-mediated excessive mitochondrial fission through upregulation of SIRT1 in granulosa cells in PCOS.
    Jingyu Zhang, Yuting Zhang, Mengyun Li, Linhui Gao, Jidong Zhou, Liang Gao, Jianjun Zhou.
      Mitochondrial dysfunction in GCs has been implicated in PCOS pathogenesis. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is critical for maintaining intact mitochondrial function. This study aims to investigate whether mitochondrial fission contributes to mitochondrial dysfunction in the GCs of individuals with PCOS and the molecular effects of melatonin on mitochondrial fission. Transmission electron microscopy (TEM) of human GCs showed that the mitochondria exhibited a condensed and small spherical morphology with a tendency toward fragmentation in PCOS patients. At the molecular level, GCs from patients with PCOS presented significant increases in both the p-Drp1(Ser616)/(Ser637) ratio and mitochondrial fission factor (MFF). In a dihydrotestosterone (DHT)-induced PCOS-like mouse model, excessive mitochondrial fission in GCs was similarly observed, characterized by fragmented mitochondrial morphology via TEM and increased expression of the mitochondrion-localized Drp1 (mito-Drp1) protein. Similarly, in vitro experiments demonstrated that DHT treatment increased the expression of mito-Drp1, the p-Drp1(Ser616)/(Ser637) ratio, and MFF in KGN cells. Melatonin treatment effectively reversed these abnormalities, restoring mitochondrial morphology, reducing fission markers (mito-Drp1, the p-Drp1 ratio, and MFF), decreasing mitochondrial reactive oxygen species, and enhancing mitochondrial membrane potential. Mechanistically, melatonin upregulated SIRT1, which restored the imbalance of Drp1 phosphorylation and blocked its MFF-dependent mitochondrial recruitment, thereby attenuating Drp1-mediated excessive mitochondrial fission. Our findings reveal a novel protective mechanism of melatonin in PCOS via the SIRT1-Drp1 signaling axis, offering a potential therapeutic target for PCOS management.
    Keywords:  Drp1; PCOS; SIRT1; melatonin; mitochondrial fission
    DOI:  https://doi.org/10.1093/reprod/xaag041
  9. Life Sci. 2026 Apr 07. pii: S0024-3205(26)00190-6. [Epub ahead of print] 124381
    Disruption of the OPTN-TBK1 axis impairs autophagosome formation in prion disease.
    Jingjing Wang, Pei Wen, Zhixin Sun, Fengting Gou, Qing Fan, Yuheng He, Deming Zhao, Lifeng Yang.
      Prion diseases are chronic, transmissible, and neurodegenerative disorders that affect both humans and other mammals. Mitophagy is essential for maintaining mitochondrial homeostasis and normal neuronal function. Our previous research show that the PINK1-Parkin-dependent mitophagy pathway is impaired in the PrP106-126 induced prion disease model, yet the underlying downstream mechanisms remain elusive. We report that impaired phosphorylation of ubiquitin at Ser65 diminishes OPTN recruitment to mitochondria, thereby influence mitochondrial translocation of TBK1 and ATG9A, consequently suppresses TBK1 autophosphorylation that depends on the OPTN-ATG9A interaction. As a result, reduction of OPTN phosphorylation dependent on TBK1 inhibits autophagosome formation and ultimately leads to defective mitophagy. Importantly, overexpression of OPTN rescued the mitophagy impairment induced by PrP106-126 and partially restoring mitochondrial morphology and function. Our findings identify OPTN as a critical node, proposing its therapeutic targeting as a strategy to counteract prion disease progression.
    Keywords:  Mitophagy; OPTN; Phosphorylation; Prion diseases; TBK1
    DOI:  https://doi.org/10.1016/j.lfs.2026.124381
  10. J Transl Med. 2026 Apr 10.
    Mitophagy in bladder cancer: a double-edged sword in tumor progression and therapy.
    Qi Chen, Tao Chen, Lifeng Gan, Yiran Lu, Biao Qian.
      
    Keywords:  Bladder cancer; Duality; Mitophagy; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-026-08042-z
  11. J Transl Med. 2026 Apr 10.
    Mitochondrial dysfunction in neonatal brain injury: from molecular mechanisms to therapeutic interventions.
    Chengqian Teng, Jianjie Wei, Yixiao Zhu, Andi Chen, Xiaohui Chen.
       BACKGROUND: Neonatal brain injury, including hypoxic-ischemic encephalopathy, preterm brain injury, and neonatal infectious brain injury, remains a major cause of death and long-term neurodevelopmental disability worldwide. The immature brain is highly dependent on oxidative metabolism yet particularly vulnerable to energy failure and oxidative stress, placing mitochondria at the core of injury cascades. By integrating disturbances in energy production, redox balance, calcium homeostasis, and cell death signaling, mitochondrial dysfunction is increasingly recognized as a unifying driver of diverse neonatal brain injury phenotypes.
    MAIN BODY: This narrative review synthesizes current knowledge on the main clinical forms of neonatal brain injury and their developmental context, alongside an overview of mitochondrial physiology in neural cells, including the regulation of bioenergetics, reactive oxygen species, calcium signaling, mitochondrial dynamics, and inter‑organelle communication. It critically examines how mitochondrial dysfunction contributes to injury across hypoxic-ischemic, preterm, and infectious or inflammatory insults, emphasizing links between impaired oxidative phosphorylation, excessive oxidative and nitrosative stress, calcium overload with pathological opening of the mitochondrial permeability transition pore, activation of apoptosis and regulated necrosis, disrupted mitochondrial fusion-fission balance and biogenesis, and defective mitophagy and mitochondrial quality control. These mitochondrial disturbances precipitate acute neuronal and oligodendroglial injury and hinder the long-term maturation and connectivity of neural circuits. Finally, we review emerging mitochondria‑targeted neuroprotective strategies, focusing on approaches that enhance mitochondrial biogenesis, reduce mitochondrial oxidative stress, and target mitochondrial dynamics to restore mitochondrial homeostasis and improve cellular resilience in the immature brain.
    CONCLUSION: By linking specific patterns of mitochondrial dysfunction to distinct forms and stages of neonatal brain injury, this review provides a mechanistic framework for identifying high‑risk infants, refining pathophysiological understanding, and guiding the rational development of mitochondria‑targeted interventions aimed at improving neurological outcomes in vulnerable newborns.
    Keywords:  Energy metabolism; Hypoxic–ischemic encephalopathy; Mitochondrial dynamics and mitophagy; Mitochondrial dysfunction; Mitochondria‑targeted therapy; Neonatal brain injury; Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1186/s12967-026-08104-2
  12. Cell Biol Toxicol. 2026 Apr 06.
    Mitochondrial dynamics and cancer: mechanisms and targeted therapy.
    Aixin Wang, Xinyu Ye, Yumeng Zhao, Chao Zhang.
      Mitochondria, as key organelles in eukaryotic cells, regulate cellular energy homeostasis and functional integrity through dynamic processes, including fission, fusion, autophagy, and transport, underpinned by precise molecular mechanisms. In healthy cells, the equilibrium of mitochondrial dynamics ensures network quality control and metabolic coordination. In contrast, cancer cells exhibit multi-dimensional dysregulation characterized by hyperactive fission, impaired fusion, and compensatory upregulation of respiratory chain assembly factors, creating a state of "morphology-function decoupling". These alterations drive tumor progression by reprogramming cellular metabolism, promoting proliferation, inhibiting apoptosis, enhancing migration and drug resistance, and facilitating immune evasion. This review elucidates the molecular mechanisms underlying mitochondrial dynamics, their dysregulation in cancer, and their influence on tumor behavior, while also addressing the core challenges of current targeted therapeutic strategies and the novel therapeutic paradigm of "network remodeling", offering new insights into tumor biology and precision cancer therapy.
    Keywords:  Cancer; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Targeted therapy
    DOI:  https://doi.org/10.1007/s10565-026-10174-3
  13. Autophagy. 2026 Apr 11. 1-15
    Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.
    Changjuan Shao, Sabina Bhatta, Meena Kumari, Fengqin Wu, Sandra L Siedlak, Sandy Torres, Fanpeng Zhao, Xiongwei Zhu, Wenzhang Wang.
      Mutations in C19orf12, an orphan gene with elusive function, cause mitochondrial membrane protein-associated neurodegeneration (MPAN). Despite the intriguing mitochondrial deficits, the mechanisms underlying the loss of function of C19orf12 in MPAN pathogenesis remain unclear. In this study, we aim to explore the functional impacts of C19orf12 mutations on mitophagy in MPAN models in vitro and in vivo. Our findings suggest that C19orf12 regulates the turnover of mitophagy receptor BNIP3 proteins through the lysosomal degradation pathway. Disruption of this process leads to the accumulation of oxidized BNIP3 proteins on mitochondria that are ineffective in initiating mitophagy. Mechanistically, C19orf12 participates in protein condensate formation by liquid-liquid phase separation to facilitate BNIP3 protein turnover on the mitochondrial membrane. Along with mitophagy deficits, a rodent MPAN model exhibits motor deficits and core pathological features of MPAN, including iron accumulation, axonal spheroids, and neuroinflammation. This study underscores the pivotal role of C19orf12 in regulating the quality control of BNIP3 protein to control mitophagy, highlighting the significance of impaired mitophagy in the pathogenesis of MPAN.Abbreviations:  ATP: adenosine triphosphate; BafA: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BTZ: bortezomib; C19orf12: chromosome 19 open reading frame 12; CFP: cyan fluorescent protein; CHX: cycloheximide; DNP: dinitrophenyl; FCCP: carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; FRAP: fluorescence recovery after photobleaching; GFP: green fluorescent protein; H&E stain: haematoxylin and eosin stain; LCD: low complexity domain; LC/MS: liquid chromatography-mass spectrometry; LLPS: liquid-liquid phase seperation; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mito-SRAI: mitochondrial signal-retaining autophagy indicator; MG132: cbz-leu-leu-leucinal; MMP: mitochondrial membrane potential; MPAN: mitochondrial membrane protein-associated neurodegeneration; NBIA: neurodegeneration with brain iron accumulation;PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; STX17: syntaxin 17; TFAM: transcription factor A, mitochondrial; TOLLES: TOLerance of lysosomal EnvironmentS; YPet: YFP for energy transfer.
    Keywords:  Iron accumulation; LLPS; NBIA; mitochondrial membrane; mitophagosome; protein degradation
    DOI:  https://doi.org/10.1080/15548627.2026.2655834
  14. Mil Med Res. 2026 Dec;13(1): 100004
    USP18 exacerbates myocardial I/R injury by inhibiting Parkin mitophagy through the deubiquitinase PTEN-L.
    Qing-Qing Wu, Yang Xiao, Ying-Ying Hu, Xiang-Yu Yang, Xin-Yi Yan, Ke-Qiong Deng, Zhi-Li Jin, Wei Zhang, Jian-Lei Cao, Li-Hua Ni, Yong-Zhen Fan, Zhi-Bing Lu, Xiao-Rong Hu.
       Background: Mitochondrial quality control is essential for limiting myocardial injury induced by ischemia/reperfusion (I/R), a major contributor to adverse outcomes after reperfusion therapy. This study aimed to determine whether the deubiquitinase ubiquitin-specific protease 18 (USP18) regulates mitophagy during cardiac I/R injury and thereby represents a potential therapeutic target to attenuate myocardial I/R injury.
    Methods: Cardiac-specific USP18 knockout mice were subjected to cardiac I/R injury. To elucidate the role of USP18 in mitophagy regulation and cardiac I/R injury, we performed RNA sequencing, proteomic mass spectrometry, transmission electron microscopy, and mitophagy assays. In parallel, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of USP18, knockdown of Parkin and phosphatase and tensin homolog-long (PTEN-L), and administration of an anti-PTEN-L neutralizing antibody were used to elucidate the underlying mechanisms. Additionally, serum samples from patients with ST-segment elevation myocardial infarction (STEMI) were collected to assess clinical relevance.
    Results: USP18 expression was upregulated in mouse hearts following I/R injury and in ischemic human heart tissue. Cardiac-specific USP18 deficiency mitigated I/R-induced acute myocardial injury, mitochondrial dysfunction, and adverse cardiac remodeling, whereas USP18 overexpression exacerbated these pathological changes. Mechanistically, USP18 interacted with PTEN-L, which in turn bound to and inhibited the phosphorylation and translocation of Parkin to mitochondria, thereby suppressing mitophagy. Parkin knockdown abolished the cardioprotective effects conferred by USP18 deficiency, whereas PTEN-L knockdown reversed the detrimental effect of USP18 overexpression. Moreover, PTEN-L also exerted pathogenic effects via a paracrine mechanism, as neutralizing PTEN-L with an antibody attenuated cardiac I/R injury. Serum PTEN-L levels were elevated in STEMI patients, particularly postintervention.
    Conclusions: USP18 impairs mitophagy and exacerbates cardiac I/R injury through a PTEN-L-Parkin axis, involving both intracellular and paracrine mechanisms. Targeting the USP18-PTEN-L pathway may represent a novel therapeutic strategy to alleviate myocardial I/R injury.
