bims-tofagi Biomed News
on Mitophagy
Issue of 2026–09–06
eight papers selected by
Michele Frison, University of Cambridge
  1. RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
  2. Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
  3. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  4. Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.
  5. UBE2N flips the switch on for mitophagy and off for MASH.
  6. UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.
  7. Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
  8. Phase Separation, Material State, and Condensate Fate in Mammalian Autophagy.
  1. Autophagy. 2026 Sep 01.
    RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.
    Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano.
      Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the de novo synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.
    Keywords:  Autophagy; Optineurin; PINK1; Parkin; RAB GTPase; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2026.2728346
  2. J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):
    Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
    Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.
      Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
    DOI:  https://doi.org/10.1172/JCI199847
  3. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  4. Sci Adv. 2026 Sep 04. 12(36): eaeg3201
    Reconstitution of multistep recruitment of ULK1 to membranes in autophagy.
    Yongjia Duan, Ye Lu, Sanjoy Paul, Johannes Betz, Léa P Wilhelm, Annan S I Cook, Xuefeng Ren, Elias Adriaenssens, Sascha Martens, Ian G Ganley, Gerhard Hummer, James H Hurley.
      The human Unc51-like kinase 1 (ULK1) autophagy-initiating complex consists of ULK1, FIP200, and the Hop/Rev7/Mad2 (HORMA) domain heterodimer ATG13:ATG101. Phosphatidylinositol 3-phosphate (PI3P) is essential to recruit ULK1 complex (ULK1C) to membranes for ULK1, but ULK1C subunits do not contain PI3P-binding domains. Here, we show that the ATG13:ATG101 dimer forms a complex with the PI3P-binding protein WD40 interacting with phosphoinositide protein 3 (WIPI3), as well as WIPI2. Bound to WIPI2 and WIPI3, ATG13:ATG101 inserts its Trp-Phe (WF) finger into the membrane. Molecular dynamics simulations show that WIPIs and the WF finger cooperatively stabilize the complex on membranes. Biochemical reconstitution and cell-based assays show that WIPI3:ATG13 engagement promotes ATG16L1 phosphorylation, autophagy, and mitophagy. A kinase domain (KD)-proximal Pro-Val-Pro (PVP) motif in the ULK1 intrinsically disordered region docks onto the ATG13:ATG101 HORMA dimer brings the ULK1 KD close to the membrane. The PVP motif is essential for in vitro ULK1 phosphorylation of ATG16L1 and important for autophagy and mitophagy. These data establish a stepwise pathway for recruitment of the ULK1 KD to the vicinity of the membrane surface.
    DOI:  https://doi.org/10.1126/sciadv.aeg3201
  5. Nat Metab. 2026 Sep 04.
    UBE2N flips the switch on for mitophagy and off for MASH.
    Emily D Madigan, Sandro L Matos, Michael J Jurczak.
      
    DOI:  https://doi.org/10.1038/s42255-026-01604-x
  6. Nat Metab. 2026 Sep 04.
    UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.
    Feng Wang, Jin Lee, Jeong-Su Park, Meizhou Huang, Hwan Ma, Guoyan Sui, Zixiong Zhou, Michitaka Matsuda, So Yeon Kim, Takashi Tsuchiya, Xuefeng Wu, Haram Lee, Soohwan Oh, Hanseul Park, Key-Hwan Lim, Chun-Woong Park, Sang-Bae Han, Jin Tae Hong, Michael Karin, Yoon Seok Roh, Ekihiro Seki.
      K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis.
    DOI:  https://doi.org/10.1038/s42255-026-01590-0
  7. Antioxid Redox Signal. 2026 Sep 02. 15230864261481794
    Mitochondrial Microautophagy: An Emerging Pathway in Maintaining Mitochondrial Homeostasis.
    Huijia Zhang, Ying Chen, Junjie Jiang, Yarong Ding, Si Hu, Zhongzhi Zhou, Li Chen.
      Background:Mitochondrial quality control has traditionally been attributed to mitophagy. However, emerging evidence indicates that mitochondrial microautophagy represents a distinct quality control pathway. This pathway enables selective removal of damaged mitochondrial subdomains while preserving overall organelle integrity. Therefore, mitochondrial microautophagy can be viewed as a redox-adaptive, sub-organelle quality control system that responds to localized mitochondrial stress.Scope of Review: In this review, we integrate recent mechanistic, imaging, and molecular studies to establish an updated framework of mitochondrial microautophagy. We describe this process as a sequential pathway involving damage sensing, mitochondria-lysosome contact formation, lysosomal membrane remodeling, selective degradation, and metabolic recycling. Localized reactive oxygen species (ROS) serve as important signals during this process. ROS define specific damage microdomains and facilitate selective mitochondrial component recognition. Subsequent cargo delivery and degradation are regulated by multiple molecular modules. These modules include the ubiquitin-autophagy-related protein 8 system, vacuolar-type H+-ATPase-dependent membrane remodeling, Ras-related in brain-endosomal sorting complexes required for transport signaling, the spermatogenesis-associated 18/mitochondria-eating protein pathway, and the mechanistic target of rapamycin complex 1-transcription factor EB and nuclear factor erythroid 2-related factor 2 stress-response networks.Outstanding Questions: Despite substantial progress, several fundamental questions remain unresolved. The mechanisms underlying cargo recognition require further clarification. The existence of specific redox-sensitive receptors remains to be determined. In addition, future technological advances will provide deeper insights into this pathway.Conclusions: Understanding mitochondrial microautophagy may reveal new therapeutic opportunities for mitochondrial dysfunction-associated disorders, including neurodegeneration, ischemic injury, metabolic disorders, and aging. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  ESCRT complex; Rab GTPase; SPATA18/Mieap; TFEB; V-ATPase; autophagy; lysosomal membrane remodeling; mitochondrial microautophagy; mitochondrial quality control
    DOI:  https://doi.org/10.1177/15230864261481794
  8. Adv Sci (Weinh). 2026 Sep 01. e77360
    Phase Separation, Material State, and Condensate Fate in Mammalian Autophagy.
    Yuanqiang Lin, Mingran Dai, Enyong Dai, Rui Kang, Daniel J Klionsky, Daolin Tang, Yu Sun, Ningning Lv, Junnan Jiang.
      Biomolecular phase separation has emerged as a key organizing principle in macroautophagy (hereafter autophagy). In mammalian cells, phase-separated condensates not only serve as substrates for selective degradation, but also act as dynamic platforms for cargo recognition, signaling integration, and autophagosome assembly. The material state of these condensates is an important determinant of autophagic fate. Condensates exist along a continuum ranging from liquid-like droplets to gel-like and solid assemblies, and their progressive maturation can alter accessibility to autophagic machinery. Scaffold proteins and selective autophagy receptors further organize these assemblies into degradation-competent mesoscale reaction fields that couple cargo recognition with phagophore formation. Dysregulation of this phase separation-autophagy axis is increasingly implicated in neurodegeneration, cancer, aging, and stress-associated degenerative disease. Here, we propose a multiscale framework in which molecular accessibility, mesoscale organization, and condensate state transitions collectively shape autophagic outcome, providing a conceptual basis for predictive models and therapeutic strategies aimed at restoring condensate degradability.
    Keywords:  autophagy; condensate; disease; phase separation; receptor
    DOI:  https://doi.org/10.1002/advs.77360
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