bims-tofagi Biomed News
on Mitophagy
Issue of 2025–11–23
seven papers selected by
Michele Frison, University of Cambridge
  1. A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
  2. Autophagy regulation by phase separation, avidity, and wetting.
  3. Bacterial CipB is an exogenous receptor to drive the mitophagy-TFEB axis and promote pathogenesis.
  4. Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.
  5. HMOX1 interacts with BNIP3 to modulate neuronal ferroptosis after spinal cord ischemia-reperfusion injury via a mitophagy-dependent mechanism.
  6. Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway.
  7. Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
  1. EMBO J. 2025 Nov 20.
    A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.
    Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, Luiza M Gruel Budet, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.
      Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.
    Keywords:  Autophagy; Glycolysis; Parkinson’s Disease; Unfolded Protein Response
    DOI:  https://doi.org/10.1038/s44318-025-00604-z
  2. Trends Biochem Sci. 2025 Nov 19. pii: S0968-0004(25)00244-0. [Epub ahead of print]
    Autophagy regulation by phase separation, avidity, and wetting.
    Riccardo Babic, Joachim Brenneisen, Florian Wilfling, Claudine Kraft.
      Autophagy enables cells to selectively degrade a wide range of macromolecules, and how this process achieves spatial precision within the densely packed cytosol is an active area of investigation. Recent advances suggest that phase separation provides a crucial organizational framework that converts autophagy into a spatiotemporally coordinated and self-organizing process. Biomolecular condensates formed by phase separation can create high-avidity binding platforms between autophagy receptors, scaffold proteins, and the cargo that stabilize transient molecular contacts. The formation of such condensates specifies the cargo and initiates autophagosome formation at defined cellular locations. Simultaneously, physical properties such as wetting govern how condensates interact with membranes, and thus influence engulfment efficiency. Viewing autophagy through the lens of condensate physics not only explains its molecular specificity but also highlights new therapeutic opportunities.
    Keywords:  autophagy; autophagy-based therapeutics; avidity; biomolecular condensates; phase separation; wetting
    DOI:  https://doi.org/10.1016/j.tibs.2025.10.003
  3. J Cell Biol. 2026 Jan 05. pii: e202503028. [Epub ahead of print]225(1):
    Bacterial CipB is an exogenous receptor to drive the mitophagy-TFEB axis and promote pathogenesis.
    Shuai Liu, Lina Ma, Ruiqi Lv, Liangting Guo, Xing Pan, Shufan Hu, Shan Li.
      Mitophagy transports mitochondria to lysosomes for degradation to maintain energy homeostasis, inflammation, and immunity. Here, we identify CipB, a type III secretion system (T3SS) effector from Chromobacterium violaceum, as a novel exogenous mitophagy receptor. CipB targets mitochondria by the mitochondrial protein TUFM and recruits autophagosomes via its LC3-interacting region (LIR) motifs. This process initiates the mitophagy-TFEB axis, triggering TFEB nuclear translocation and suppression of proinflammatory cytokines, thereby promoting bacterial survival and pathogenesis. CipB represents a conserved family of T3SS effectors employed by diverse pathogens to manipulate host mitophagy. Using a mouse model, CipB's mitophagy receptor function is critical for C. violaceum colonization in the liver and spleen, underscoring its role in bacterial virulence. This study reveals a novel mechanism by which bacterial pathogens exploit host mitophagy to suppress immune responses, defining CipB as a paradigm for exogenous mitophagy receptors. These findings advance our understanding of pathogen-host interactions and highlight the mitophagy-TFEB axis as a potential signaling pathway against bacterial infection.
    DOI:  https://doi.org/10.1083/jcb.202503028
  4. Mol Biol Cell. 2025 Nov 19. mbcE25050235
    Kenny mediates the recruitment of the phagophore for ubiquitin-dependent mitophagy in Drosophila neurons.
    Hubert Osei Acheampong, Emily Rozich, Zachary Haupt, Charlee Tokarz, Mousumee Khan, Zahraa A Ghosn, Ryan Insolera.
      The maintenance of healthy mitochondria is essential to neuronal homeostasis. Mitophagy is a critical mechanism that degrades damaged mitochondria, and disruption of this process is associated with neurodegenerative disease. Previous work has shown that mammalian optineurin (OPTN), a gene mutated in familial forms of amyotrophic lateral sclerosis (ALS) and glaucoma, is an adaptor to recruit autophagy machinery to mitochondria for ubiquitin-dependent mitophagy in cultured cells. However, OPTN's role in neuronal mitophagy in vivo remains largely unknown. Here, we demonstrate the Drosophila autophagy adaptor gene Kenny, a homolog of OPTN, mediates the recruitment of the phagophore to mitochondria undergoing ubiquitin-dependent mitophagy. We find that Kenny colocalizes with ubiquitinated mitochondria targeted for autophagic degradation in larval motoneurons, and is concentrated on the mitochondrial surface in areas opposed to the phagophore. Removal of Kenny in conditions of induced mitophagy eliminates the recruitment of the phagophore to ubiquitinated mitochondria and decreases mitophagic flux. In basal conditions, loss of Kenny causes accumulation of ubiquitinated mitochondria in neurons, indicative of stalled mitophagy. These phenotypes were reproduced in Kenny mutants ablating the LC3-interacting region domain. Overall, this work establishes Kenny as a functional homolog of OPTN in flies, and a mediator of neuronal mitophagy in vivo.