    Keywords:  Mitophagy; Myocardial ischemia/reperfusion (I/R) injury; Parkin; Phosphatase and tensin homolog-long (PTEN-L); Ubiquitin-specific protease 18 (USP18)
    DOI:  https://doi.org/10.1016/j.mmr.2026.100004
  15. Neuropeptides. 2026 Mar 23. pii: S0143-4179(26)00027-2. [Epub ahead of print]117 102611
    Kisspeptin-10 attenuates pulmonary arterial hypertension via restoration of mitochondrial function in pulmonary artery smooth muscle cells.
    Sijia Huang, Zixuan Chen, Wanwei Gong, Yuxiao Song, Wenqin Ding, Lu Zhang, Jun Li.
      Mitochondrial dysfunction and dysregulated mitophagy in pulmonary artery smooth muscle cells (PASMCs) critically drive pulmonary arterial hypertension (PAH). Here we show that Kisspeptin-10, acting via its receptor GPR54, markedly attenuates PAH in the SU5416/hypoxia mouse model. The administration of kisspeptin-10 resulted in a considerable reduction in the systolic pressure of the right ventricle, as well as in the level of right ventricular hypertrophy and pulmonary vascular remodeling. Mechanistically, Kisspeptin-10 restored mitochondrial membrane potential, ATP production, and cytochrome c oxidase activity in hypoxic PASMCs and PAH lungs while normalizing excessive accumulation of the mitophagy proteins PINK1, Parkin, and FUNDC1. In vitro, Kisspeptin-10 directly inhibited hypoxia-induced PASMC proliferation. Therefore, Kisspeptin-10 is able to alleviate experimental PAH predominantly by recovering mitochondrial homeostasis and limiting aberrant mitophagy in PASMCs. This provides evidence that the Kisspeptin/GPR54 axis is a potential therapeutic target in PAH.
    Keywords:  Kisspeptin-10; Mitochondrial dysfunction; Mitophagy; Pulmonary arterial hypertension; Pulmonary artery smooth muscle cells
    DOI:  https://doi.org/10.1016/j.npep.2026.102611
  16. Redox Biol. 2025 Dec 20. pii: S2213-2317(25)00489-6. [Epub ahead of print]93 103976
    Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.
    Kai-Yang Chen, Hoi-Chun Chan, Wan-Wan Lin, Chi-Ming Chan.
      Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly and has a multifactorial etiology involving advanced age, genetic susceptibility, and environmental risk factors. Accumulating evidence suggests that mitochondrial dysfunction is a central pathogenic mechanism in AMD, particularly in the retinal pigment epithelium (RPE). The RPE is critical for retinal homeostasis, and its high metabolic activity renders it vulnerable to age-related mitochondrial dysfunction. In AMD, the core processes of mitochondrial dynamics-fission, fusion, biogenesis, and mitophagy-are profoundly dysregulated, leading to a fragmented and dysfunctional mitochondrial network. This failure of quality control results in bioenergetic deficits, excessive oxidative stress, and the release of damage-associated molecular patterns that fuel chronic inflammation and complement-mediated damage. Experimental models and human tissue studies have strengthened the link between mitochondrial dysfunction and AMD pathology, revealing structural abnormalities, mitochondrial DNA (mtDNA) damage, and altered metabolic signatures. Therapeutic strategies targeting mitochondrial pathways, including mitochondria-targeted antioxidants, dynamic modulators, and enhancers of biogenesis and mitophagy, such as agents that restore defective mitophagosome formation, represent promising avenues for intervention. As the field advances, the integration of biomarker development and personalized approaches holds the potential to transform the clinical landscape of AMD by addressing the root causes of cellular dysfunction.
    Keywords:  Age-related macular degeneration; Biogenesis; Fission; Fusion; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Retinal pigment epithelium
    DOI:  https://doi.org/10.1016/j.redox.2025.103976
  17. Stem Cells Int. 2026 ;2026 1581661
    Mitochondrial Dynamics Disorder Drives Nucleus Pulposus Cell Senescence in Lumbar Scoliosis of Aging Bipedal Rats Under Asymmetric Force.
    Ji Wang, Daigui Cao, Jing Peng, Xu Zhou, Zhiwei Liu, Xinxing Wang, Anwei Zhang, Kai Shen.
       Objective: The purpose of this study was to investigate the effect of mitochondrial dynamics disorder driving nucleus pulposus cell (NPC) senescence in lumbar scoliosis of aging bipedal rats under asymmetric force.
    Methods: A rat model of lumbar scoliosis with asymmetric force was established using nickel-titanium springs and anchorage screws. The condition of lumbar scoliosis was observed by X-ray. MicroCT was used for 3D reconstruction of the microporous structure of the lumbar endplates. Histopathological changes in the L4/5 intervertebral disc were observed using Hematoxylin and Eosin (H&E) staining and Safranin O-Fast Green staining. Immunohistochemical staining was used to observe the expression of IL-8, IL-6, MMP-3, and MMP-13 in the cells of the L4/5 intervertebral disc tissue. Western blot was performed to analyze the protein expression of p53, p21, p16, p-p65, NLRP3, mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), OPA1, and Fis1. The mitochondrial morphology in NPCs of the L4/5 intervertebral disc was observed by transmission electron microscopy (TEM). The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and adenosine triphosphate (ATP) in the nucleus pulposus tissue of lumbar scoliosis were measured using commercial assay kits. Reactive oxygen species (ROS) content in the nucleus pulposus tissue was quantified by flow cytometry.
    Results: X-ray and MicroCT-3D revealed that rats in the asymmetric group exhibited significant scoliosis deformity, accompanied by marked reductions in bone mineral density (BMD), tissue mineral density (TMD), bone volume fraction (BV/TV), and trabecular thickness (Tb.Th). H&E staining and Safranin O-Fast Green staining demonstrated that asymmetric force significantly exacerbated pathological changes in the intervertebral disc, particularly damage to the cartilage endplate, chondrocyte necrosis, and hyperplasia. Immunohistochemical results indicated a significant increase in the positive expression of IL-8, IL-6, MMP-3, and MMP-13 in the asymmetric group, suggesting a synergistic effect of aging and asymmetric force in amplifying inflammatory responses and matrix degradation. Western blot analysis showed that the expression of senescence-associated proteins (p53, p21, and p16) and inflammation-related proteins (p-p65, NLRP3) was significantly upregulated in the asymmetric group, indicating that asymmetric force accelerated the senescence of NPCs and activated inflammatory pathways. TEM revealed that asymmetric force markedly aggravated mitochondrial swelling and structural damage in the L4/5 intervertebral disc, with the most severe mitochondrial injury observed in the 48-week asymmetric group. Western blot further demonstrated that the expression of mitochondrial fusion proteins (Mfn2, OPA1) was significantly decreased, while mitochondrial fission proteins (Drp1, Fis1) were significantly increased in the asymmetric group, indicating disrupted mitochondrial fission-fusion balance. Additionally, the asymmetric loading group exhibited significantly reduced SOD activity and ATP levels, along with elevated MDA content, suggesting oxidative stress-induced mitochondrial dysfunction. Flow cytometry results confirmed a significant increase in ROS levels in the asymmetric group, highlighting that asymmetric force intensified oxidative stress in the nucleus pulposus tissue, and this effect was further exacerbated with aging.
    Conclusion: Asymmetric force drives the NPC senescence by disrupting mitochondrial fission-fusion balance, triggering oxidative stress and inflammatory responses, ultimately leading to the progression of degenerative lumbar scoliosis. This pathological cascade is significantly exacerbated in the context of aging.
    Keywords:  asymmetric force; degenerative lumbar scoliosis; mitochondrial dynamics; nucleus pulposus cell senescence
    DOI:  https://doi.org/10.1155/sci/1581661
  18. Apoptosis. 2026 Apr 07. pii: 121. [Epub ahead of print]31(4):
    SIRT1-regulated mitophagy mitigates lipotoxicity-induced ferroptosis in diabetic kidney disease.
    Yingchun Jian, Yongqin Zeng, Zhengdi Wang, Xingyan Zhou, Haiping Zhang, Dan Liang, Rui Yan.
      Diabetic kidney disease (DKD) is characterized by renal lipid deposition, andlipotoxicity-induced ferroptosis plays a pivotal role in its progression. This study aimed to elucidate the regulatory mechanism of silent information regulator 1 (SIRT1) in lipotoxicity-induced ferroptosis in DKD using clinical samples, animal models, and cellular experiments. Renal tissues from DKD patients and non-diabetic controls were collected for pathological and molecular analyses. DKD mouse model was established by combining a high-fat diet (HFD) with streptozotocin (STZ) injection. Human renal proximal tubular epithelial cells (HK-2) were exposed to palmitic acid/high glucose (PA/HG) to mimic lipotoxic sress. SIRT1 overexpression or knockdown was achieved using lentiviral vectors. Mitophagy was evaluated by Western blot, qPCR, and immunohistochemistry (IHC), and transmission electron microscopy (TEM), focusing on the expression of PINK1, Parkin, LC3B, and P62. Ferroptosis was assessed by detecting the expression of glutathione peroxidase 4 (GPX4), xCT, Ferritin, as well as the levels of malondialdehyde (MDA), and reactive oxygen species (ROS), alongside TEM observations of ferroptotic mitochondrial alterations. The mitophagy inhibitor Mdivi-1 and ferroptosis inhibitor Ferrostatin-1 (Fer-1) were used for mechanistic validation. In renal tubules of DKD patients and HFD/STZ-induced DKD mice, lipid droplet membrane protein (Perilipin-2) expression and lipid deposition were markedly elevated, while SIRT1 expression was significantly reduced and negatively correlated with lipid deposition (P < 0.05). PA/HG treated HK-2 cells reproduced these features. SIRT1 deficiency impaired mitophagy, as evidenced by reduced expression of PINK1, Parkin, and LC3B, increased P62 levels (P < 0.05), and TEM revealed mitochondrial swelling with decreased autophagosomes. Furthermore, SIRT1 knockdown exacerbated ferroptosis, characterized by reduced GPX4, xCT, and Ferritin expression, increased MDA and ROS levels (P < 0.05), and mitochondrial pyknosis with loss of cristae. Conversely, SIRT1 overexpression restored mitophagy activity and alleviated ferroptosis (P < 0.05). The protective effect of SIRT1 overexpression against PA-induced ferroptosis was abolished by Mdivi-1, while Fer-1 partially rescued SIRT1 downregulation-induced renal fibrosis (P < 0.05). SIRT1 attenuates lipotoxicity-induced ferroptosis in renal tubular epithelial cells by promoting mitophagy, thereby mitigating DKD progression. These findings suggest that SIRT1-mediated mitophagy may represent a potential therapeutic target for DKD.
    Keywords:  Diabetic kidney disease; Ferroptosis; Lipotoxicity; Mitophagy; SIRT1
    DOI:  https://doi.org/10.1007/s10495-026-02267-5
  19. Cell Biochem Funct. 2026 Apr;44(4): e70211
    High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.
    Liying Tang, Xiuting Huang, Pei Li.
      Chronic hyperglycemia accelerates immune aging and contributes to diabetic complications, yet the mitochondrial mechanisms responsible for macrophage senescence remain unclear. In this study, both cultured and primary macrophages were treated with high glucose to model hyperglycemic conditions. High glucose significantly increased markers of macrophage senescence, including SA-β-Gal staining, expression of p16 and p21, and secretion of pro-inflammatory cytokines. Mitochondrial dysfunction was evident, as shown by loss of mitochondrial membrane potential (ΔΨm) and elevated mitochondrial reactive oxygen species (mtROS). In addition, mitophagy was impaired, with PINK1 accumulation and reduced Parkin recruitment. Rescue experiments demonstrated that treatment with the mitochondria-targeted antioxidant MitoTempo, the general antioxidant N-acetylcysteine, or the anti-diabetic drug metformin effectively restored mitochondrial function and alleviated senescence. These findings indicate that mitochondrial dysfunction and impaired mitophagy are central to high glucose-induced macrophage senescence, and that targeting mitochondrial oxidative stress with antioxidants or metformin may offer a promising strategy to mitigate immune aging and inflammation associated with metabolic disorders.
    Keywords:  high glucose; inflammation; macrophage; mitophagy; senescence
    DOI:  https://doi.org/10.1002/cbf.70211
  20. Pak J Pharm Sci. 2026 Jun;39(6): 1645-1654
    Platycodin D alleviates myocardial ischemia-reperfusion injury by suppressing aberrant mitophagy.
    Jiang Li, Chengyang Xu.
       BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury represents a critical complication in cardiovascular diseases, profoundly influencing patient prognosis.
    OBJECTIVES: This study endeavors to elucidate the protective mechanisms and effects of Platycodin-D (PD) on myocardial ischemia-reperfusion injury (MIRI).
