bims-tofagi Biomed News
on Mitophagy
Issue of 2026–10–11
eight papers selected by
Michele Frison, University of Cambridge
  1. Inheritance and selection of the mitochondrial genome.
  2. Evolutionarily conserved selective autophagy pathways.
  3. OXR1 is a dual redox-mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model.
  4. SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.
  5. Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy.
  6. Mitophagy during bush-cricket oogenesis and its potential role in mitochondrial quality control.
  7. Mitochondrial transfer protects against cisplatin-induced hearing loss by fumarate-mediated activation of mitophagy.
  8. TBK1-mediated phosphorylation of WIPI2 links bacteria recognition to autophagosome formation in xenophagy.
  1. Nat Rev Genet. 2026 Oct 05.
    Inheritance and selection of the mitochondrial genome.
    Qin Xie, Harry E Walker, Michal Minczuk, Marcos R Chiaratti, Patrick F Chinnery.
      The functioning mitochondrial genome is essential for cellular energy production. Being strictly maternally inherited and possessing limited DNA repair capacity, mitochondrial DNA (mtDNA) replication errors tend to accumulate over time. If left unchecked, these errors can accumulate through the female germline over successive generations, potentially leading to species extinction. However, this outcome is not observed in most species, including humans, which implies the existence of mechanisms that counteract the progressive accumulation of deleterious mtDNA mutations. Recent technological advances are building a deeper understanding of the processes that preserve mtDNA integrity, including the molecular and cellular basis and timing of purifying selection. This new knowledge helps to explain how mtDNA can change rapidly over just a few generations, whilst remaining compatible with the independently inherited, evolving nuclear genome.
    DOI:  https://doi.org/10.1038/s41576-026-01019-0
  2. Autophagy. 2026 Oct 06. 1-26
    Evolutionarily conserved selective autophagy pathways.
    András Jipa, Virág Vincze, Daniela Evdokimova, Dániel Dénes, Lilla Beatrix Péter, Zsombor Esküdt, Bence Csaba Béres, Gábor Juhász.
      Selective autophagy is a regulated process that ensures the specific recognition and lysosomal degradation of defined intracellular substrates, including damaged organelles, protein aggregates, and invading pathogens. Despite intense research interest, several mechanistic aspects of selective autophagy remain incompletely understood. Comparative analysis across different models offers a valuable framework for identifying evolutionarily conserved molecular components and regulatory principles. In this review, we provide a detailed overview of seven major evolutionarily conserved selective autophagy pathways: mitophagy, xenophagy, pexophagy, lysophagy, ER-phagy, Golgiphagy, and ribophagy, building on data from four widely used model organisms (mammals, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae). We focus on the core molecular machinery including the modes of cargo recognition via already characterized and predicted selective receptors, and orchestration of cargo capture into forming autophagosomes.
    Keywords:  Er-phagy; Golgiphagy; lysophagy; mitophagy; pexophagy; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2736925
  3. Nat Commun. 2026 09 05. pii: 10553. [Epub ahead of print]17(1):
    OXR1 is a dual redox-mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model.
    Xiaojun Chen, Chengyu Zhou, Xiangyun Jin, Qiongxiang Lin, Lizhen Li, Zhongxiang Wang, Buran Chen, Qiu Dong, Jianbo He, Kavishadhi Chandrasekaran, Chau Bui, Alysia Hubbard, Qunwei Dong, Lei Chen, K Swaminathan Iyer, Jiandong Yuan, Nathan J Pavlos, Haibo Jiang, Kai Chen.
      Osteoclasts are mitochondria-rich cells that rely on oxidative phosphorylation to fuel differentiation and bone resorption. Oxidative phosphorylation generates reactive oxygen species (ROS), which support signaling but can also threaten mitochondrial integrity. Oxidation Resistance 1 (OXR1) is a redox-responsive regulator involved in antioxidant defense, but its role in osteoclasts remains unclear. Here, we show that OXR1 is upregulated during mouse osteoclastogenesis and OXR1 mRNA is enriched in human osteoclasts. Knockdown of Oxr1 in mouse osteoclast precursors causes excessive ROS accumulation, mitochondrial damage, and impaired autophagic flux. Accordingly, myeloid-specific loss of Oxr1 results in defective osteoclast formation and increased bone mass in mice. Mechanistically, OXR1 binds the antioxidant response regulator KEAP1 and promotes KEAP1 association with the autophagy adaptor P62/SQSTM1, thereby supporting mitochondrial ubiquitination and mitophagic clearance. In an ovariectomy-induced osteoporosis mouse model, intraosseous AAV9-shRNA-mediated Oxr1 silencing or pharmacological OXR1 inhibition suppresses osteoclast activity and attenuates bone loss. Thus, our findings suggest OXR1 to be a dual-function regulator that buffers ROS and simultaneously orchestrates the autophagic clearance of damaged mitochondria during osteoclastogenesis, hinting at OXR1 as a potential target for preventing osteoclast‑driven bone loss.
    DOI:  https://doi.org/10.1038/s41467-026-77379-2
  4. FASEB J. 2026 Oct 15. 40(19): e72361
    SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.