    DOI:  https://doi.org/10.1091/mbc.E25-05-0235
  5. Cell Death Discov. 2025 Nov 17. 11(1): 536
    HMOX1 interacts with BNIP3 to modulate neuronal ferroptosis after spinal cord ischemia-reperfusion injury via a mitophagy-dependent mechanism.
    Yanni Duan, Yibao Zhang, Fengguang Yang, Mingtao Zhang, Yujun Shi, Zongyan Ma, Xingxing Huang, Wen Li, Yun Lang, Xuchang Hu, Xuewen Kang.
      Spinal cord ischemia-reperfusion injury (SCIRI) is a severe secondary complication of trauma, spinal cord decompression, and thoracoabdominal aortic surgery. Ferroptosis, a regulated cell death pathway characterized by iron-dependent accumulation of lethal reactive oxygen species and lipid peroxidation, has been implicated in various pathological conditions. However, its precise role and molecular mechanisms in SCIRI remain unclear. In this study, we demonstrated that ferroptosis contributes to the pathophysiology of SCIRI. Heme oxygenase 1 (HMOX1) was upregulated in both SCIRI rats and neuronal cells subjected to hypoxia-reoxygenation. Genetic knockdown of HMOX1 in vivo and in vitro markedly attenuated neuronal ferroptosis, improving neurological function, whereas HMOX1 overexpression reproduced characteristic ferroptotic events in vitro. HMOX1 upregulation appeared to stimulate autophagic flux and induce substantial mitophagy, suggesting a potential mechanistic link between HMOX1 and ferroptosis promotion. Mitophagy reduction diminished HMOX1-mediated ferroptosis, whereas mitophagy induction acted synergistically with HMOX1. HMOX1 physically interacted with BNIP3, triggering excessive mitophagy and subsequent ferroptosis. In this study, we establish ferroptosis as a critical contributor to SCIRI pathogenesis and identify HMOX1 as a central regulator of this process. Furthermore, mitophagy-dependent ferroptosis, mediated by the HMOX1-BNIP3 axis, emerges as a promising therapeutic target for SCIRI intervention.
    DOI:  https://doi.org/10.1038/s41420-025-02831-z
  6. Mol Cell. 2025 Nov 20. pii: S1097-2765(25)00889-5. [Epub ahead of print]
    Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway.
    Stephanie Patchett, Seyed Arad Moghadasi, Ankita Shukla, Farid El Oualid, Beatrix M Ueberheide, Shaun K Olsen, Tony T Huang.
      In eukaryotes, each ribosomal subunit includes a ribosomal protein (RP) that is encoded as a fusion protein with ubiquitin (Ub). In yeast, each Ub-RP fusion requires processing by deubiquitylating enzymes (DUBs) to generate ribosome assembly-competent RPs and contribute to the cellular Ub pool. However, how Ub-RP fusions are processed by DUBs in human cells remains unclear. Here, we discovered that Ub-RPs are substrates of the Ub-fusion degradation (UFD) pathway in human cells via lysine 29 and 48 (K29/K48)-specific ubiquitylation and proteasomal degradation. We identified a pool of DUBs that catalytically process Ub-RPs, as well as DUBs that physically occlude Ub-RP interaction with UFD pathway Ub E3 ligases to prevent their degradation in a non-catalytic manner. Our results suggest that DUBs both process and stabilize Ub-RPs, whereas the UFD pathway regulates levels of Ub-RPs that cannot be fully processed by DUBs to fine-tune protein homeostasis.
    Keywords:  Cezanne; DUBs; HUWE1; OTUD7B; RPL40; RPS27a; TRIP12; UBA52; UBA80; UFD; deubiquitinases; deubiquitinating enzymes; ubiquitin fusion degradation pathway
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.028
  7. Exp Physiol. 2025 Nov 19.
    Mitophagy in skeletal muscle: Impact of ageing, exercise and disuse.
    Anastasiya Kuznyetsova, David A Hood.
      Skeletal muscle plays an important role in whole-body health, quality of life and regulation of metabolism. The maintenance of a healthy mitochondrial pool is imperative for the preservation of skeletal muscle quality and is mediated through mitochondrial quality control consisting of mitochondrial turnover mediated by a balance between organelle synthesis and degradation. The selective tagging and removal of dysfunctional mitochondria is essential for maintaining mitochondrial quality control and is termed mitophagy. The mechanisms of the initial stages of mitophagy involving the recognition and tagging of mitochondria within skeletal muscle are well established, but our understanding of the terminal step involving organelle degradation mediated via lysosomes is in its infancy. An assessment of the proteolytic functions to facilitate the removal and breakdown of dysfunctional mitochondria is crucial for our understanding of the mechanisms of mitophagy, which is essential for maintaining skeletal muscle health. The aim of this review is to address the current knowledge surrounding mitophagy and lysosomal function, alongside distinct physiological conditions, such as ageing, exercise and disuse, that have varying effects on mitophagy and lysosomal adaptations within skeletal muscle.
    Keywords:  Parkin; adaptation; lysosomes; mitophagy; skeletal muscle; transcription factor EB
    DOI:  https://doi.org/10.1113/EP093041
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