    METHODS: A rat model of myocardial ischemia-reperfusion was employed to assess the impact of PD treatment on cardiac performance, myocardial injury biomarkers (CK-MB, LDH, cTnI), and infarct size. Further mechanistic insights were gained through Western blot and JC-1 staining, which analyzed the modulation of the HIF-1α/BNIP3 signaling pathway and mitochondrial autophagy by PD.
    RESULTS: PD treatment markedly improved cardiac function, decreased levels of myocardial injury biomarkers (CK-MB, LDH, cTnI), and reduced infarct size. Mechanistically, PD was found to regulate the HIF-1α/BNIP3 signaling pathway, inhibit mitochondrial autophagy, and enhance mitochondrial function. Western blot and JC-1 staining confirmed that PD increases mitochondrial membrane potential and reduces the number of damaged mitochondria in cardiomyocytes.
    CONCLUSIONS: This study underscores the significant protective effects of Platycodin-D against myocardial ischemia-reperfusion injury, presenting a promising therapeutic approach for cardiovascular disease management.
    Keywords:   MIRI ; Acute myocardial infarction ; Mitophagy ; Myocardial ischemia-reperfusion injury ; Platycodin D
    DOI:  https://doi.org/10.36721/PJPS.2026.39.6.156.1
  21. Int Immunopharmacol. 2026 Apr 04. pii: S1567-5769(26)00410-8. [Epub ahead of print]179 116565
    Bergapten ameliorates osteoarthritis progression by inhibiting the PI3K/AKT/mTOR pathway to activate mitophagy and suppress pyroptosis.
    Xiangxiang Huang, Jialuo Zhang, Nuo Chen, Binquan Huang, Yan Zhao, Chenggong Zhu, Shuliang Zhang, Jiarui Xia, Lingzhou Zhang, Lei Liu, Xiaoyong Lin.
      Osteoarthritis (OA) is a frequently occurring degenerative joint condition involving progressive loss of cartilage integrity accompanied by prolonged inflammatory activity within the joint. Current therapies mainly alleviate symptoms without halting disease progression. This study was designed to assess the pharmacological efficacy of bergapten (BeG), a naturally derived furanocoumarin, in osteoarthritis and to clarify its molecular mechanisms of action. In IL-1β-stimulated mouse primary chondrocytes, BeG treatment significantly inhibited extracellular matrix degradation, suppressed the expression of inflammatory mediators (IL-1β, IL-6, COX-2, iNOS) and reduced NLRP3 inflammasome activation and pyroptosis-related markers (GSDMD-NT, cleaved caspase-1). BeG also restored mitochondrial function, enhanced PINK1/Parkin-mediated mitophagy, and downregulated the PI3K/AKT/mTOR pathway. Pharmacological inhibition of mitophagy (Mdivi-1) or activation of PI3K (740Y-P) abolished these protective effects. In a murine destabilization of the medial meniscus (DMM) model, intra-articular administration of BeG attenuated cartilage destruction, reduced osteophyte formation, and lowered OARSI scores, accompanied by enhanced mitophagy and suppressed pyroptosis in joint tissues. Collectively, our findings demonstrate that BeG mitigates OA progression by inhibiting the PI3K/AKT/mTOR pathway, promoting mitophagy, and subsequently suppressing NLRP3-mediated pyroptosis, underscoring its promise as a disease-modifying osteoarthritis therapeutic.
    Keywords:  Bergapten; Mitophagy; OA; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2026.116565
  22. Acta Pharmacol Sin. 2026 Apr 09.
    ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.
    Xiao-Ou Hou, Miao Wang, Rong Deng, Yi-Fan Lu, Jin-Ru Zhang, Li Ren, Jing Chen, Chun-Feng Liu, Ya-Ping Yang, Li-Fang Hu.
      Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release H2S compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of H2S. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation.
    Keywords:  ADT-OH; Parkinson’s disease; cGAS-STING; microglia; mitochondrial DNA; mitophagy
    DOI:  https://doi.org/10.1038/s41401-026-01789-7
  23. Circ Res. 2026 Apr 10. 138(8): e326985
    Two Routes for Removing Unhealthy Mitochondria: Degradation and Secretion.
    Xi Fang, Åsa B Gustafsson.
      Mitochondria are highly dynamic, double-membraned organelles that generate the majority of ATP in cardiomyocytes while supporting cellular homeostasis and signal transduction. Accumulation of dysfunctional mitochondria can promote cardiomyocyte loss, impair contractile function, and ultimately lead to myocardial damage. To preserve mitochondrial integrity, cardiomyocytes rely on multilayered quality control mechanisms to remove defective mitochondria. Two major routes have emerged for this process: degradation, primarily via autophagy, and secretion via extracellular vesicles. This review summarizes the mechanisms of mitochondrial degradation and secretion in the heart and highlights their contributions to cardiac disease progression and potential as therapeutic targets.
    Keywords:  extracellular vesicles; homeostasis; mitochondria; mitophagy; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326985
  24. J Cell Biol. 2026 Jun 01. pii: e202508040. [Epub ahead of print]225(6):
    PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization.
    Shan Zhao, Jie Zhang, Tengfei Ma, Jinglin Li, Mei Duan, Xin Wang, Meijiao Li, Chonglin Yang.
      Mitochondria form highly complex and dynamic networks to maintain their homeostasis. However, the underlying mechanisms remain elusive. Here we report a PI(3)P-dependent mechanism that regulates the mitochondrial dynamics required for formation of mitochondrial networks. Using genetic screening, we reveal that mutations of Caenorhabditis elegans EXC-5/FGD lead to formation of spherical and unconnected mitochondria. EXC-5 binds to endosomal PI(3)P generated by the PI 3-kinase VPS-34 and is recruited to endosome-mitochondrion contacts, where it acts as the guanine nucleotide exchange factor to activate the CDC-42 GTPase. Loss of exc-5 or vps-34 similarly disrupts mitochondrial and actin networks as well as mitochondrial recruitment of DRP-1, leading to failure of mitochondrial fission, branching, and elongation. In contrast, expression of constitutively activated CDC-42 ameliorates the defective mitochondrial networks in an actin-dependent manner. Together, these findings suggest a PI(3)P-EXC-5-CDC-42 axis that acts at endosome-mitochondrion contacts to regulate actin organization for maintenance of mitochondrial dynamics and networks.
    DOI:  https://doi.org/10.1083/jcb.202508040
  25. Andrology. 2026 Apr 10.
    USP2 Attenuates Spermatogenic Cell Apoptosis Via PINK1/Parkin-Dependent Mitophagy in Varicocoele: A Functional Study.
    Rui-Jie Yao, Hong Xiao, Jun-Hang Zheng, Bin Lin, Shi-Jie Liao, Hao-Han He, Ning Xu, Hui-Liang Zhou.
       BACKGROUND: Varicocoele is a major cause of male infertility, yet its underlying molecular mechanisms and determinants of surgical efficacy remain unclear.
    OBJECTIVE: This study aimed to identify key proteins involved in varicocoele-related infertility and to investigate the expression and functional role of ubiquitin-specific peptidase 2 in spermatozoa and spermatogenic cells.
    METHODS: Ubiquitin-specific peptidase 2 expression in spermatozoa from varicocoele patients was analyzed before and after varicocelectomy by Western blotting. In vitro, ubiquitin-specific peptidase 2 was overexpressed or silenced in mouse GC-2 spermatocyte cells to assess mitochondrial autophagy (PINK1/Parkin pathway), autophagic flux, apoptosis, and reactive oxygen species. In vivo, a left-sided varicocoele rat model was established, and ubiquitin-specific peptidase 2 activity was inhibited by intratesticular injection of ML364. Testicular histopathology and sperm motility were evaluated.
    RESULTS: Ubiquitin-specific peptidase 2 protein expression was significantly reduced in spermatozoa after varicocelectomy. Ubiquitin-specific peptidase 2 overexpression enhanced PINK1/Parkin-mediated mitochondrial autophagy and protected spermatogenic cells from apoptosis, whereas ubiquitin-specific peptidase 2 knockdown impaired mitochondrial autophagy and increased cell apoptosis. In varicocoele rats, ubiquitin-specific peptidase 2 inhibition aggravated seminiferous tubule damage, reduced spermatogenic cell density, and impaired sperm motility. In human spermatozoa, ML364 treatment significantly decreased progressive motility without affecting sperm concentration.
    CONCLUSION: Ubiquitin-specific peptidase 2 is essential for maintaining mitochondrial quality control and spermatogenic cell survival in varicocoele by regulating PINK1/Parkin-mediated autophagy and oxidative stress, highlighting its potential as a biomarker and therapeutic target for varicocoele-related male infertility.
    Keywords:  mitochondrial autophagy; oxidative stress; spermatogenesis; ubiquitin‐specific peptidase 2; varicocoele
    DOI:  https://doi.org/10.1111/andr.70230
  26. Biochemistry. 2026 Apr 06.
    Mitochondrial Ubiquitination as a Signaling Hub: Balancing Mitophagy, Inflammation, and Cell Death.
    Ashwini Kumar, Emmanouil Zacharioudakis.
      Mitochondria are increasingly recognized as signaling organelles that coordinate cell-fate decisions during stress. Because outer mitochondrial membrane (OMM) proteins are exposed to the cytosol, they are prominent substrates for ubiquitination, a dynamic post-translational modification that encodes information through diverse chain architectures and linkage types. In this review, we examine how ubiquitination of OMM proteins functions as a molecular switch that integrates mitochondrial stress signals and engages three major, often antagonistic, stress-response mechanisms: mitophagy, cell death, and innate immune signaling. We highlight an emerging concept that a stress-responsive "ubiquitin code" is written on OMM substrates, in which pathway selection is coordinated by the identity of ubiquitinated OMM proteins together with the linkage type and branching of attached polyubiquitin chains. We provide an updated overview of the E3 ubiquitin ligases and deubiquitinases (DUBs) that write and erase this code and summarize ubiquitin linkage types reported on key OMM substrates across these pathways. For mitophagy, we cover both PARKIN-dependent and PARKIN-independent mechanisms mediated by other E3 ligases and counteracted by DUBs. For innate immunity, we discuss how ubiquitination of OMM proteins regulates the MDA5/RIG-I-MAVS axis and NF-κB signaling. For cell death, we describe how ubiquitination of anti- and pro-apoptotic BCL-2 family proteins can either lower or increase the threshold for the induction of apoptosis. We also highlight the newfound role of PARKIN to drive apoptosis through a BAX/BAK-independent mechanism. Finally, we discuss therapeutic opportunities to reprogram OMM ubiquitination by targeting E3 ligases or DUBs directly, or by using PROTAC- and DUBTAC-based strategies.
    Keywords:  E3 ubiquitin ligases; apoptosis; deubiquitinases; innate immune signaling; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1021/acs.biochem.6c00007
  27. Trends Cell Biol. 2026 Apr 03. pii: S0962-8924(26)00037-1. [Epub ahead of print]
    Targeting mitochondrial dynamics against cancer.
    Yu-Lu Cao, Chao-Pin Yang, Birong Shen, Junjie Hu, Song Gao.
      Although cancer treatment has improved, many patients exhibit limited responses due to the intrinsic heterogeneity and adaptability of tumors, coupled with immunosuppressive conditions in the tumor microenvironment (TME). Mitochondrial dynamics, characterized by continuous fusion and fission, influences cellular processes such as metabolism, cell cycle, cell death, and stemness, thereby profoundly shaping tumor cell evolution and TME plasticity. In this review, we summarize recent advances regarding the roles of mitochondrial dynamics in cancer biology and discuss how it regulates the behavior of both tumor cells and tumor-associated immune cells in the TME. We propose that targeting mitochondrial dynamics represents a dual therapeutic strategy that disrupts core oncogenic programs while potentiating antitumor immunity, offering a promising direction for future cancer treatment.
    Keywords:  TME; immunotherapy; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.006
  28. Mol Cell Endocrinol. 2026 Apr 08. pii: S0303-7207(26)00081-X. [Epub ahead of print] 112804
    Glucose deprivation impairs lipid tolerance related to mitophagy disorder in cardiomyocytes.
    Lishan Huang, Cuihua Huang, Zhiwen Xiao, Xin Chen, Menglan Zhan, Shuang Yao, Shuaijun Zhu, Zhou Chen, Libin Liu.
      Severe hypoglycemia (SH) is associated with adverse cardiac outcomes in individuals with diabetes; however, the underlying mechanisms remain poorly understood. Our previous study demonstrated that the myocardium of diabetic mice, characterized by hyperglycemia and hyperlipidemia, exhibited greater susceptibility to SH than that of non-diabetic mice. This study aimed to investigate the effects of glucose deprivation on cardiomyocytes pretreated with high glucose and lipids. The results indicated that brief exposure to high glucose and lipid levels maintained cardiomyocyte viability and enhanced PTEN-induced kinase 1 (PINK1)/Parkin-related mitophagy. However, glucose deprivation following high glucose and lipid treatment significantly increased cardiomyocyte susceptibility to injury compared with glucose deprivation after high glucose treatment alone. This was evidenced by reduced cell viability, increased apoptosis, and mitochondrial dysfunction-characterized by disrupted mitochondrial structure, depolarization, decreased adenosine triphosphate production, and impaired PINK1/Parkin-related mitophagy in the cells. These adverse effects were reversed by treatment with the mitophagy activator urolithin A. Our findings suggest that glucose plays a critical role in maintaining lipid tolerance via mitophagy in cardiomyocytes, a mechanism that may contribute to the pathogenesis of SH-induced myocardial injury.
