bims-tofagi Biomed News
on Mitophagy
Issue of 2025–10–12
seven papers selected by
Michele Frison, University of Cambridge
  1. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  2. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
  3. STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  4. Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
  5. PEX14 acts as a molecular link between optineurin and the autophagic machinery to induce pexophagy.
  6. PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis.
  7. P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma.
  1. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  2. Sci Adv. 2025 Oct 10. 11(41): eadw4153
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1126/sciadv.adw4153
  3. Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2508809122
    STAR/STARD1: A mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the alternate pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet rapid mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process have remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    Keywords:  cholesterol; intermembrane space; lipoid congenital adrenal hyperplasia; mitochondria; steroidogenesis
    DOI:  https://doi.org/10.1073/pnas.2508809122
  4. Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01192-1. [Epub ahead of print]44(10): 116421
    Mycobacterium bovis induces macrophage mitochondrial release of hexokinase 2 to enhance intracellular survival.
    Lin Li, Yulan Chen, Yuanzhi Wang, Yuhui Dong, Haoran Wang, Ziyi Liu, Xin Ge, Puxiu Shen, Yue Li, Dingpu Liu, Xiangmei Zhou.
      Hexokinases (HKs) are essential enzymes in sugar metabolism, but their mitochondrial release also reflects cellular status in disease. Mycobacterium bovis (M. bovis), the causative agent of bovine and human tuberculosis, infects macrophages and induces mitophagy, yet the role of HKs in this process remains unclear. We find that M. bovis infection induces the release of HK2 from mitochondria, where it dissociates from voltage-dependent anion channel (VDAC). This dissociation promotes VDAC oligomerization, pore formation in the outer mitochondrial membrane, and mitochondrial damage. Damaged mitochondria subsequently undergo mitophagy, which enhances the intracellular survival of M. bovis. Consistent with this mechanism, we show that ESAT6-mediated phagosome membrane rupture is critical for HK2 release and subsequent mitochondrial events. Our study identifies a pathway by which M. bovis manipulates host cell processes to promote survival, providing insights into the host-pathogen interaction and potential avenues for tuberculosis prevention and therapy.
    Keywords:  CP: Microbiology; Mycobacterium bovis; VDAC; autophagy; hexokinase; macrophage; mitochondria; mitophagy; tuberculosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116421
  5. J Cell Biol. 2025 Nov 03. pii: e202411184. [Epub ahead of print]224(11):
    PEX14 acts as a molecular link between optineurin and the autophagic machinery to induce pexophagy.
    Hongli Li, Suyuan Chen, Celien Lismont, Bram Vandewinkel, Mohamed A F Hussein, Cláudio F Costa, Dorien Imberechts, Yiyang Liu, Jorge E Azevedo, Wim Vandenberghe, Steven Verhelst, Hans R Waterham, Pieter Vanden Berghe, Myriam Baes, Marc Fransen.
      Pexophagy, the selective degradation of peroxisomes, is essential for removing excess or dysfunctional peroxisomes, and its dysregulation has been linked to various diseases. Although optineurin (OPTN), an autophagy receptor involved in mitophagy, aggrephagy, and xenophagy, has also been implicated in pexophagy in HEK-293 cells, the underlying mechanisms remain unclear. Using proximity labeling, we identified PEX14, a peroxisomal membrane protein, as a neighboring partner of OPTN. Microscopy analyses revealed that clustering of peroxisomes with OPTN is a key feature of OPTN-mediated pexophagy. Biochemical studies demonstrated that PEX14 and OPTN interact through their coiled-coil and ubiquitin-binding domains, respectively. Further analyses showed that the C-terminal half of overexpressed OPTN triggers pexophagy, likely by oligomerizing with endogenous OPTN. The colocalization of PEX14-OPTN complexes with LC3, together with the suppression of OPTN-mediated peroxisome degradation by bafilomycin A1, supports a model in which PEX14 acts as a docking site for OPTN on the peroxisomal membrane, enabling the recruitment of the autophagic machinery for OPTN-mediated pexophagy.
    DOI:  https://doi.org/10.1083/jcb.202411184
  6. Autophagy. 2025 Oct 08.
    PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis.
    Ningning Li, Hongyu Hou, Dan Su, Bojun Yang, Rui Ni, Guoqiang Ma, Shan Sun, Qilian Ma, Qiang Peng, Siqian Chen, Kin Yip Tam, Hongfeng Wang, Zheng Ying.
      Atg8-family proteins are autophagosome-associated proteins and play important roles in macroautophagy/autophagy, a conserved process for degrading defective or excessive cellular components. Post-translational modifications of mammalian Atg8-family proteins, including phosphorylation, regulate multiple steps in the autophagic process. In this context, several Atg8-family protein-associated kinases have been found to regulate autophagy, yet the phosphatases in the dephosphorylation of Atg8-family proteins remain unknown. Here, we report that the heterotrimeric PPP2/PP2A (protein phosphatase 2) is a novel regulator in modulating LC3B dephosphorylation. Mechanistically, we find that PPP2-mediated LC3B dephosphorylation reduces the interaction between LC3B and the mitophagy receptor OPTN, thereby impeding the mitochondrial recruitment of phagophores during PINK1-PRKN/Parkin-mediated mitophagy. Interestingly, we find that overexpression of the β2 isoform of PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta; PPP2R2Bβ2), which mimics the spinocerebellar ataxia type 12 (SCA12) pathological condition, harms neuronal survival by enhancing PPP2-mediated LC3B dephosphorylation and reducing mitochondrial recruitment of phagophores upon mitochondrial damage. Importantly, pharmacological induction of mitophagy by the small molecule compound deferiprone (DFP) relieves PPP2R2Bβ2-mediated neuronal toxicity. Overall, our results not only uncover a mechanism by which protein dephosphorylation negatively regulates mitophagy but also provide insights into the pathogenesis of PPP2R2Bβ2-mediated SCA12.
    Keywords:  LC3B; PINK1-PRKN/Parkin-mediated mitophagy; PPP2/PP2A; PPP2R2Bβ2; dephosphorylation; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2025.2572528
  7. Cell Death Dis. 2025 Oct 06. 16(1): 685
    P4HA2 interacted with ATAD3A to modulate PINK1/parkin-dependent mitophagy and 125I brachytherapy sensitization in esophageal carcinoma.
    Xijuan Yao, Cheng Feng, Xing Huang, Songzhe Wu, Shuting Lu, Yang Gao, Tong Sun, Xiaxing Bai, Chenghui Li, Kaizhi Jia, Xue Han, Zhongkai Wang, Binda Chen, Xiaobin Wang, Jinhe Guo, Jian Lu.
      Interventional brachytherapy, such as iodine-125(125I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after 125I brachytherapy. It is key to decipher the underlying mechanism of 125I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to 125I treatment. Mechanistically, P4HA2 enhances mitochondrial autophagy (mitophagy) via the PINK1/parkin pathway by binding to ATAD3A. Clinically, high expression of P4HA2 correlates with shorter overall survival and predicts poor prognosis with 125I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m6A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to 125I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated 125I radioresistance, which provides a potential therapeutic target and combinatorial strategy. Schematic diagram of the role of P4HA2 in 125I brachytherapy for tumors.
    DOI:  https://doi.org/10.1038/s41419-025-07864-x
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