bims-tofagi Biomed News
on Mitophagy
Issue of 2025–08–17
eight papers selected by
Michele Frison, University of Cambridge
  1. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  2. Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy.
  3. Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
  4. Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve.
  5. USP30 inhibition augments mitophagy to prevent T cell exhaustion.
  6. A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
  7. Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
  8. Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based virtual screening and biological validation.
  1. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  2. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2504921122
    Plant-specific mitochondrial fission machinery connects mitochondrial dynamics and mitophagosome formation for piecemeal mitophagy.
    Juncai Ma, Chaorui Li, Kaike Ren, Kaiyan Zhang, Lanlan Feng, Kai Ching Law, Ka Kit Chung, Yizhou Bing, Caiji Gao, Byung-Ho Kang, Xiaohong Zhuang.
      As the energy center of the cell, mitochondria display enormous metabolic plasticity to meet the cellular demand for plant growth and development, which is tightly linked to their structural and dynamic plasticity. Mitochondrial number and morphology are coordinated through the actions of the mitochondrial division and fusion. Meanwhile, damaged mitochondrial contents are removed to avoid excess toxicity to the plant cells. Mitophagy, a selective degradation pathway of mitochondria through a double-membrane sac named autophagosome (also known as mitophagosome), plays a crucial role in maintaining mitochondrial homeostasis. Typically, wholesale mitophagy requires the elongation of a cup-shaped phagophore along the entire mitochondrion, which finally seals and closes as a mitophagosome. How plant mitophagosome formation and mitochondria sequestration are coordinated remains incompletely understood. In this work, we report an unappreciated role of the plant-specific mitochondrial fission regulator ELM1, together with the dynamin-related protein family DRP3 and the autophagic regulator SH3P2, to coordinate mitochondria segregation for piecemeal mitophagy under heat stress conditions. Dysfunction in mitochondrial fission activity impairs heat-induced mitophagy, leading to an accumulation of interconnected megamitochondria which are partially sequestered by the ATG8-positive phagophore. Furthermore, we show that the ELM1-mediated piecemeal mitophagy also engages the plant archetypal selective autophagic receptor NBR1. Using 3D tomography analysis, we illustrate the morphological features and spatial relationship of the megamitochondria and phagophore intermediates in connection with the mitochondrial fission sites. Collectively, our study provides an updated model of mitophagosome formation for piecemeal mitophagy mediated by the plant-unique mitochondrial fission machinery.
    Keywords:  ELM1; SH3P2; mitochondrial fission; mitophagosome; mitophagy
    DOI:  https://doi.org/10.1073/pnas.2504921122
  3. Elife. 2025 Aug 13. pii: RP105834. [Epub ahead of print]14
    Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
    Hiroki Taoka, Tadayoshi Murakawa, Kohei Kawaguchi, Michiko Koizumi, Tatsuya Kaminishi, Yuriko Sakamaki, Kaori Tanaka, Akihito Harada, Keiichi Inoue, Tomotake Kanki, Yasuyuki Ohkawa, Naonobu Fujita.
      Differentiated muscle cells contain myofibrils and well-organized organelles, enabling powerful contractions. Muscle cell reorganization occurs in response to various physiological stimuli; however, the mechanisms behind this remodeling remain enigmatic due to the lack of a genetically trackable system. Previously, we reported that a subset of larval muscle cells is remodeled into adult abdominal muscle through an autophagy-dependent mechanism in Drosophila. To unveil the underlying mechanisms of this remodeling, we performed a comparative time-course RNA-seq analysis of isolated muscle cells with or without autophagy. It revealed both transcriptional dynamics independent of autophagy and highlighted the significance of BNIP3-mediated mitophagy in muscle remodeling. Mechanistically, we found that BNIP3 recruits autophagic machinery to mitochondria through its LC3-interacting motif and minimal essential region, which interact with Atg8a and Atg18a, respectively. Loss of BNIP3 leads to a substantial accumulation of larval mitochondria, ultimately impairing muscle remodeling. In summary, this study demonstrates that BNIP3-dependent mitophagy is critical for orchestrating the dynamic process of muscle remodeling.
    Keywords:  BNIP3; D. melanogaster; Drosophila; autophagy; cell biology; developmental biology; metamorphosis; mitochondria; muscle
    DOI:  https://doi.org/10.7554/eLife.105834
  4. Elife. 2025 Aug 12. pii: e103844. [Epub ahead of print]14
    Glaucoma-associated Optineurin mutations increase transcellular degradation of mitochondria in a vertebrate optic nerve.
    Yaeram Jeong, Chung-Ha O Davis, Aaron Muscarella, Hector H Navarro, Viraj Deshpande, Lucy G Moore, Keun-Young Kim, Mark H Ellisman, Nicholas Marsh-Armstrong.