    Keywords:  Diabetes; Glucose metabolism; Hypoglycemia; Lipid metabolism; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.mce.2026.112804
  29. Autophagy. 2026 Apr 08.
    In situ architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
    Yufei Huang, Tianyu Zheng, Xiaofeng Sun, Ruoxi Wang, Shujun Cai.
      Selective mitochondrial clearance by autophagy (mitophagy) is essential for development and cellular homeostasis. However, how phagophores acquire sufficient membrane to engulf large mitochondria remains poorly understood. Here, we studied the in situ architecture of forming mitophagosomes in the developing Drosophila intestine by combining cryo-electron tomography (cryo-ET), serialized on-grid lift-in sectioning for tomography (SOLIST), cryo-focused ion beam (cryo-FIB) milling, and volume electron microscopy. Our data reveal that the endoplasmic reticulum (ER) forms continuous membrane connections with the phagophore during mitophagosome formation. In Vps13D mutant enterocytes, stalled mitochondrial phagophore membrane expansion is associated with an accumulation of persistent ER-phagophore membrane continuities. Together, our findings support a model in which the ER can establish direct membrane continuity with the phagophore to facilitate rapid mitophagosome formation. AbbreviationAPF: after puparium formation; BLTP: bridge-like lipid transfer protein; CCS: cleaning cross-section; cryo-ET: cryo-electron tomography; cryo-FIB: cryo-focused ion beam; CTF: contrast transfer function; ER: endoplasmic reticulum; HPF: high-pressure freezing; mitolysosome: autolysosome containing a mitochondrion; mitophagophore: mitochondrial phagophore; mitophagy: selective mitochondrial clearance by autophagy; NGS: normal goat serum; OMM: outer mitochondrial membrane; OsO4: osmium tetroxide; PB: phosphate buffer; PBSTx: PBS containing 0.3% (w:t) Triton X-100; RCS: regular cross-section; RT: room temperature; RT-FIB-SEM: room-temperature focused ion beam scanning electron microscopy; SOLIST: serialized on-grid lift-in sectioning for tomography; TLD: Through-the-Lens Detector.
    Keywords:  Cryo-ET; Cryo-FIB; Drosophila; Vps13D; mitochondria; mitophagy; serial cryo-lift-out
    DOI:  https://doi.org/10.1080/15548627.2026.2657543
  30. J Appl Toxicol. 2026 Apr 09.
    Vps34 Knockdown Alleviated the Long-Term Effect of Nano-Alumina on Cognitive Impairment in Zebrafish When in Embryos.
    Ying Zhang, Jinjin Zhao, Tao Huang, Xiaocheng Gao, Lan Zhang, Yanhong Wang, Xinyue Guo, Ling Zhang, Qiao Niu, Qinli Zhang.
      Nano-alumina (AlNPs) exposure induced learning and memory impairment, which was associated with over-activation of mitophagy. Our previous study found that reduction of Vacuolar Protein Sorting 34 (Vps34), a core initiating gene for autophagy, alleviated AlNPs-exposed neurodevelopmental toxicity, so we hypothesized that Vps34 knockdown may mitigate the damage to learning and memory induced by AlNPs. This study aimed to investigate the effects and mechanisms of Vps34 knockdown on the long-term cognitive impairment of AlNPs in the zebrafish brain. A 500 μL of morpholino oligonucleotide at 1 mmol/L was microinjected into embryos within 1 h postfertilization (hpf). These embryos and control embryos were randomly assigned to control, negative control, Vps34 knockdown, AlNPs exposure (100 mg/L), and AlNPs exposure with Vps34 knockdown up to 144 hpf. After zebrafish were given to brine shrimp and E3 medium up to 6 months, their locomotor activity and cognitive behavior were assessed. Meanwhile, we investigated brain structure, oxidative stress, mitochondria, and mitophagy. Our results indicated that AlNPs exposure with Vps34 knockdown significantly enhanced the average speed, moving distance, time spent in the outer zone, and cumulative time in the T-maze while decreasing latency in the T-maze compared with the AlNPs-exposed group. Moreover, AlNPs exposure with Vps34 knockdown increased the number of neurons while lowering the mitophagosome in the brain compared with exposure to AlNPs. Then, AlNPs exposure with Vps34 knockdown enhanced higher activities of superoxide dismutase (SOD), Na+-K+ATPase and Ca2+-Mg2+ATPase, and levels of mitochondrial membrane potential (MMP) and translocase of outer mitochondrial membrane 20 (TOMM20) protein, while decreasing activities of reactive oxygen species (ROS) and lactate dehydrogenase (LDH), and levels of microtubule-associated protein 1 light chain 3 (LC3II) and translation of the inner member (TIM23) protein compared with AlNPs exposure. At last, AlNPs exposure significantly increased the abundances of the Vps34 and PTEN-induced putative kinase 1 (PINK1) mRNA in the brain compared with the control and AlNPs exposure with Vps34 knockdown groups. Therefore, inhibiting Vps34 protected against the cognitive impairment caused by AlNPs exposure by reducing mitophagy and restoring mitochondrial structure and function.
    Keywords:   Danio rerio ; Vps34 ; cognition; mitophagy; nano‐alumina
    DOI:  https://doi.org/10.1002/jat.70186
  31. Autophagy. 2026 Apr 11. 1-20
    African swine fever virus pE199L, as a mitophagy receptor, suppresses antiviral innate immunity to promote viral replication.
    Xiaoxuan Li, Binbin Ren, Danyang Zhang, Miao Dan, Dongying Liu, Ziwei Zhang, Jiakai Zhao, Yuchen Nan, Julian A Hiscox, James P Stewart, Zixiang Zhu, Qin Zhao, Yani Sun.
      The African swine fever virus (ASFV) employs sophisticated strategies to promote viral replication in the host; however, the underlying mechanisms remain incompletely understood. Here, we demonstrated that the ASFV encoded pE199L protein acts as a potential mitophagy receptor that disrupted innate immunity through structural mimicry. The pE199L protein localized to mitochondria via its C terminal hydrophobic domain (155-199 aa) and induced mitochondrial fission by promoting DNM1L/Drp1 phosphorylation. Importantly, pE199L contained three LC3-interacting regions (LIRs: W35-I38, F157-L160, F193-L196) that directed autophagic degradation of key immune adaptors. Specifically, pE199L mediated mitophagic clearance of TBK1 (the CGAS-STING1 pathway) and MAVS (the RLR-MAVS pathway), thereby inhibiting type I interferon production and enhancing viral replication. This dual degradation mechanism was confirmed through rescue experiments using autophagy inhibitors and functional assays with LIR mutants. We identifted pE199L as the first canonical mitophagy receptor encoded by ASFV, unveiling a novel immune evasion strategy and a potential target for antiviral vaccine development.Abbreviations: 3-MA: 3-methyladenine; aa: amino acid; ASFV: African swine fever virus; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM1L/Drp1: dynamin 1 like; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; hpi: hour post-infection; IFN: interferon; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MT-CO2/COXII: mitochondrially encoded cytochrome c oxidase II; PINK1: PTEN induced kinase 1; poly(dA:dT): poly(deoxyadenylic-thymidylic) acid; poly(I:C): polyinosinic-polycytidylic acid; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type.
    Keywords:  African swine fever virus; LC3; innate immunity; mitophagy; pE199L
    DOI:  https://doi.org/10.1080/15548627.2026.2654982
  32. Photodermatol Photoimmunol Photomed. 2026 May;42(3): e70089
    Interplay of Skin Aging: Mitochondrial Stress and Ultraviolet Exposure.
    Wanxing Liao, Yihao Wang, Yiping Wang, Junlin Liao, Nian Chen, Chiyu Jia, Li Zeng.
       BACKGROUND: Skin photoaging, clinically characterized by wrinkles and hyperpigmentation, accounts for 80% of extrinsic aging. Chronic UV exposure drives this process via oxidative damage. However, its synergistic axis with mitochondrial dysfunction remains mechanistically elusive. This study aims to elucidate the mechanistic link between mitochondrial oxidative stress and UV-induced photoaging, focusing on reactive oxygen species overproduction as a central driver of cellular decline.
    METHODS: Through integrative analysis of molecular pathways and experimental validation, we investigated mitochondrial dysfunction, ROS accumulation, and UV-induced damage in skin cells. Therapeutic interventions, including mitochondrial-targeted antioxidants (e.g., MitoQ) and protective agents, were tested to assess their efficacy in restoring mitochondrial integrity and mitigating oxidative stress.
    RESULTS: UV radiation exacerbates mitochondrial dysfunction by inducing ROS overproduction, mtDNA mutations and membrane permeability alterations, creating a vicious cycle that accelerates skin aging. Conversely, mitochondrial oxidative stress amplifies UV-induced damage, promoting collagen degradation and apoptosis. Interventions targeting mitochondrial function, such as MitoQ and mesenchymal stem cell-derived exosomes, significantly reduced ROS levels, preserved membrane potential, and enhanced skin resilience. Notably, PINK1/Parkin-mediated mitophagy and STAT3/p53 pathways were identified as critical regulators of mitochondrial homeostasis during photoaging.
    CONCLUSION: This study clarifies the bidirectional relationship between mitochondrial stress and photoaging, highlighting ROS as a pivotal mediator. Restoring mitochondrial function via antioxidants or mitophagy enhancers offers actionable strategies to delay skin aging. These findings provide a foundation for novel anti-aging therapies with potential clinical and cosmetic applications.
    Keywords:  ROS; mitochondrial; photoaging; skin aging
    DOI:  https://doi.org/10.1111/phpp.70089
  33. Biochim Biophys Acta Mol Basis Dis. 2026 Apr 06. pii: S0925-4439(26)00118-3. [Epub ahead of print]1872(6): 168255
    Targeting GHSR-1α with silibinin to enhance mitophagy and prevent tubular injury in diabetic kidney disease.
    Nannan Zhang, Chao Chen, Lin Chen, Yuqiong Chen, Peiran Yu, Hao Yu, Bimin Shi, Bin Feng.
      Diabetic kidney disease (DKD) remains a leading cause of global renal failure, with tubular injury driven by mitochondrial dysfunction representing a critical yet therapeutically unaddressed mechanism. Although the flavonolignan silibinin has demonstrated renoprotective potential, its precise molecular targets and mechanisms in DKD have remained unclear. In this study, we combined integrated computational docking, biophysical assays, and comprehensive in vivo and in vitro models to investigate silibinin's interaction with the growth hormone secretagogue receptor-1α (GHSR-1α). We demonstrated that silibinin directly binds to and activates GHSR-1α, triggering a signaling cascade characterized by liver kinase B1 (LKB1) phosphorylation, nuclear export, and complex formation with mouse protein 25 (MO25). This interaction leads to sustained AMP-activated protein kinase (AMPK) activation, which in turn restores mitophagy and alleviates oxidative stress, inflammation, and apoptosis in renal tubular cells. Crucially, these protective effects were abolished by the genetic or pharmacological inhibition of GHSR-1α. Collectively, these findings establish that silibinin mitigates DKD-associated tubular injury by activating the GHSR-1α/LKB1/AMPK axis to promote mitochondrial quality control.
    Keywords:  Diabetic kidney disease; GHSR-1α; LKB1; Mitophagy; Silibinin
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168255
  34. Inflamm Res. 2026 Apr 10. pii: 89. [Epub ahead of print]75(1):
    Suppression of Nr1d1/Bnip3-dependent mitophagy by notch signaling aggravates inflammatory response in RSV-infected mice lungs.
    Yuxi Lei, Zhi Liu, Hui Du, Ruiyu Zhang, Huizhi Hu, Pu Yang, Junwen Zheng, Dongchi Zhao.
       BACKGROUND: Alveolar macrophages (AMs) are crucial for defending against respiratory syncytial virus (RSV) and regulating lung inflammation. Notch signaling is essential for macrophage polarization and its functional diversity.However, the role of macrophages Notch1 in RSV-induced lung injury and its underlying mechanisms remain incompletely understood.
    METHODS: This study used macrophage-specific Notch1 knockout (MKO) mice to investigate the lung lesions and inflammation in RSV-infected mice. The effects of various interventions, including JAG1, Nr1d1 inhibitor, and Bnip3 gene manipulation, were assessed in RSV-infected mice. Western blot (WB) was used to measure the expression of inflammasome-related proteins, such as NLR family, pyrin domain containing 3 (Nlrp3), Asc, Cleaved-caspase1, and nuclear receptor subfamily 1, group D, member 1 (Nr1d1), BCL2/adenovirus E1B 19 kDa interacting protein 3 ‌(Bnip3) in lung or macrophages. Additionally, RNA sequencing (RNA-seq) of macrophages from RSV-infected mice was performed to identify differential gene expression between MKO and wild-type (Flox) mice. Confocal microscopy visualized the localization of autophagy complexes in cellular mitochondria. ELISA assays measured LDH, IL-1β and IL-18 levels in bronchoalveolar lavage fluid (BALF).
