bims-tofagi Biomed News
on Mitophagy
Issue of 2024–04–21
two papers selected by
Michele Frison, University of Cambridge and Aitor Martínez Zarate, Euskal Herriko Unibertsitatea
  1. RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes.
  2. Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
  1. Free Radic Biol Med. 2024 Apr 12. pii: S0891-5849(24)00385-X. [Epub ahead of print]
    RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes.
    Yifei Chen, Fuji Yang, Yujie Shi, Jingyu Sheng, Yanjin Wang, Liting Zhang, Jing Zhou, Yi Jin, Yongmin Yan.
       BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is one of the liver illnesses that may be affected by mitophagy, which is the selective removal of damaged mitochondria. RNF31, an E3 ubiquitin ligase, is carcinogenic in many malignancies. However, the influence of RNF31 on mitochondrial homeostasis and NAFLD development remains unknown.
    METHODS: Oleic-palmitic acid treated hepatocytes and high-fat diet (HFD)-fed mice were established to observe the effect of RNF31 on hepatocyte mitophagy and steatosis. Mitophagy processes were comprehensively assessed by mt-Keima fluorescence imaging, while global changes in hepatic gene expression were measured by RNA-seq.
    RESULTS: The present study discovered a reduction in RNF31 expression in lipotoxic hepatocytes with mitochondrial dysfunction. The observed decrease in RNF31 expression was associated with reduced mitochondrial membrane potential, disturbed mitophagy, and increased steatosis. Additionally, the findings indicated that RNF31 is a pivotal factor in the initiation of mitophagy and the facilitation of mitochondrial homeostasis, resulting in a decrease in steatosis in lipotoxic hepatocytes. Mechanistically, RNF31 enhanced p53 ubiquitination and subsequent proteasomal degradation. Down-regulation of p53 led to increased expression of the mitophagy receptor protein BCL2 and adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), thereby promoting mitophagy in hepatocytes. Furthermore, it was demonstrated that the transportation of RNF31 via small extracellular vesicles derived from mesenchymal stem cells (referred to as sEV) had a substantial influence on reducing hepatic steatosis and restoring liver function in HFD-fed mice.
    CONCLUSIONS: The findings highlight RNF31's essential role in the regulation of mitochondrial homeostasis in hepatocytes, emphasizing its potential as a therapeutic target for NAFLD.
    Keywords:  Extracellular vesicles; Mitophagy; RNF31; Steatosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.04.214
  2. Nat Commun. 2024 Apr 18. 15(1): 3326
    Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
    Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen.
      Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. We show that Cdk8 promotes the phosphorylation of Drp1 at S616, a protein required for mitochondrial fission. Interestingly, Pink1, a mitochondrial kinase implicated in Parkinson's disease, also phosphorylates Drp1 at the same residue. Indeed, overexpression of Cdk8 significantly suppresses the phenotypes observed in flies with low levels of Pink1, including elevated levels of ROS, mitochondrial dysmorphology, and behavioral defects. In summary, we propose that Pink1 and Cdk8 perform similar functions to promote Drp1-mediated fission.
    DOI:  https://doi.org/10.1038/s41467-024-47623-8
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