GAK and PRKCD are positive regulators of PRKN-independent mitophagy

Michael J. Munson (), Benan J. Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R. Ballina, Sebastian W. Schultz, Yahyah Aman, Alf H. Lystad, Sakshi Singh, Sachin Singh, Jørgen Wesche, Evandro F. Fang and Anne Simonsen ()
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Michael J. Munson: University of Oslo
Benan J. Mathai: University of Oslo
Matthew Yoke Wui Ng: University of Oslo
Laura Trachsel-Moncho: University of Oslo
Laura R. Ballina: University of Oslo
Sebastian W. Schultz: University of Oslo
Yahyah Aman: University of Oslo and Akershus University Hospital
Alf H. Lystad: University of Oslo
Sakshi Singh: University of Oslo
Sachin Singh: University of Oslo
Jørgen Wesche: University of Oslo
Evandro F. Fang: University of Oslo and Akershus University Hospital
Anne Simonsen: University of Oslo

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: Abstract The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remains elusive. Here, we have screened for regulators of PRKN-independent mitophagy using an siRNA library targeting 197 proteins containing lipid interacting domains. We identify Cyclin G-associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as regulators of PRKN-independent mitophagy, with both being dispensable for PRKN-dependent mitophagy and starvation-induced autophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD facilitates recruitment of ULK1/ATG13 to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C. elegans or knockout of PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy regulation.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26331-7

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DOI: 10.1038/s41467-021-26331-7

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