    RESULTS: Compared to Flox mice, MKO mice showed milder lung lesions, increased Nr1d1 and Bnip3 expression, and decreased Nlrp3 inflammasome activity in RSV-exposed mice. Moreover, Nr1d1 inhibitor reduced Bnip3 expression, increased IL-1β and IL-18 release, and exacerbated pulmonary inflammation. Inhibiting Bnip3 exacerbated RSV-induced lung injury by enhancing Nlrp3 inflammasome activity and impairing mitophagy.
    CONCLUSION: These results suggest that Notch signaling regulates Nr1d1/Bnip3-induced mitophagy, influencing the Nlrp3 inflammasome and the inflammatory response during RSV infection.
    Keywords:  Macrophages; Mitophagy; Notch; Nr1d1/Bnip3; Respiratory syncytial virus
    DOI:  https://doi.org/10.1007/s00011-026-02235-4
  35. Pharmacol Res. 2026 Apr 07. pii: S1043-6618(26)00103-9. [Epub ahead of print] 108188
    Mitochondrial Quality Control as a Central Pharmacological Target in Aging.
    Kuan-Hao Tsui, Shih-Hsuan Cheng, Boyang Wang, Pei-Hsuan Lin, Emmanuel Naveen Raj, Li-Te Lin, Renin Chang, Zhi-Hong Wen, Andy P Tsai, Chia-Jung Li.
      Mitochondrial dysfunction is a convergent hallmark of biological aging and a mechanistically attractive target for gerotherapeutic development. Yet translation of mitochondria-focused interventions has been limited by pathway complexity, tissue heterogeneity, and insufficiently harmonized endpoints. This review synthesizes recent original evidence through a unifying mitochondrial quality control (MQC) framework comprising four interdependent modules: removal (mitophagy and mitochondrial-derived vesicles), repair (mitochondrial proteostasis and UPRmt/ISR signaling), remodeling (fission-fusion control and cristae architecture), and renewal (biogenesis coupled to turnover). We map druggable nodes across these modules and organize therapeutic efforts into five pharmacological classes: autophagy/mitophagy enhancers (including pathway-brake inhibitors and emerging mitophagy-targeting chimeras), NAD+/sirtuin-AMPK-mTOR axis modulators, mitochondria-targeted redox modulators, cristae/mPTP/cardiolipin-directed stabilizers, and mitochondria-targeted delivery platforms. Drawing on recent human studies and late-stage mitochondrial therapeutic programs, we highlight practical lessons on dosing schedules, baseline vulnerability, and the importance of pairing molecular engagement with performance endpoints. We then outline a translational strategy that prioritizes flux-aware readouts and triangulates mechanism with function using in vivo bioenergetics (31P-MRS), blood-based cellular respiration (PBMC/platelet assays and composite indices), and circulating stress/damage signals (cell-free mtDNA species and mitokines). Finally, we discuss key bottlenecks including tissue selective exposure, long term safety for maintenance therapies, and inconsistency in clinical endpoints, and we propose actionable directions such as biomarker guided precision geroscience, intermittent or sequential combination strategies that balance clearance with renewal, and next generation chemical biology approaches to improve target specificity. Collectively, this framework seeks to accelerate the development of pharmacotherapies targeting mitochondrial quality control with clinically interpretable endpoints in aging.
    Keywords:  Aging; Metabolism; Mitochondrial quality control; Mitophagy; Translational biomarkers
    DOI:  https://doi.org/10.1016/j.phrs.2026.108188
  36. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2510914123
    Microvesicle release drives cycles of mitophagy flux disruption and inflammatory amplification in sepsis-induced myocardial dysfunction.
    Rui Song, Yinrui Ma, Junfang Wan, Shuai Hao, Bing Chen, Yichen Liao, Yingjiao Liao, Yuzhou Xiao, Xi Zhang, Zhaocai Zhang, Shuang Ren, Xuxin Tan, Jiahe Tan, He Huang, Milad Ashrafizadeh, Gautam Sethi, João Conde, Liangming Liu, Chenyang Duan.
      Sepsis-induced myocardial dysfunction strongly contributes to high mortality in patients with sepsis by exacerbating systemic organ failure; however, the onset and molecular mechanisms driving this vicious cycle remain unclear. Here, we revealed that DRP1-mediated mitochondrial fission and excessive reactive oxygen species (ROS) accumulation are central to the disruption of mitophagy flux and triggering of inflammatory cascades. Using cecal ligation and puncture mice and lipopolysaccharide-treated HL-1 cell models, combined with advanced imaging and molecular analyses, we demonstrated that elevated ROS activates the RIP1/RIP3 pathway, impairing mitophagy flux and promoting the release of microvesicles containing mitochondrial inner membrane components and mitochondrial DNA. These microvesicles amplify inflammatory responses through the cGAS-STING and RIP1/RIP3 pathways, driving the production of damage- and pathogen-associated molecular patterns. This study highlights two interlinked vicious cycles, mitophagy flux disruption and damage- and pathogen-associated molecular pattern amplification, as critical drivers of sepsis-induced myocardial injury, providing therapeutic targets for mitigating inflammatory damage and improving clinical outcomes in patients with sepsis.
    Keywords:  cGAS-STING signaling; mitochondrial microvesicles; sepsis-induced myocardial dysfunction
    DOI:  https://doi.org/10.1073/pnas.2510914123
  37. Biochim Biophys Acta Mol Basis Dis. 2026 Apr 07. pii: S0925-4439(26)00119-5. [Epub ahead of print]1872(6): 168256
    Dusp22 deficiency in cardiomyocytes exacerbates doxorubicin-induced cardiotoxicity by aggravating mitochondria-dependent apoptosis via JNK pathway.
    Miao Xiao, Bo Liao, Bo Zhou, Sen Wen, Yue Hu, Zhongxia Li.
      The dose-cumulative cardiotoxicity of Doxorubicin (Dox) severely limits clinical anti-tumor treatment. Dual-specificity phosphatase 22 (DUSP22), which is expressed in various tissues, plays a key biological role in immune responses and tumor growth. However, the mechanism of DUSP22 on Dox-induced cardiotoxicity (DIC) remains unknown. Employing Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence analysis, we detected a notable decline in the expression of DUSP22 in the cardiac tissues of mice exposed to Dox. Cardiac-specific knockout of Dusp22 exacerbated Dox-induced deterioration of cardiac function and increased mortality in mice. In contrast, cardiac-specific overexpression of Dusp22 significantly improved Dox-induced deterioration of cardiac function and reduced mortality in mice. The mechanistic evidence we provided indicates that DUSP22 directly interacts with JNK, inhibits its phosphorylation, and then promotes mitophagy flux, improves mitochondrial quality, and reduces mitochondrial disorder-related apoptosis. The binding of DUSP22 to JNK and the dephosphorylation of JNK are crucial for DUSP22 to mitigate the process of DIC. Our findings ultimately identify DUSP22 as a key inhibitor of DIC and reveal that the DUSP22-JNK axis can serve as an important therapeutic target for the treatment of DIC. This finding may offer a novel cardioprotective strategy during Dox-based cancer chemotherapy, thereby enhancing treatment safety and patient prognosis.
    Keywords:  Apoptosis; DUSP22; Doxorubicin-induced cardiotoxicity; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168256
  38. Chin Med. 2026 Apr 10. pii: 115. [Epub ahead of print]21(1):
    Moxibustion delays ovarian aging by regulating mitochondrial biogenesis and improving oocyte quality.
    Yaoli Yin, Yan Xu, Zemin Li, Meilin Chen, Ziwei Song, Hongxiao Li, Ge Lu, Meihong Shen.
       BACKGROUND: The growing trend of delayed childbearing in contemporary society has made fertility preservation a significant issue, prompting the search for diverse therapeutic options. Conversely, moxibustion is gaining increasing attention as a potential non-pharmacological therapy for supporting reproductive health.
    METHODS: Mice aged 2 to 14 months were assessed for ovarian function detection to determine the age of reproductive senescence and to identify the optimal time for moxibustion intervention to delay senescence. Oocyte quality and mitochondrial function assessments were conducted to investigate the role of mitochondrial biogenesis in ovarian aging and the underlying mechanisms following moxibustion intervention.
    RESULTS: Mice aged 10 months demonstrated ovarian dysfunction associated with aging. Moxibustion significantly elevated hormone levels, increased the number of growing follicles, enhanced embryo implantation and viable birth rates, and reduced embryonic mortality in aging mice. The most pronounced effects were observed in 10-month-old mice. These beneficial outcomes might be linked to improved oocyte quality. Crucially, moxibustion positively increased mitochondrial quantity, enhanced mitochondrial quality, and influenced mitochondrial biogenesis, an effect comparable to that of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) agonist valproic acid. Furthermore, the beneficial effects of moxibustion were partially attenuated by a PGC-1α inhibitor.
    CONCLUSIONS: Moxibustion, as a non-pharmacological intervention, may mitigate ovarian aging and serve as an effective therapeutic strategy for extending human fertility.
    Keywords:  Mitochondrial biogenesis; Moxibustion; Oocyte; Ovarian aging
    DOI:  https://doi.org/10.1186/s13020-026-01375-3
  39. J Biochem Mol Toxicol. 2026 Apr;40(4): e70830
    From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.
    Nandini Dubey, Gauri Chaturvedi, Pranav Panchbhai, Satnam Singh, Ahsas Goyal, Nirmal Singh, Vishal Kumar Vishwakarma, Neeraj Parakh, Lakshmy Ramakrishnan, Harlokesh Narayan Yadav.
      Cardiomyopathy is a disease unique to the heart muscle that increases a patient's risk of death due to heart failure, contrary to vascular conditions. Cellular powerhouses called mitochondria produce oxygen species that are reactive, that may damage both the mitochondria as well as the heart muscle if they are not managed. They also provide energy for contractions in the heart. Maintaining proper heart function both at base and in reaction to various stress and illness circumstances depends on autophagy as well as mitochondrial autophagy, which eliminates damaged mitochondria. Understanding the pathogenesis of heart diseases, which includes a wide spectrum of cardiovascular problems connected to related cardiomyopathies, is still hampered by autophagy and mitophagy. Additionally, heart failure continues to be a primary source of increased morbidity among people with cardiomyopathy, despite notable advances in lowering death rates from cardiovascular diseases (CVDs). Due to their role in the development of cardiovascular conditions, these cellular processes are appealing targets for diagnosis and therapy. They are crucial for preserving cellular equilibrium and eliminating damaged or malfunctioning components. Further, cardiomyopathies remain a major concern despite the availability of several traditional diagnostic and treatment approaches. Thus, we are going to explore the possible autophagy and mitophagy in the development and progression of cardiomyopathy and provide an overview of current research in this area in this review.
    Keywords:  autophagy; cardiomyopathy; heart failure; mitochondria; mitophagy
    DOI:  https://doi.org/10.1002/jbt.70830
  40. Free Radic Biol Med. 2026 Apr 08. pii: S0891-5849(26)00296-0. [Epub ahead of print]
    Echinacoside Improves Antioxidant Responses and Angiogenesis Through Parkin-MFN2-Mediated Mitophagy to Promote Diabetic Wound Healing.
    Zi Li, Zhi Li, Qiubo Li, Ronghui Miao, Yuchao Ma, Silei Wei, Junnan Mao, Xuan Wang, Xiangtao Zeng, Yi Zhou, Jingjing Ye, Weidong Xia, Cai Lin, Cong Mao.
      Due to complex immune and metabolic dysfunctions, diabetic wounds commonly suffer from infection, oxidative stress, impaired angiogenesis, thereby leading to chronic non-healing lesions. Since current therapies remain insufficient, increasing attention has been directed toward mitophagy, a key regulator of energy balance and stress responses, with mitochondrial dysfunction recognized as a critical driver of defective repair. In this study, we explored the therapeutic role of echinacoside (Ech), a phenylethanol glycoside from Echinacea, known for its potent antioxidant, anti-inflammatory, and pro-angiogenic properties, in promoting diabetic wound healing. Network pharmacology analysis was employed to identify the potential targets of Ech in diabetic condition. In vitro, under H2O2-induced oxidative stress, Ech mitigated the functional impairment of human umbilical vein endothelial cells (HUVECs), enhancing their proliferation, migration, angiogenesis, and antioxidant capacity. Mechanistically, Ech restored HUVECs function by activating Parkin-MFN2-mediated mitophagy through ubiquitination and concurrently upregulated USP35 expression, which mitigated excessive mitophagy. These effects were confirmed using the Parkin-dependent mitophagy inhibitor cyclosporin A (CsA) and USP35-specific siRNA (siUSP35). In a diabetic mouse full-thickness cutaneous wound model, Ech treatment significantly activated Parkin-dependent mitophagy, leading to enhanced neovascularization and collagen deposition at wound site, thereby accelerated the healing process of diabetic wounds. Collectively, these findings identify Ech as a promising therapeutic agent for diabetic wound repair and provide mechanistic insights into its regulation of mitophagy to improve antioxidant responses and angiogenesis, offering a foundation for the development of targeted treatment strategies.
