bims-tofagi Biomed News
on Mitophagy
Issue of 2025–09–28
seven papers selected by
Michele Frison, University of Cambridge
  1. Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
  2. The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
  3. PINK1 deficiency permits the development of Lewy body dementia with coexisting Aβ pathology.
  4. Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
  5. Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
  6. PINK1 functions in mitophagy and mitochondrial homeostasis during mice oocyte maturation.
  7. Mechanisms of mitochondrial autophagy-mediated crosstalk between ferroptosis and cuproptosis in lung cancer.
  1. Mol Cell. 2025 Sep 23. pii: S1097-2765(25)00737-3. [Epub ahead of print]
    Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
    Selver Altin, Tânia Simões, Christina Behrendt, Vincent Anton, Dennis Domke, Kai Mayor Völtzke, Rajesh Kumar, Hendrik Nolte, Thomas Hermanns, Nahal Brocke-Ahmadinejad, Katja Bendrin, Marcel Zimmermann, Reinhard Büttner, Natascia Ventura, Marcus Krüger, R Jürgen Dohmen, Kay Hofmann, Thorsten Hoppe, Andreas S Reichert, Mafalda Escobar-Henriques.
      Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eukaryotes, polyubiquitin precursors are generated and processed into ubiquitin monomers. The final ubiquitin unit always contains a C-terminal extension, but its physiological significance is unknown. Here, we show that C-terminally extended ubiquitin, termed CxUb, is essential for stress resistance, mitophagy, and longevity in Saccharomyces cerevisiae and Caenorhabditis elegans. CxUb forms ubiquitin chains and binds to a previously undescribed region within the ubiquitin chain-elongating E4 enzyme Ufd2, which also functions during stress and aging. Ufd2 recognizes CxUb and conjugates it to substrate proteins, triggering their degradation. By contrast, CxUb is not required for basal housekeeping functions of the ubiquitin-proteasome system. These data suggest that the CxUb encodes a functionally unique ubiquitin form, specialized for proteostasis defects, expanding the code of post-translational modification processes.
    Keywords:  CxUb; E4; Ufd2; aging; mitochondria; mitofusin; mitophagy; proteostasis; stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.032
  2. J Biol Chem. 2025 Sep 18. pii: S0021-9258(25)02591-8. [Epub ahead of print] 110739
    The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
    Wei-Hua Chu, Yu-Shan Lin, Jing Guo, Wann-Neng Jane, Wong-Jing Wang, Yu-Yang Lin, Pei-Han Liu, Po-Yu Huang, Wei-Chung Chiang.
      PINK1/Parkin-mediated mitophagy is a major homeostatic mechanism by which cells selectively remove damaged, depolarized mitochondria. A signature event in this form of mitophagy is the rupture of the mitochondrial outer membrane (OMM), a process required for the proper disposal of the damaged, depolarized mitochondria. The OMM rupture results in the topological exposure of mitochondrial inner membrane (IMM) mitophagy receptors, which are recognized by autophagy machinery, thus promoting the turnover of the depolarized mitochondria. However, due to the lack of efficient tools to measure OMM rupture, our mechanistic understanding of this process has been limited. In this study, we identified ANKRD13A as a novel mitophagy factor that interacts with multiple mitochondrial proteins and re-localizes to the depolarized mitochondria. ANKRD13A promotes PINK1/Parkin-mediated mitophagy by recruiting Valosin-containing protein (VCP), an AAA-ATPase that functions to remodel protein complexes or membranes via the extraction of protein substrates. Through the development of a novel biosensor that fluorescently marks the sites of OMM rupture, we visualized the OMM rupture events in cellulo and revealed that VCP and its recruitment factors, including ANKRD13A, are required for the rupture of OMM. This finding demonstrated that VCP-dependent remodeling of OMM during PINK1/Parkin-mediated mitophagy is a key driving force behind the OMM rupture. Furthermore, our newly developed biosensor represents an effective, reliable method to detect OMM rupture during PINK1/Parkin-mediated mitophagy, and it is valuable for future mechanistic investigation of this process.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110739
  3. Alzheimers Dement. 2025 Sep;21(9): e70730
    PINK1 deficiency permits the development of Lewy body dementia with coexisting Aβ pathology.
