bims-tofagi Biomed News
on Mitophagy
Issue of 2025–12–21
seven papers selected by
Michele Frison, University of Cambridge
  1. MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
  2. Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
  3. Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation.
  4. VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
  5. Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
  6. CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.
  7. Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases.
  1. Nat Cell Biol. 2025 Dec 15.
    MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
    Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.
      Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
    DOI:  https://doi.org/10.1038/s41556-025-01829-0
  2. Cell Chem Biol. 2025 Dec 18. pii: S2451-9456(25)00390-3. [Epub ahead of print]32(12): 1439-1441
    Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
    Chih-Yao Chung, Kritarth Singh, Brigida R Pinho, Jorge M A Oliveira, Michael R Duchen.
      Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.010
  3. J Biol Chem. 2025 Dec 12. pii: S0021-9258(25)02906-0. [Epub ahead of print] 111054
    Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation.
    Jiayu Chen, Hairong Zhao, Yuemei Xi, Shanpan Fu, De Xie, Linqian Yu, Qiang Wang, Binyang Chen, Qian Zhang, Mingyan Zhang, Xueling Ye, Mengni Wu, Wanling Que, Shuyi Chen, Yayan Liu, Tetsuya Yamamoto, Hidenori Koyama, Hong Zhao, Jidong Cheng.
      The rising prevalence of hyperuricemia associated with lifestyle changes has been confirmed as an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Mitochondria, as central regulators of lipid metabolism, maintain functional homeostasis through mitophagy, the selective removal of damaged or dysfunctional mitochondria. However, whether and how high uric acid (HUA) induces mitophagy and the mechanistic role of mitophagy in hyperuricemia-induced hepatic lipid metabolism disorders remain to be elucidated. Our study demonstrated that HUA induces hepatic fat accumulation and damaging mitochondria in primary mouse hepatocytes. Simultaneously, mitophagy was activated by HUA, evidenced by upregulated expression and phosphorylation of PINK1 and Parkin, enhanced LC3B-I to LC3B-II conversion, and enhanced TOM20-LC3B immunofluorescence co-localization. In urate oxidase gene knockout (Uox-KO) mice (a model of sustained hyperuricemia), we detected significantly elevated expression of mitophagy-related proteins in liver tissues, accompanied by marked lipid accumulation and inflammatory responses. Further studies demonstrated that HUA upregulates CD36 protein expression. CD36 knockdown alleviated lipid accumulation in primary mouse hepatocytes, whereas PINK1 knockdown exacerbated this effect through further CD36 upregulation. Notably, treatment with the mitophagy activator Urolithin A significantly ameliorated hepatic lipid accumulation and inflammation in Uox-KO mice. These findings demonstrate that the PINK1-Parkin-mediated mitophagy activated by HUA serves as a protective mechanism against HUA-induced hepatic fat accumulation. Our results suggest that mitophagy regulation may represent a novel therapeutic target for HUA-induced hepatic fat accumulation.
    Keywords:  CD36; Hepatic lipid accumulation; Hyperuricemia; Mitophagy; PINK1-Parkin pathway
    DOI:  https://doi.org/10.1016/j.jbc.2025.111054
  4. Nat Commun. 2025 Dec 16.
    VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
    Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.
      Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.
    DOI:  https://doi.org/10.1038/s41467-025-67445-6
  5. Aging Dis. 2025 Dec 14.
    Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
    Sen Huang, Ang Li, Yixia Ling, Xinyu Yang, Jiayu Wang, Jing Yuan, Dajiang Qin, Xiaoli Yao.
      Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1G93A, TDP43A315T, and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1G93A transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1G93A transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.
    DOI:  https://doi.org/10.14336/AD.2025.1224
  6. Cell Death Dis. 2025 Dec 19.
    CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.
    Feifei Sun, Ying Qu, Shuyu Mei, Lin Zhang, Xianhao Shao, Xinpei Wang, Shijia Liu, Meng Wang, Wenyao Liu, Muyi Yang, Jing Hu, Benkang Shi, Lin Gao, Bo Han.