    Keywords:  Diabetic wound; angiogenesis; echinacoside; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.012
  41. J Dairy Sci. 2026 Apr 03. pii: S0022-0302(26)00317-6. [Epub ahead of print]
    Maternal Insulin Resistance during Late Gestation Impairs Brown Adipose Tissue Development and Thermogenic Function in Calves.
    Rui He, Guiling Ma, Zhiyong Hu, Yang Gai, Yu Zhang, Shilong Huang, Shengyong Mao, Morteza Hosseini Ghaffari, Yanting Chen.
      This study investigated the impact of maternal insulin resistance (IR) during late gestation on brown adipose tissue (BAT) development and thermogenic function in neonatal calves. Forty-four dry Holstein cows were selected for the study. Blood samples were collected during the dry period to assess insulin and glucose concentrations, and maternal IR was evaluated using the Homeostasis Model Assessment (HOMA-IR). The cows were divided into 2 groups: maternal-low-IR (n = 22) and maternal-high-IR (n = 22). Immediately after birth, calves were separated from their dams and closely monitored for growth. Calf health was monitored from birth to one month of age, 3 times per week, using standardized clinical scoring of fecal consistency, cough, nasal discharge, and respiration rate. Body weight, body length, withers height, and rectal temperature were recorded at birth, and blood glucose levels were assessed at various intervals following a glucose tolerance test (GTT). At birth (n = 10 per group) and at one month (n = 12 per group), calves were euthanized, and perirenal BAT samples were collected for histological and molecular analyses. Thermogenic and mitochondrial dynamics markers were evaluated at the mRNA and protein levels using quantitative PCR and Western blotting. Stromal vascular fractions (SVFs) from perirenal BAT collected from calves at 0 d of age were cultured under hyperglycemic and hyperinsulinemic conditions to assess their differentiation into brown adipocytes, lipid droplet formation, and gene expression of key thermogenic markers, including UCP1 and dynamin-related protein 1 (DRP1). The results showed that maternal IR significantly increased serum insulin and glucose levels in cows but did not affect body condition score (BCS) or backfat thickness (BFT). At birth, calves from high-IR dams had significantly lower perirenal BAT mass and larger brown adipocytes. Gene expression of thermogenic markers, such as UCP1 and PGC-1α, was downregulated, and mitochondrial density in BAT was significantly reduced in maternal-high-IR calves. These effects persisted at one month, with continued reductions in BAT mass, mitochondrial density, and thermogenic gene expression. maternal-high-IR calves exhibited impaired glucose tolerance, with delayed glucose clearance in the GTT. Maternal-high-IR calves also showed increased clinical morbidity, including higher fecal scores, increased cough scores, and a greater incidence of diarrhea. In vitro, SVFs from calves demonstrated significantly reduced lipid droplet formation and impaired thermogenic gene expression. Mitochondrial fission markers DRP1 and FIS1 were downregulated in the maternal-high-IR group. These results suggest that maternal IR during late gestation impairs BAT development, mitochondrial dynamics, and glucose metabolism in neonatal calves, leading to long-term consequences for thermogenic function and metabolic health.
    Keywords:  brown adipose tissue; calf; insulin resistance; mitochondrial dynamics
    DOI:  https://doi.org/10.3168/jds.2025-28031
  42. Biomed Pharmacother. 2026 Apr 03. pii: S0753-3322(26)00353-7. [Epub ahead of print]198 119320
    Icariin, astragaloside IV and puerarin mixture salvages synaptic loss by enhancing mitochondrial biogenesis: A multi-target strategy for Alzheimer's disease therapy.
    Jianmin Zhong, Xiaoping He, Haoyue Yang, Jiayun Zhang, Jiayi Liu, Jingqi Yang, Xianhui Dong.
       OBJECTIVE: This study aimed to elucidate the potential mechanism by which the Icariin, astragaloside IV and puerarin (Ying-Huang-Ge, YHG) mixture regulates mitochondrial-synaptic homeostasis in Alzheimer's disease (AD) MOD mice through the Glycogen Synthase Kinase-3β (GSK-3β)/Peroxisome Proliferator-Activated Receptor γ Coactivator-1α (PGC-1α) signaling axis.
    METHODS: Thirty 5-month-old male APP/PS1 mice were randomly divided into the MOD group, the YHG treatment group (YHG), and the Donepezil treatment group (DNP) (n = 10 per group). Ten age-matched male C57BL/6 J mice served as the CON group. Following two months of continuous administration, cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Dendritic spine density in the hippocampal CA1 region was evaluated via Golgi staining, and ultrastructural changes were examined using transmission electron microscopy (TEM). Hippocampal levels of adenosine triphosphate (ATP), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured using biochemical assay kits. Protein expression levels of GSK-3β, p-GSK-3β (Ser9), PGC-1α, mitochondrial functional proteins (NRF-1, TFAM), and synaptic plasticity-related proteins (PSD95, SYN) were determined by Western blot.
    RESULTS: Compared with the CON group, the MOD group exhibited significantly impaired learning and memory capabilities, reduced dendritic spine density in the hippocampal CA1 region, and disrupted synaptic ultrastructure. Mitochondria displayed pathological changes, including swelling and vacuolization. Furthermore, ATP and SOD levels were significantly decreased, while MDA content was elevated. Western blot analysis revealed increased total GSK-3β expression and significantly decreased expression of p-GSK-3β (Ser9), PGC-1α, downstream mitochondrial biogenesis proteins (NRF-1, TFAM), and synaptic proteins (PSD95, SYN). Intervention with YHG significantly ameliorated these cognitive deficits, mitigated pathological damage to mitochondria and synapses, and reversed the abnormal molecular expression profiles.
    CONCLUSION: The YHG ameliorates cognitive dysfunction and attenuates synaptic impairment in APP/PS1 mice. The underlying mechanism may involve the inhibition of GSK-3β activity, which subsequently activates PGC-1α-mediated mitochondrial biogenesis, enhances mitochondrial quality, and mitigates oxidative stress, ultimately leading to the restoration of synaptic structural integrity.
    Keywords:  APP/PS1; Alzheimer's disease; GSK-3β/PGC-1α Signaling Axis; Mitochondrial dysfunction; Oxidative Stress; Synapse
    DOI:  https://doi.org/10.1016/j.biopha.2026.119320
  43. Cell Signal. 2026 Apr 08. pii: S0898-6568(26)00184-1. [Epub ahead of print] 112532
    Chlorogenic acid (CGA) exerts antidepressant-like effects by regulating SIRT1/FoxO3a/PINK1/Parkin pathway in LPS-induced depressive mice.
    Xinmiao Piao, Jinfang Song, Jingjing Piao, Yuhan Shang, Yang Jin, Ranji Cui, Bingjin Li.
      A growing focus in nutritional psychiatry is examining dietary interventions as a therapeutic strategy for depression. Chlorogenic acid (CGA), a naturally occurring polyphenol, has demonstrated promising anti-inflammatory and neuroprotective effects. This study aimed to elucidate the underlying molecular targets and mechanisms responsible for CGA's antidepressant-like actions. The potential targets and pathways of CGA related to FoxO3a were initially predicted using network pharmacology and molecular docking. In vitro, the protective effects of CGA were investigated in H2O2-stimulated HT-22 cells by assessing cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential, and the expression of mitophagy-related proteins. In vivo, a depression model was established in male mice via intraperitoneal injection of lipopolysaccharide (LPS). The antidepressant efficacy of CGA was evaluated through a behavioral test battery. Microglial activation was detected via immunofluorescence. Furthermore, mitochondrial ultrastructure was examined by transmission electron microscopy (TEM), and the expression of mitophagy-related proteins was additionally validated by Western blotting. Finally, the direct interaction between SIRT1 and FoxO3a was examined by co-immunoprecipitation. In vitro, CGA pretreatment improved HT-22 cells viability under H2O2-induced oxidative stress, reduced ROS levels, and restored mitochondrial membrane potential. In vivo, CGA reduced neuroinflammation by lowering the levels of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), inhibited microglial activation, and alleviated depressive-like behaviors in LPS-treated mice. Additionally, CGA activated the sirtuin 1 (SIRT1) / forkhead box O3a (FoxO3a) / PTEN-induced kinase 1 (PINK1) / Parkin signaling pathway, promoting hippocampal mitophagy. The antidepressant-like effects of CGA were suppressed upon SIRT1 antagonism with EX527. This study suggests that CGA may serve as a potential therapeutic agent for depression.
    Keywords:  Chlorogenic acid; Depression; FoxO3a; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112532
  44. Mater Today Bio. 2026 Jun;38 102974
    A dual-responsive CO-releasing nanogel ameliorates retinal ischemia-reperfusion injury by restoring mitochondrial homeostasis and attenuating cGAS-STING pathway activation.
    Duncheng Xiao, Jiaqi Qin, Fangpu Zhang, Tianchang Tao, Weiwei Tang, Xiaojun Cai, Liming Tao, Xianwen Wang, Zhengxuan Jiang.
      Retinal ischemia-reperfusion injury (RIRI) represents a central pathological mechanism underlying neurodegeneration in multiple blinding ocular diseases, including glaucoma, diabetic retinopathy, and retinal vein occlusion. Ischemic stress triggers a surge of reactive oxygen species (ROS) within retinal ganglion cells, leading to mitochondrial dysfunction and initiating a vicious cycle of cellular damage. Targeting the regulation of redox balance within the RIRI microenvironment to restore mitochondrial homeostasis remains a major challenge in RIRI therapy. Here, a dual ROS-responsive carbon monoxide (CO) prodrug nanoplatform (COPN) was developed. This system integrates a ROS-sensitive CO-releasing molecule, CORM401, as the active prodrug unit, which is encapsulated within a disulfide-crosslinked dendritic nanogel matrix, thereby enabling site-specific CO release under pathological oxidative conditions. Locally released CO effectively neutralizes excessive ROS, restores mitochondrial quality control, and prevents mitochondrial DNA cytosolic leakage, thereby attenuating cGAS-STING pathway activation and subsequent neuroinflammatory responses. Furthermore, COPN successfully reverses ischemia-induced immunometabolic dysregulation, restores oxidative phosphorylation capacity, and enhances cellular metabolic resilience. This study offers a promising therapeutic strategy with strong translational potential for treating oxidative retinal diseases.
    Keywords:  Antioxidative; Carbon monoxide prodrug nanoplatform; Metabolic reprogramming; Mitochondrial dysfunction; Mitochondrial quality control; Neuroprotection; Retinal ischemia‒reperfusion injury
    DOI:  https://doi.org/10.1016/j.mtbio.2026.102974
  45. J Physiol. 2026 Apr 09.
    SARS-CoV-2 targets mitochondria, exacerbating COVID-19 pneumonia.
    Danchen Wu, Asish Dasgupta, Jaskaran Singh Hora, Kuang-Hueih Chen, Arinjay Banerjee, Stephen L Archer.
      Mitochondrial damage is a conserved feature of coronavirus infection, occurring with human (SARS-CoV-2, HCoV-OC43) and murine (MHV-1) coronaviruses. Coronaviruses damage mitochondria in airway epithelial cells (AEC), pulmonary artery smooth muscle cells (PASMC), pulmonary artery endothelial cells, immune cells and cardiomyocytes by causing rapid transcriptomic changes in nuclear-encoded genes regulating mitochondria and by viral proteins interacting with host mitochondrial proteins. Coronavirus infection causes mitochondrial depolarization, mitochondrial transition pore (MTP) opening, inhibition of the electron transport chain (ETC) and ATP synthetic apparatus, increased mitochondrial fission, apoptosis, and impaired mitochondrial oxygen sensing. Within hours of infection, SARS-CoV-2 induces transcriptional reprogramming of genes relevant to the mitochondrial matrix in AECs, downregulating mRNA encoding ETC complex I components and the ATP synthesis complex. These bioenergetic consequences of SARS-CoV-2 mitochondriopathy may contribute to long COVID. Infection also upregulates dynamin-related protein 1 (DRP1), activating mitochondrial fission while promoting apoptosis by activating apoptosis inducing factor (AIF) and caspase 7. Even without infection, transfection with specific coronaviral proteins opens the MTP and depolarizes the mitochondria, or activates DRP1 and AIF, promoting AEC damage or apoptosis, thereby contributing to diffuse alveolar damage. In human PASMCs, coronaviral M and Nsp9 proteins suppress hypoxic pulmonary vasoconstriction (HPV), a homeostatic mechanism in PASMCs that uses a mitochondrial oxygen sensor to redistribute blood flow to well-ventilated lung regions during pneumonia. Impairment of HPV, seen as intrapulmonary shunting, contributes to the profound hypoxaemia in COVID-19 pneumonia. Coronavirus-induced mitochondriopathy may have therapeutic relevance as blocking AIF-induced apoptosis or enhancing HPV appears beneficial in a MHV-1 model of COVID-19 pneumonia.