    Atsushi Kuno, Yukika Saga, Ryusuke Hosoda, Hiroki Aida, Ayuka Kurihara, Yuki Tatekoshi, Koki Abe, Ryo Numazawa, Naotoshi Iwahara.
      Sirtuin-1 (SIRT1) is an NAD+-dependent deacetylase implicated in autophagosome formation; however, whether SIRT1 also regulates autophagosome clearance during late-stage autophagy remains unclear. Here, we investigated the role of SIRT1 in autophagosome clearance during autophagy and mitophagy in cardiomyocytes. Mitochondrial stress induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) decreased mitochondrial protein levels and increased phosphorylation of ubiquitin, a PINK1 target, in H9c2 cardiomyocytes. These CCCP-induced decreases in mitochondrial proteins were prevented by co-treatment with chloroquine, an inhibitor of lysosomal degradation, supporting the induction of CCCP-triggered mitophagy. SIRT1 knockdown similarly prevented the CCCP-induced reduction in mitochondrial proteins and led to the accumulation of autophagosomes containing fragmented mitochondria without attenuating ubiquitin phosphorylation, suggesting that SIRT1 acts downstream of mitochondrial tagging. Tandem GFP-RFP LC3 assay and LC3-LAMP1 colocalization analysis demonstrated impaired autophagosome-lysosome fusion following SIRT1 knockdown. In vivo, cardiomyocyte-specific SIRT1 knockout mice exhibited elevated basal LC3-II levels and a blunted LC3-II response to chloroquine, consistent with impaired autophagic flux. In a doxorubicin (DOX)-treated model, SIRT1 deficiency attenuated autophagosome degradation during the early period after DOX administration. Mechanistically, SIRT1 interacted with Rab7, a key regulator of autophagosome-lysosome fusion, raising the possibility that SIRT1 might regulate fusion through post-translational modification of Rab7 or related components. Collectively, these findings identify SIRT1 as a regulator of autophagosome-lysosome fusion that promotes autophagosome degradation during autophagy and mitophagy in cardiomyocytes.
    Keywords:  Sirtuin‐1; autophagosome–lysosome fusion; autophagy; doxorubicin; mitophagy
    DOI:  https://doi.org/10.1096/fj.202601047R
  5. bioRxiv. 2026 Aug 10. pii: 2026.08.07.743589. [Epub ahead of print]
    Structural basis for the selective inhibition of the PI3KC3-C2 complex by Rubicon in endolysosome maturation and mitophagy.
    Minghao Chen, Aniketh Bishnu, Yongjia Duan, Julia F Riley, Qingyang Ni, Aaron Joiner, Isaac J Allen, Erika L F Holzbaur, Ian G Ganley, James H Hurley.
      Rubicon is a negative regulator of autophagy and the endolysosomal network (ELN) and an antagonist of the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). Inhibition of Rubicon is considered a potential means to therapeutically upregulate autophagy and the ELN to treat Parkinson's disease and other conditions characterized by autophagic and ELN dysfunction. Rubicon is specific for the UVRAG-containing PI3KC3-C2 over the purely autophagic ATG14- containing PI3KC3-C1 complex. Here, we determined the high-resolution cryo-electron microscopy structure of PI3KC3-C2 in complex with the PI3KC3-binding domain (PIKBD) of Rubicon and compared it to cryo-EM structures of unbound PI3KC3-C2 and PI3KC3-C1. Rubicon binds directly to PI3KC3-C2 only via the BARA domain of the BECN1 subunit, which is common to both C1 and C2. The selectivity of Rubicon for the PI3KC3-C2 complex over the PI3KC3-C1 complex is attributed to a conformation of the BECN1 BARA domain induced by UVRAG, rather than to direct contact with UVRAG or direct antagonism by the ATG14 subunit of PI3KC3-C1. Targeted disruption of the Rubicon:PI3K3-C2 structural interface by site-directed mutations enhances mitophagic activity in human epithelial cells to levels comparable to those observed in Rubicon knockout (KO) cells. Similarly, disruption of the interaction in Rubicon-overexpressing hippocampal neurons restored lysosomal flux to wild-type levels. These data show that suppressing the function of PI3K3- C2 can fully account for the negative regulatory effects of Rubicon in the autophagy and ELN pathways.
    Significance Statement: Endolysosome maturation and autophagosome-lysosome fusion require the production of phosphatidylinositol 3-phosphate (PI(3)P) by the class III phosphatidylinositol 3-kinase complex II (PI3KC3-C2). Rubicon is a key negative regulator of endolysosomes and autophagy that suppresses PI3KC3-C2 activity. Here, we reveal in atomistic detail how Rubicon selectively recognizes PI3KC3-C2. Disrupting the Rubicon-PI3KC3-C2 interaction restores mitophagy and enhances lysosomal activity to the same extent as Rubicon gene deletion, establishing that PI3KC3-C2 inhibition fully accounts for the biological regulatory effects of Rubicon in the autophagy and lysosome pathways.