      We previously described a process whereby mitochondria shed by retinal ganglion cell (RGC) axons are transferred to and degraded by surrounding astrocytes in the optic nerve head of mice. Since the mitophagy receptor Optineurin (OPTN) is one of few large-effect glaucoma genes and axonal damage occurs at the optic nerve head in glaucoma, here we explored whether OPTN mutations perturb the transcellular degradation of mitochondria. Live-imaging of Xenopus laevis optic nerves revealed that diverse human mutant but not wildtype OPTN increase stationary mitochondria and mitophagy machinery and their colocalization within, and in the case of the glaucoma-associated OPTN mutations also outside of, RGC axons. These extra-axonal mitochondria are degraded by astrocytes. Our studies demonstrate that expression of OPTN carrying a glaucoma-associated mutation results in increased transcellular degradation of axonal mitochondria.
    Keywords:  neuroscience; xenopus
    DOI:  https://doi.org/10.7554/eLife.103844
  5. Sci Adv. 2025 Aug 15. 11(33): eadv6902
    USP30 inhibition augments mitophagy to prevent T cell exhaustion.
    Ruohan Zhang, Fengxia Gao, Jianying Li, Jiacheng Jin, Kangxuan Chen, Samhita Chaudhuri, Zhiwei Liao, Tong Xiao, Yang Xu, Haitao Wen, Kai He, Zihai Li, Gang Xin, Nuo Sun.
      The exhaustion of tumor-infiltrating CD8+ T cells poses a substantial challenge in cancer immunotherapy, with mitochondrial health essential for sustaining T cell functionality. Mitophagy, a critical process for mitochondrial quality control, is severely impaired in exhausted CD8+ T cells, yet the underlying mechanisms remain unclear. We identified ubiquitin-specific protease 30 (USP30), a mitochondrial deubiquitinase that inhibits mitophagy, as a key factor up-regulated in exhausted CD8+ T cells. Notably, prolonged antigen stimulation triggers the T cell receptor and nuclear factor of activated T cell 1 signaling, which drives the transcriptional up-regulation of USP30. Excitingly, our interventions targeting USP30 through genetic deletion or pharmacological inhibition effectively restored mitophagy, improved mitochondrial fitness, and rejuvenated CD8+ T cell effector functions. These interventions reinvigorated antitumor responses and markedly suppressed tumor growth. Our findings establish USP30 as a critical regulator of mitophagy and a promising therapeutic target for reversing T cell exhaustion and enhancing the efficacy of cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.adv6902
  6. Autophagy. 2025 Aug 11.
    A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
    Qing Shen, Madiha Natchi Samu Shihabdeen, Fan Yang, Naweed I Naqvi.
      Ferroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human and plant diseases and to immunity thereof. Here, we utilized chemical cell biology, molecular genetics and biochemical analyses to gain insights into how the fungal pathogen Magnaporthe oryzae undergoes ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a complex functional interdependency and crosstalk between intrinsic ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the ferroptosis defects therein. Graded inhibition of mitochondrial coenzyme Q biosynthesis with or without ferroptosis inhibitor liproxstatin-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of tricarboxylic acid cycle enzyme AcoA (aconitase A) in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to ferroptosis. Last, we present an important bioenergetics- and redox-based mitochondrial regulon essential for intrinsic ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease.
    Keywords:  Cell death; coenzyme Q; iron; mitochondrial metabolism; mitophagy; rice blast
    DOI:  https://doi.org/10.1080/15548627.2025.2546944
  7. Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]
    Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
    Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.
      Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.
    Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
  8. Free Radic Biol Med. 2025 Aug 11. pii: S0891-5849(25)00885-8. [Epub ahead of print]
    Discovery of a novel mitophagy inducer attenuating postoperative cognitive dysfunction through structure-based virtual screening and biological validation.
    Lina Zhang, Yujin Wu, Jiaying Li, Chenglong Li, Shuai Liu, Sihua Qi.
      Postoperative cognitive dysfunction (POCD), a prevalent complication following surgery and anesthesia, currently lacks effective therapeutics. Given the crucial regulatory role of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in maintaining mitochondrial homeostasis and suppressing neuroinflammatory responses, we aimed to identify novel mitophagy inducers as potential therapeutic interventions for POCD. Employing structure-based virtual screening of a small-molecule library of compounds, we identified tamarixetin as a potent and selective PINK1 activator. Comprehensive molecular dynamics simulations and cellular thermal shift assays validated its stable binding interaction with PINK1. Treatment with tamarixetin significantly enhanced mitophagic activity in the hippocampal region of surgically treated mice, concurrently reducing cytosolic mitochondrial DNA accumulation and reactive oxygen species levels, attenuating neuroinflammatory responses, and improving cognitive function in behavioral tests. Mechanistically, tamarixetin treatment promoted PINK1 stabilization and strengthened PINK1-Translocase Of Outer Mitochondrial Membrane 40 interactions, while facilitating Parkin recruitment to mitochondria and enhancing mitofusin 2 ubiquitination, ultimately promoting mitophagic flux in both lipopolysaccharide-stimulated HT22 neuronal and BV2 microglial cell lines. Our study identifies tamarixetin as a novel pharmacological activator of PINK1-dependent mitophagy and elucidates its therapeutic potential in POCD by counteracting mitochondrial dysfunction and neuroinflammation. These findings provide a promising foundation for developing mitophagy-targeted therapies for POCD.
    Keywords:  PTEN-induced kinase 1; Parkin; Postoperative cognitive dysfunction; mitophagy; tamarixetin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.016
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