    Keywords:  apoptosis inducing factor (AIF); dynamin‐related protein1 (DRP1); human coronavirus OC43 (HCoV‐OC43); hypoxic pulmonary vasoconstriction (HPV); long COVID; mitochondrial permeability transition pore (mPTP); mouse hepatitis virus 1 (MHV‐1); transcriptomics
    DOI:  https://doi.org/10.1113/JP290297
  46. Can J Physiol Pharmacol. 2026 Jan 01. 104 1-7
    Inhibition of ADAMTS1 and ATP citrate lyase attenuates connexin-43 degradation and HFrEF.
    Yu-Ting Zheng, Suresh C Tyagi.
      Human genome- and transcriptome-wide analyses revealed that 56% of heart failure cases have unknown causes. Interestingly, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is one of those causes. Previously, we have shown a robust increase in the degradation of a disintegrin and metalloproteinase (ADAM) and connexin-43 (Cx43) in human end-stage heart failure with reduced ejection fraction (HFrEF). We also observed Cx43 degradation and blood-heart barrier leakage during HFrEF in mice. Although Cx43 coordinates mitochondrial fusion-fission with myocyte contraction-relaxation, respectively, the mechanism is unclear. Interestingly, inhibition of mitochondrial ATP citrate lyase (ACYLi, a lipid-lowering agent) causes HFpEF, but its role in HFrEF is unknown. We hypothesize that during HFrEF, activation of ADAMTS1 degrades Cx43, causing dyssynchronous endothelial-myocyte-mitochondrial contraction coupling, as well as myocyte slippage during contraction and HFrEF. Because HFrEF is more prevalent in males than females, we created chronic cardiopulmonary volume overload by aorta-vena cava fistula (AVF) below the kidney in male wild-type (C57BL/6J) mice aged 12 weeks. By serial echocardiography, we observed HFrEF after 16 weeks. The ADAMTS1 inhibitor (epigallocatechin gallate) or ACYLi (hydroxycitric acid lactone) was administered in drinking water at the same time as AVF. Also, to assess interoceptive inhibition via Piezo channels, we ganglionally denervated the heart prior to AVF. By gel-specific substrate zymography, we measured NGAL, MMP2, MMP9, ADAMTS1, ADAMTS14, and TMPRSS2. The levels of Cx43, ADAMTS1, mitochondrial Drp1 (fission protein), and ACYL were measured by Western blot analysis. The results suggest that ADAMTS1 is activated during HFrEF. Connexin-43 degradation and mitochondrial mitophagy were increased by an increase in Drp1. The therapeutic effects of ADAMTS1 and ACYL inhibitors for systolic HFrEF are suggested.
    Keywords:  ACYL; Drp1; MMP; TIMP; fission; fusion
    DOI:  https://doi.org/10.1139/cjpp-2025-0162
  47. Carbohydr Polym. 2026 Jun 01. pii: S0144-8617(26)00281-X. [Epub ahead of print]381 125165
    Chitosan-gelatin hybrid hydrogel incorporating strontium-doped ceria nanoparticles for enhanced wound healing and mitochondrial function recovery.
    Peng Zhang, Ruixun Chen, Xinmiao Luo, Zuqiang Shi, Renzhou Zhang, Yang Li, Xiaotong Liu, Yuanzhi Gao, Zipeng Zhou, Weiran Gao, Yajiang Yuan.
      Infected wound healing poses a significant global challenge due to persistent bacterial colonization, oxidative stress, and impaired angiogenesis. To address these issues, we developed a microenvironment-responsive GDQS/GA/SrHMCe hydrogel, crafted from quaternized chitosan (QCS) and dopamine-functionalized gelatin methacrylate (GelMA-DA), incorporating glycyrrhetinic acid (GA) and strontium-doped hollow mesoporous ceria nanoparticles (SrHMCe). The hydrogel's unique properties stem from the synergistic combination of its components, which enhance tissue adhesion, antibacterial efficacy, anti-inflammatory response, and free radical scavenging. The SrHMCe nanoparticles exhibit pH-dependent enzyme-like activities: generating bactericidal hydroxyl radicals (•OH) in acidic environments and promoting antioxidant functions in neutral/alkaline settings. Notably, the hydrogel also protects mitochondrial function, aiding in the restoration of mitochondrial membrane potential under oxidative stress. In vivo studies demonstrated significant improvements in wound healing rates, collagen deposition, and vascularization in S. aureus-infected rat models treated with GDQS/GA/SrHMCe, confirming its potential as an effective treatment option. These multifunctional properties highlight the hydrogel's robust clinical applicability in promoting infected wound healing through comprehensive management of inflammatory, oxidative, and healing processes.
    Keywords:  Antioxidation; Dopamine; Hydrogel; Infectious wound healing; Mitophagy; Nanozyme; Triple crosslinking
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125165
  48. J Bioenerg Biomembr. 2026 Apr 10. pii: 6. [Epub ahead of print]58(1):
    Vitamin B3 rescues mitochondrial homeostasis in dexamethasone-induced skeletal muscle atrophy by reducing oxidative stress.
    Akash Mitra, Samanwita Mandal, Anna Timothy Dsouza, Debajit Chaudhury, Bipasha Bose, Sudheer Shenoy P.
      Prolonged glucocorticoid exposure leads to oxidative stress, mitochondrial damage and impaired myogenesis reducing the overall health of the skeletal muscles. Dexamethasone (dex), a synthetic glucocorticoid, induces proteolysis and inflammation by disrupting cellular energetics and mitochondrial function. Vitamin B3 (vit B3), an NAD+ precursor, is known to be a natural antioxidant and anti-inflammatory compound. This study investigates the protective role of vit B3 against dex-induced skeletal muscle damage, focusing on mitochondrial homeostasis and the IKK/FoxO3a signalling axis. C2C12 myoblasts were treated with dex (200 µM) and/or vit B3 (1 mM). Oxidative stress, mitochondrial potential and DNA damage was evaluated using DCFDA, JC1, and γH2AX immunostaining, respectively. Gene expression analysis was performed to assess the mitochondrial fission/fusion and the extent of electron transport chain (ETC) gene expression. Protein expression of inflammatory (IKKα/β, NFκB) and atrophy markers were analysed using immunoblotting and flow cytometry. The extent of myogenic differentiation was evaluated using MyoD and MyHC1 immunostaining along with measurement of the morphometric parameters. Vit B3 treatment significantly enhanced C2C12 viability and reduced dex-induced ROS production while restoring Nrf2 expression. It prevented DNA damage and preserved mitochondrial membrane potential. The results also implicated increased mitochondrial fusion upon vit B3 treatment as seen by the elevated gene expression of Mfn1, Mfn2 and Opa1 and decreased fission as observed by the reduced expression of Fis1 and Drp1. The NADH levels were also seen to be rescued by vit B3 supplementation which translates to better energy production by the electron transport system. Additionally, vit B3 was observed to suppress inflammation and prevent muscle proteolysis by modulating an IKK/FoxO3a axis. Finally, vit B3 was able to improve differentiation as seen by the levels of MyoD and MyHC1 expression in the cells. Vit B3 acts in a multifaceted manner and reduces dex-induced skeletal muscle atrophy which is primarily a result of reduced oxidative stress and restored mitochondrial homeostasis. These findings highlight vit B3 as a potential therapeutic and nutritional supplement for maintaining the skeletal muscle health under myopathic conditions.
    Keywords:  Mitochondrial fragmentation; Mitochondrial homeostasis; Muscle differentiation; Reactive Oxygen Species; Skeletal muscle atrophy; Vitamin B3
    DOI:  https://doi.org/10.1007/s10863-026-10106-0
  49. Cell Signal. 2026 Apr 02. pii: S0898-6568(26)00151-8. [Epub ahead of print] 112499
    Chloride intracellular channel 4 contributes to Aβ-induced cognitive impairment in mice through the regulation of mitochondrial fission. CLIC4 promotes mitochondrial fission.
    Jiao Wang, Xinyu Mao, Renji Zheng, Huiqing Gao, Gang Chen, Yantong Zhang, Mengting Xu, Qicheng Lin, John Nivar, Yuan-Xiang Tao, Mingyang Sun, Hong Cao, JiaQiang Zhang, Jun Li.
      Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by impaired memory and cognitive decline. The early stages of AD in mice present with neuropathy in the hippocampus. Excessive mitochondrial fragmentation and dysfunction are critical pathological features of AD. Chloride intracellular channel 4 (CLIC4) is involved in neuronal apoptosis and regulates mitochondrial functions. Glial maturation factor β (GMFβ) inhibits mitochondrial DNA replication and energy metabolism, causes mitochondrial dysfunction, and regulates apoptosis. Dynamic related protein 1 (DRP1), a key protein in mitochondrial division, exhibits increased activity when its Ser616 site is phosphorylated. However, the role of CLIC4 in Aβ-induced cognitive impairment through the modulation of GMFβ and p-DRP1 (Ser616) to induce mitochondrial dysfunction remains unclear. This study examined the role of CLIC4 in Aβ-induced cognitive impairment in AD mice, focusing on its regulation of GMFβ and p-DRP1 (Ser616) and the subsequent effects on mitochondrial hyperfission and dysfunction. Our findings demonstrate that overexpression of CLIC4 in the mouse hippocampus or in HT22 cells resulted in pathological changes analogous to those observed following Aβ exposure. These changes include elevated levels of GMFβ and p-DRP1 (Ser616) proteins, mitochondrial fission, and increased intracellular ROS production. Conversely, CLIC4 knockdown mitigated Aβ-induced neuronal damage. These findings indicate that CLIC4 may be crucial in Aβ-induced hippocampal neurological damage in mice by regulating GMFβ and DRP1 phosphorylation.
    Keywords:  Alzheimer's disease; Chloride intracellular channel 4; Glia maturation factor β; Mitochondria; P-DRP1 (Ser616)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112499
  50. J Adv Res. 2026 Apr 06. pii: S2090-1232(26)00302-4. [Epub ahead of print]
    GL-V9 disrupts the mitochondrial homeostasis and triggers the integrated stress response by promoting the binding of cytosolic MDM2 with NDUFS1 in colorectal cancer.
    Yibo Zhang, Chen Xun, Chenxiao Shi, Rui Wang, Yuan Gao, Di Pan, Yongjian Guo, Libin Wei.
       INTRODUCTION: The oncogenic role of mouse double minute 2 (MDM2) is primarily attributed to its regulation of p53-dependent signaling cascades. The colorectal cancer (CRC) remains in the top five most prevalent and lethal cancers. P53 mutations are detected in 45-50% of CRC, leading to the failure of such MDM2 inhibitors in clinical trials.
    OBJECTIVES: Small molecular compound GL-V9 targets MDM2 and leads a non-canonical function of MDM2 mediated anti-CRC effects.
    METHODS: Interaction of MDM2 with NDUFS1 as well as the mitochondrial location of NDUFS1 were assessed by a pull-down assay and immunofluorescence analysis. The binding of GL-V9 to MDM2, was analyzed by molecular docking, cellular thermal shift assay (CESTA), surface plasmon resonance (SPR), GST-pulldown and amino acid mutations. Mitochondrial homeostasis was evaluated by mitochondrial membrane potential, mitochondrial superoxide, ATP generation and oxygen consumption rate.
    RESULTS: Different from MDM2 inhibitors, GL-V9 binds to the MDM2 amino-terminal domain (amino acids 1-101) and facilitates the interaction of MDM2 with NDUFS1 in cytoplasm through a p53-independent manner, instead of disruption of p53-MDM2 binding or the promotion of MDM2 protein degradation. This process additionally inhibits the formation of electron transport chain complex I and disrupts the mitochondrial homeostasis, which finally activates OMA1-DELE1 signaling axis and induces the integrated stress response (ISR)-triggered apoptosis.
    CONCLUSION: This study provides a novel candidate for CRC therapy with favorable safety profile. Importantly, the novelty mode of action by GL-V9, working as molecular glue for MDM2/NDUFS1, provides a new insight for targeting MDM2 regardless of p53 status.
    Keywords:  Colorectal cancer; GL-V9; Integrated stress response; MDM2-NDUFS1 interaction; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.jare.2026.04.019
  51. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2526136123
    mtHsp70 chaperone converts mitochondrial proteostasis stress into impaired protein import.
    Rupa Banerjee, Vanessa Trauschke, Nils Bertram, Ina Aretz, Christof Osman, Don C Lamb, Dejana Mokranjac.
