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 () and Esther M. Verheyen ()
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Jenny Zhe Liao: Simon Fraser University
Hyung-lok Chung: Houston Methodist Research Institute
Claire Shih: Simon Fraser University
Kenneth Kin Lam Wong: Simon Fraser University
Debdeep Dutta: Baylor College of Medicine
Zelha Nil: Baylor College of Medicine
Catherine Grace Burns: Baylor College of Medicine
Oguz Kanca: Baylor College of Medicine
Ye-Jin Park: Baylor College of Medicine
Zhongyuan Zuo: Baylor College of Medicine
Paul C. Marcogliese: University of Manitoba
Katherine Sew: Simon Fraser University
Hugo J. Bellen: Baylor College of Medicine
Esther M. Verheyen: Simon Fraser University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47623-8

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