    DOI:  https://doi.org/10.64898/2026.08.07.743589
  6. J Insect Physiol. 2026 Oct 07. pii: S0022-1910(26)00145-9. [Epub ahead of print]174 105072
    Mitophagy during bush-cricket oogenesis and its potential role in mitochondrial quality control.
    Magda Sochaczewska, Waclaw Tworzydlo.
      The female germline cells must ensure that only fully functional mitochondria are transmitted to the next generation. Although mitophagy has been implicated in mitochondrial maintenance in numerous systems, its occurrence during insect oogenesis remains poorly understood. Here, we analyzed previtellogenic oocytes of the bush-cricket, Roeseliana roeselii using transmission electron microscopy, histochemistry, and immunocytochemistry. Our ultrastructural analyses revealed numerous membrane-bound compartments within the ooplasm. These structures were consistently associated with antibody signals for Beclin-1, LC3, Atg5, ubiquitin, and the lysosomal marker LAMP1. Moreover, mitochondria were frequently observed within lysosome-associated compartments, suggesting their incorporation into degradative pathways. Our findings provide evidence for mitophagy in insect oocytes and suggest that selective mitochondrial degradation may contribute to mitochondrial turnover and, potentially, to mitochondrial quality control during oogenesis. These results expand our understanding of germline maintenance in insects and support the hypothesis that mitophagy may represent an evolutionarily conserved mechanism safeguarding maternally inherited mitochondria.
    Keywords:  Autophagy; Germline; Mitochondrial quality control; Mitophagy; Oogenesis; Orthoptera
    DOI:  https://doi.org/10.1016/j.jinsphys.2026.105072
  7. Cell Rep. 2026 Oct 07. pii: S2211-1247(26)01186-1. [Epub ahead of print]45(10): 118107
    Mitochondrial transfer protects against cisplatin-induced hearing loss by fumarate-mediated activation of mitophagy.
    Yunhao Wu, Yunhui Gu, Yukai Wang, Rui Li, Weiwei Shi, Jiaxin Liu, Changjie Lai, Xinyu Wang, Jie Tang, Donghui Pan, Yi Zhang, Ning Wei, Yiwen Zheng, Jing Wang, Min Yang, Xiaolong Fu, Renjie Chai, Guangji Wang, Yunlong Shan.
      Sensorineural hearing loss (SNHL) affects millions of individuals worldwide, with platinum-based chemotherapeutics identified as a significant cause. In this study, we elucidate the mechanism by which mitochondrial transfer from mesenchymal stem/stromal cells (MSCs) protects against cisplatin-induced cochlear injury in a mouse model. Systemically administered MSCs home to the cochlea and transfer mitochondria to damaged spiral ganglion neurons (SGNs) via tunneling nanotubes, leading to elevated intracellular levels of the Krebs cycle intermediate fumarate, which activates mitophagy to eliminate dysfunctional mitochondria. Mechanistically, dimethyl fumarate (DMF)-a clinically available fumarate derivative-covalently modifies the phosphatase PPP1CB at cysteine 126, thereby blocking PPP1CB-mediated dephosphorylation of mitofusin 2 (MFN2), which in turn enhances mitophagy and ultimately preserves auditory function. These findings reveal that MSCs orchestrate mitochondrial replacement in damaged SGNs by delivering healthy mitochondria and facilitating the removal of impaired ones, underscoring the therapeutic potential of this strategy for treating SNHL related to mitochondrial dysfunction.
    Keywords:  CP: cell biology; PPP1CB; dimethyl fumarate; mesenchymal stem/stromal cells; sensorineural hearing loss; spiral ganglion neurons
    DOI:  https://doi.org/10.1016/j.celrep.2026.118107
  8. Autophagy. 2026 Oct 09.
    TBK1-mediated phosphorylation of WIPI2 links bacteria recognition to autophagosome formation in xenophagy.
    Chuying Qian, Hongtao Zhang, Jin Li, Wei Wan, Wei Liu.
      Xenophagy, a selective autophagy pathway, is a critical innate immune defense mechanism that targets pathogens for lysosomal degradation. However, the molecular mechanisms enabling autophagosomes to specifically recognize and engulf bacteria remain incompletely understood. Here, we identify WIPI2, a core component that drives autophagosome biogenesis, as a novel phosphorylation substrate of TBK1 during Salmonella Typhimurium infection. We demonstrate that TBK1 phosphorylates WIPI2 at Ser96, which enhances its interaction with ATG16L1 and its binding to PtdIns3P. Crucially, the recruitment of WIPI2 to intracellular bacteria is dependent on its interaction with ATG16L1, which is localized to the Salmonella-containing vacuole. Furthermore, TBK1-mediated phosphorylation of WIPI2 is required for efficient bacterial clearance. Collectively, our findings reveal a molecular mechanism whereby TBK1-mediated phosphorylation of WIPI2 directs localized phagophore expansion around invading bacteria, thereby bridging bacterial recognition with autophagosome assembly.
    Keywords:  ATG16L1; PtdIns3P; Salmonella; TBK1; V-ATPase; WIPI2; phosphorylation; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2746965
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