      Although androgen receptor (AR)-targeted therapies, such as enzalutamide, initially improve outcomes of prostate cancer (PCa) patients, resistance inevitably develops, partly driven by prostate cancer stem-like cells (PCSCs). However, the molecular mechanisms linking the maintenance of PCSCs to enzalutamide resistance (ENZR) remain incompletely elucidated. Here, we implicate Ca²⁺/calmodulin-dependent protein kinase 1D (CAMK1D) in PCSC-mediated ENZR. CAMK1D was consistently upregulated in PCa with ENZR and contributed to ENZR by enhancing mitophagy in PCa cells both in vitro and in vivo. Mechanistically, CAMK1D promotes the expansion of PCSCs by enhancing mitophagy through activation of the AMP-activated protein kinase (AMPK)/PINK1 signaling pathway, thereby facilitating cellular adaptation. We revealed that CAMK1D interacts with and phosphorylates AMPK at Thr172, which in turn activates PINK1 to modulate mitophagy, ultimately supporting the expansion of PCSCs under enzalutamide treatment. In a mouse orthotopic PCa model, targeting the CAMK1D/AMPK pathway with the siCAM/HLNP nanoformulation suppresses tumor growth by depleting the PCSCs population, achieving a synergistic effect with enzalutamide therapy. Our findings identify CAMK1D as a key regulator of ENZR that maintains stemness by orchestrating mitophagy, thereby establishing mitophagy as an important nexus between CAMK1D-mediated ENZR and AMPK-driven PCSC enrichment. Therapeutically, we developed a CAMK1D-targeted approach that potently reverses ENZR and improves treatment responses.
    DOI:  https://doi.org/10.1038/s41419-025-08342-0
  7. Aging Dis. 2025 Dec 05.
    Phosphorylated Ubiquitin as a Clinical Biomarker for Mitochondrial Damage in Neurodegenerative Diseases.
    Fabienne C Fiesel, Jens O Watzlawik, Michael G Heckman, Sophia G Blumenfeld, Michael J Rigby, Mohammed Kehili, Katja Lohmann, Christine Klein, Derek P Narendra, Clemens R Scherzer, Nilufer Ertekin-Taner, Neill R Graff-Radford, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer.
      Phosphorylated ubiquitin (pS65-Ub) is generated by the kinase-ligase pair PINK1-Parkin to selectively label damaged mitochondria for degradation via the autophagy-lysosome system (mitophagy). Consistent with increasing mitochondrial and lysosomal dysfunctions, pS65-Ub accumulates with aging in human autopsy brain and in mice. pS65-Ub levels are strongly and independently elevated in brains from subjects with Alzheimer's or Parkinson's disease compared to age-matched, neurologically normal controls. Furthermore, pS65-Ub levels have been used to identify disease risk and potential resilience factors in cells and in human brain. However, it remains unknown whether pS65-Ub measured in biofluids may also be suitable as a clinical biomarker. Here, we used a validated sandwich ELISA based on the Mesoscale discovery platform to assess pS65-Ub levels in over 1500 plasma samples from different cohorts across a spectrum of mild cognitive impairment, Alzheimer's disease, or Parkinson's disease. We further analyzed almost 150 CSF samples from two independent case-control series with Parkinson's disease to determine whether pS65-Ub levels are associated with disease status and other clinical parameters. While pS65-Ub levels are significantly changed with disease compared to controls in certain samples, current measurements in plasma are not sufficiently discriminatory to serve as a robust diagnostic marker. However, in CSF, pS65-Ub levels were decreased in patients with Parkinson's disease compared to controls, and there was better discrimination between these groups. Our data indicate that pS65-Ub shows promise as a biomarker in CSF but will require further replication in larger cohorts and possibly in combination with additional other measures.
    DOI:  https://doi.org/10.14336/AD.2025.1220
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