    Tong-Yao Gao, Xu-Zheng Wang, Yu-Han Xie, Tong Wang, Yun-Bi Lu, Lu-Long Huang, Cong Chen, Ming Zhang, Xin Ma, Ya-Ling Chen, Fu-Xiang Liang, Zhi-Ling Lou, Jin-Sheng Li, Yi-Fan Yu, Jian-Bin Wu, Xiao-Ru Ma, Hua-Li Wang, Chun Tang, Wei-Ping Zhang.
       INTRODUCTION: Dementia with Lewy bodies (DLB), a prevalent neurodegenerative dementia, involves α-synuclein (α-syn) aggregates and frequent amyloid beta (Aβ) co-pathology, but mechanistic drivers remain unclear.
    METHODS: We crossed pink1 knockout with APP/PS1 mice, and assessed behavioral and pathological phenotypes of the resulting animals. We also performed biochemical and biophysical characterizations of PTEN-induced kinase 1 (PINK1) phosphorylation of α-syn.
    RESULTS: DLB brains show PINK1 deficiency alongside α-syn and Aβ co-pathology. Mirroring human DLB patients, APP/PS1::pink1-/- mice spontaneously develop Lewy pathology at endogenous α-syn levels, affecting both central and peripheral nervous systems with heterogeneous phenotypes. Mechanistically, PINK1 phosphorylates α-syn at Thr44, suppressing Aβ-induced α-syn aggregation. Moreover, pT44-α-syn levels are correlated with PINK1 expression and activity in human brains.
    DISCUSSION: PINK1 deficiency synergizes with Aβ to promote Lewy pathology via loss of protective α-syn phosphorylation. The APP/PS1::pink1-/- model recapitulates key DLB features without α-syn overexpression, offering a valuable tool for future mechanistic and therapeutic studies.
    HIGHLIGHTS: PTEN-induced kinase 1 (PINK1) deficiency, either through reduced expression or impaired activity, is found in human dementia with Lewy bodies (DLB) patients with amyloid beta (Aβ) co-pathology. PINK1 specifically phosphorylates α-synuclein at Thr44, inhibiting Aβ-induced aggregation and preventing the development of Lewy pathology. The APP/PS1::pink1-/- mouse model recapitulates key features of human DLB, exhibiting widespread Lewy pathology and heterogeneous phenotypes. PINK1 alterations emerge as a novel genetic risk factor for DLB, opening new avenues for diagnosis and therapeutic intervention.
    Keywords:  APP/PS1 mouse; Alzheimer's disease; Lewy body; Lewy neurite; PTEN‐induced kinase 1; Parkinson's disease; amyloid beta; dementia with Lewy bodies; phosphorylation; α‐synuclein
    DOI:  https://doi.org/10.1002/alz.70730
  4. Life Sci. 2025 Sep 23. pii: S0024-3205(25)00631-9. [Epub ahead of print] 123995
    Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.
    Paola Zanfardino, Alessandro Amati, Stefano Doccini, Francesco Girolamo, Apollonia Tullo, Giovanna Longo, Filippo M Santorelli, Vittoria Petruzzella.
       AIMS: Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is a rare autosomal recessive neuropathy caused by biallelic MTMR5/SBF1 variants, which encode a catalytically inactive myotubularin involved in phosphoinositide metabolism and autophagy regulation. This study investigates the impact of MTMR5/SBF1 dysfunction on autophagy and mitophagy in patient-derived fibroblasts and examines the relationship between protein aggregates and autophagic machinery.
    MATERIALS AND METHODS: Fibroblasts from a CMT4B3 patient with compound heterozygous MTMR5/SBF1 mutations were compared with a healthy control. Autophagic flux was analyzed via LC3B and SQSTM1; mitophagy was assessed through PINK1 and PRKN recruitment and by quantifying mitophagosomes and autolysosomes under mitochondrial stress. Protein aggregates were visualized using Proteostat and tested for colocalisation with autophagic structures.