      Heat shock proteins 70 (Hsp70) represent a ubiquitous and conserved family of molecular chaperones involved in a variety of cellular processes. The conformational cycles of several Hsp70 chaperones, driven by ATP binding and hydrolysis, and regulated by cochaperones and substrate proteins, were analyzed in vitro in great detail. In contrast, little is known about the conformation Hsp70s adopt in their natural environments. In mitochondria, mtHsp70 is distributed between the TIM23 complex at the inner membrane, where it is involved in import of proteins from the cytosol, and a matrix-pool that is primarily involved in folding of proteins and prevention of their aggregation. Here, we used fluorescence microscopy to analyze the conformation of mtHsp70 at the single molecule level within physiologically active mitochondria. Our results revealed that the majority of mtHsp70 molecules are present in a substrate-bound state, suggesting that the mtHsp70 network functions at the limits of its capacity. To understand the biological significance of this finding, we modulated the levels of unfolded proteins in the matrix. Unfolded proteins reduced the association of mtHsp70 with the TIM23 complex and specifically impaired mtHsp70-dependent import of proteins. Our data show that unfolded proteins lead to a redistribution of mtHsp70 within mitochondria revealing how mitochondrial proteostasis stress is signaled to the cell-unfolded proteins remove mtHsp70 from the import sites, reducing the efficiency of protein import and initiating cellular programs to rescue or remove dysfunctional mitochondria. Thus, mtHsp70 acts as a mitochondrial quality control sensor that converts proteostasis stress into impaired protein import.
    Keywords:  Hsp70 chaperones; mitochondria; protein homeostasis; protein import; single molecule FRET
    DOI:  https://doi.org/10.1073/pnas.2526136123
  52. Cell Mol Life Sci. 2026 Apr 09.
    Exogenous lactate administration alleviates post-cardiac arrest brain injury by coordinating metabolic reprogramming and pathological mitophagy suppression.
    Chenghao Wu, Wenbin Zhang, Yao Lin, Minjie Lin, Taiwen Rao, Ziwei Chen, Xiaodan Zhang, Jiefeng Xu, Mao Zhang.
      
    Keywords:  Energy crisis; Exogenous lactate administration; Lactylation; Metabolic reprogramming; Pathological mitophagy; Post-cardiac arrest brain injury
    DOI:  https://doi.org/10.1007/s00018-026-06190-5
  53. J Cell Mol Med. 2026 Apr;30(7): e71132
    DAPK1-Mediated Parkin Inactivation Enhances Neurotoxicity via MITOL-Dependent Degradation.
    Chul Hong Park, Donghyuk Shin, Kwang Chul Chung.
      Parkinson's disease (PD) is characterised by progressive neurodegeneration and is marked by the formation of Lewy bodies, which are intracellular aggregates primarily composed of α-synuclein. Mitochondrial dysfunction and impaired protein degradation pathways are thought to play critical roles in PD progression, contributing to the loss of dopaminergic neurons in the substantia nigra. Phosphorylation of α-synuclein has been shown to promote its aggregation, underscoring its potential role in disease progression. Parkin, an E3 ubiquitin ligase, is widely regarded as a pleiotropic neuroprotective protein that modulates the mitochondrial quality control, as well as metabolic turnover and the accumulation of α-synuclein. Death-associated protein kinase 1 (DAPK1), which is involved in the regulation of apoptosis and autophagy, has recently emerged as an important factor in neurodegeneration. While DAPK1 has been implicated in Alzheimer's disease through its role in tau aggregation and amyloid-β production, our findings suggest that DAPK1 may also influence PD-related pathways by phosphorylating parkin at Ser136 and Ser198. This phosphorylation promotes the mitochondrial transport of parkin, enhancing interaction with mitochondria-localised E3 ubiquitin ligase MITOL and consequently leading to the degradation of parkin. Given the neuroprotective role of parkin, its reduction increases the vulnerability of neurons to 6-hydroxydopamine-induced toxicity, potentially contributing to decreased neuronal survival. Together, these findings suggest that DAPK1 functions as a previously unrecognised modulator of parkin and could potentially influence PD-related neurodegenerative processes. This pathway may provide a mechanistic link between mitochondrial dysfunction, α-synuclein pathology and neuronal cell death.
    Keywords:  6‐OHDA; DAPK1; MITOL; neuronal toxicity; parkin; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.1111/jcmm.71132
  54. Trends Cell Biol. 2026 Apr 08. pii: S0962-8924(26)00043-7. [Epub ahead of print]
    Proteostasis regulation in T cell dysfunction: dual regulation by KLHL6.
    Yang Yu, Jing Zhuang, Changgang Sun.
      T cell exhaustion represents a major barrier to the efficacy of cancer immunotherapy, driven by complex transcriptional reprogramming, epigenetic remodeling, and metabolic imbalance. Cheng et al. report in Nature that the E3 ubiquitin ligase Kelch-like protein 6 (KLHL6) dually suppresses T cell exhaustion and mitochondrial dysfunction via proteostasis control, establishing a new therapeutic target.
    Keywords:  KLHL6; T cell exhaustion; mitochondrial dynamics; proteostasis; ubiquitination
    DOI:  https://doi.org/10.1016/j.tcb.2026.03.012
  55. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2523913123
    Diffusive spreading across dynamic mitochondrial network architectures.
    Keaton B Holt, Camryn Zurita, Lizzy Teryoshin, Samantha C Lewis, Elena F Koslover.
      In eukaryotic cells, mitochondria form networks that range from highly fused interconnected structures to fragmented populations of individual organelles that undergo transient interactions. These structures can be described as temporal networks of physical units, whose dynamic topology is determined by fusion, fission, and motion of the mitochondria through intracellular space. The heterogeneity of the mitochondrial population is governed by diffusive transport and interunit exchange of proteins, lipids, ions, and RNA within these networks. We present a unifying framework for the dispersion of material within temporal networks of spatially embedded units that span across a broad connectivity range. Specifically, we consider filling of the networks with a locally produced but globally consumed material, demonstrating that the steady-state content is determined by the balance of timescales for spatial encounter between clusters, local fusion, fission, and diffusive transport within a cluster. As the connectivity increases, filling behavior transitions from three-dimensional spread through a "social network" limited by cluster interactions to low-dimensional transport through a largely stationary "physical network" limited by material diffusivity. We extract parameters for mitochondrial networks in three human cell lines, demonstrating that different cells can access both the social and the physical network regimes. These results provide a quantitative basis for predicting the homogenization of biomolecules through a mitochondrial population. Our framework unifies a variety of temporal network structures into an overarching theory for transport through populations of interacting and interconnected units.
    Keywords:  intracellular transport; mitochondria; networks; organelle dynamics; temporal networks
    DOI:  https://doi.org/10.1073/pnas.2523913123
  56. Sci Data. 2026 Apr 06.
    A single-nucleus RNA-seq dataset of the colon in Pink1-deficient and wild-type mice.
    Muhammad Junaid, Soo Jung Park, Yiseul Bae, Eun Jeong Lee, Su Bin Lim.
      PTEN-induced kinase 1 (Pink1), a familial Parkinson's associated gene, is a key regulator of mitochondrial and cellular energy homeostasis. Mutations in Pink1 disrupt mitophagy and perturbations in gastrointestinal homeostasis. This suggests the possibility that Pink1 deficiency may influence neurodegenerative processes by altering gut-to-brain signaling mechanisms. To facilitate investigation of gut-specific consequences of Pink1 deficiency, we generated a single-nucleus RNA sequencing (snRNA-seq) dataset from gut tissue of wild-type (WT) and Pink1 knockout (KO) mice. We identified major cell populations such as goblet cells, immune cells, and colonocytes, and characterized their transcriptional profiles. For technical validation, we utilized a publicly available murine gut (snRNA-seq) dataset. We then applied anchor-based label transfer and confirmed cell-type assignments via random forest classification. This rigorously validated dataset provides a robust resource for exploring shifts in cell-type composition and transcriptional alterations associated with Pink1 loss.
    DOI:  https://doi.org/10.1038/s41597-026-07193-4
  57. Mater Today Bio. 2026 Jun;38 103023
    Extracellular biogenic nanoscale mitochondria reprogram the wound microenvironment via ROS scavenging independent of cellular uptake.
    Fang Lin, Jing Liu, Yue Ding, Kexin Ma, Qingshu Meng, Xiaohui Zhou, Qingliu Zhang, Hao Hu, Zhongmin Liu, Xiaoting Liang.
      Mitochondria are nanoscale organelles essential for cellular metabolism and redox regulation, making them a compelling target for regenerative therapeutics. Analysis of wound-edge tissues from pediatric patients with chronic non-healing ulcers revealed marked metabolic insufficiency and impaired regenerative signaling, underscoring an unmet clinical need for mitochondrial-based interventions. Here, we show that topically applied mesenchymal stem cell-derived mitochondria (MSC-mt), functioning as naturally derived nanoscale organelles, markedly accelerate wound closure in a murine full-thickness skin injury model. MSC-mt enhanced angiogenesis, collagen deposition, and fibroblast survival while reducing oxidative stress and apoptosis. Mechanistically, their cytoprotective effects occur primarily through extracellular scavenging of reactive oxygen species (ROS), independent of cellular internalization. Excessive immobilization of MSC-mt within a thermosensitive hydrogel compromised their efficacy, emphasizing the importance of mitochondrial mobility and microenvironmental access. Under high oxidative stress, internalized MSC-mt activated PINK1-Parkin-mediated mitophagy, indicating a context-dependent intracellular quality-control response. These findings position MSC-mt as a cell-free, organelle-level nano-therapeutic that operates through a dual extracellular-intracellular mechanism and emphasize the importance of delivery strategies that preserve mitochondrial functionality and spatial freedom.
    Keywords:  Mesenchymal stem cells; Mitochondrial transplantation; Mitophagy; ROS scavenging; Wound healing
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103023
  58. bioRxiv. 2026 Mar 13. pii: 2026.03.12.711310. [Epub ahead of print]
    Impaired Endosomal Recycling of Signaling Receptors Activates an Extracellular UPR.
    Avijit Mallick, Yunguang Du, Cole Haynes.
      Mitochondrial dysfunction and extracellular protein aggregation occur in neurodegenerative diseases such as Alzheimer's disease (AD). However, it remains unclear if these processes are functionally linked. Here, we identify a signaling pathway that is activated upon accumulation of aggregation-prone proteins in the extracellular space. We find that the transcription factor ATFS-1, which regulates the mitochondrial unfolded protein response, also regulates transcripts required for endosomal recycling, multiple plasma membrane-localized signaling receptors, and secreted proteins that bind aggregation-prone proteins in the extracellular space, including transthyretin and Aβ, and promote their degradation. Interestingly, Aβ(1-42) aggregation induces atfs-1 -dependent transcription by promoting degradation of the bZIP protein ZIP-3, which antagonizes ATFS-1. ZIP-3 accumulates in the cytosol when it is phosphorylated by kinases that function downstream of plasma membrane-localized signaling receptors, including the WNT and glutamate receptors. Upon ligand binding, the signaling receptors stimulate the cognate kinase, many of which we found phosphorylate ZIP-3, impeding ZIP-3 degradation, allowing it to antagonize atfs-1 -dependent transcription. However, accumulation of aggregation-prone proteins such as Aβ(1-42) causes endosomal swelling, which impairs endosomal recycling, instead diverting signaling receptors to lysosomes for degradation. In turn, the depletion of signaling receptors reduces the level of ZIP-3 phosphorylation, resulting in ZIP-3 degradation and activation of atfs-1 -dependent transcription, which promotes extracellular proteostasis. Our findings uncover an unexpected coupling between endocytic quality control and mitochondrial signaling, revealing a circuit that preserves extracellular proteostasis and promotes organismal resilience.
    DOI:  https://doi.org/10.64898/2026.03.12.711310
  59. J Recept Signal Transduct Res. 2026 Apr 08. 1-8
    β1/β2 adrenergic dysregulation: a missing link between mitochondrial fission/fusion in the failing heart.
    Pranav Panchbhai, Gauri Chaturvedi, Satnam Singh, Nandini Dubey, Rajiv Narang, Neeraj Parakh, Prabhakar Singh, Upendra Baitha, Ved Prakash, Harlokesh Narayan Yadav.
      Heart failure (HF) is characterized by notable alterations in β-adrenergic receptor (β-AR) signaling. It is well known that a prolonged overstimulation of β-ARs, a member of the G-protein-coupled receptor (GPCR) family, alters receptor density and function, contributing to cardiac dysfunction and the development and progression of HF. Moreover, recently, many studies have highlighted the role of β-ARs in the regulation of mitochondrial fission/fusion. A dysfunctional mitochondrial fission/fusion balance is a characteristic hallmark of a failing heart. However, a mechanistic link between β-ARs and mitochondrial dynamics is lacking. Furthermore, growing evidence links β-AR activity to changing mitochondrial size, distribution, and functional integrity. Yet these findings remain scattered across diverse studies with differing perspectives. This review demonstrates a clear mechanistic view of β-ARs regulation of mitochondrial fission/fusion in a failing heart.
    Keywords:  fission; fusion; mitochondria; β1-AR; β2-AR
    DOI:  https://doi.org/10.1080/10799893.2026.2652855
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