    KEY FINDINGS: CMT4B3 fibroblasts showed normal basal macroautophagy but failed to increase autophagy in response to mitochondrial stress or protein aggregates. Conversely, mitophagy was strongly activated via the PINK1-PRKN pathway.
    SIGNIFICANCE: These results reveal an uncoupling between mitophagy and macroautophagy, indicating that MTMR5/SBF1 mutations modify autophagic selectivity. Our findings provide new mechanistic insights into the pathogenesis of CMT4B3 and highlight the value of patient-derived fibroblasts for studying selective autophagy defects.
    Keywords:  CMT4B3; Charcot-Marie-Tooth disease; Macroautophagy; PINK1–PRKN pathway; Phosphoinositide metabolism; Proteasome
    DOI:  https://doi.org/10.1016/j.lfs.2025.123995
  5. Nat Aging. 2025 Sep 24.
    Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
    Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.
      Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.
    DOI:  https://doi.org/10.1038/s43587-025-00957-4
  6. Cell Biosci. 2025 Sep 26. 15(1): 126
    PINK1 functions in mitophagy and mitochondrial homeostasis during mice oocyte maturation.
    Shiwei Wang, Xuan Wu, Mengmeng Zhang, Yixiao Zhu, Yajun Guo, Shuang Song, Shenming Zeng.
       BACKGROUND: As a serine/threonine kinase, PINK1 (PTEN-induced putative kinase 1) is widely expressed in mammalian tissues and cells, especially in the female reproductive system. However, its role in meiotic oocytes remains obscure. Here, we report that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis.
    RESULTS: In the present study, we found that PINK1 protein levels in aged oocytes showed a substantial increase. Importantly, we revealed that murine oocytes overexpressing Pink1 are unable to completely progress through meiosis. This leads to inadequate mitochondrial redistribution, an elevated reactive oxygen species (ROS) level, severely disrupted spindle/chromosome organization, and abnormal mitophagy. Furthermore, we noted that elevated Pink1 expression significantly compromises the developmental ability of the mouse early embryo. In addition, we revealed that RAB8A activity is a key factor for PINK1-mediated mitophagy in old oocytes and active guanosine triphosphate (GTP)-bound state RAB8A could partially rescue the quality of aged oocytes by promoting the formation of autolysosome.
    CONCLUSIONS: Collectively, our data display critical functions for PINK1 in meiotic progression and mitochondrial homeostasis in murine oocytes, and RAB8A activity is required for PINK1-mediated mitophagy in senescent oocytes.
    Keywords:  Mitochondrial homeostasis; Mitophagy; Oocyte; PINK1; RAB8A
    DOI:  https://doi.org/10.1186/s13578-025-01460-4
  7. Tissue Cell. 2025 Sep 18. pii: S0040-8166(25)00430-6. [Epub ahead of print]98 103148
    Mechanisms of mitochondrial autophagy-mediated crosstalk between ferroptosis and cuproptosis in lung cancer.
    Lang Jiang, Zhijun Shen.
      Globally, lung cancer has an extremely high morbidity and fatality rate among malignant tumors. Studies on the mechanisms of cell death have yielded fresh concepts and treatment approaches for lung cancer in recent years. As a crucial mitochondrial quality control mechanism, mitochondrial autophagy is strongly related to new forms of cell death, ferroptosis and cuproptosis, and it is crucial for the development, progression, management, and outcomes of lung cancer. In order to provide a theoretical foundation and possible therapeutic targets for precision lung cancer treatment, this review provides an overview of the molecular mechanisms of mitochondrial autophagy, ferroptosis, and cuproptosis as well as how these mechanisms of action interact with one another in lung cancer.
    Keywords:  Crosstalk mechanisms; Cuproptosis; Ferroptosis; Lung cancer; Mitochondrial autophagy
    DOI:  https://doi.org/10.1016/j.tice.2025.103148
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