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GAK and PRKCD are positive regulators of PRKN-independent mitophagy

Author

Listed:
  • Michael J. Munson

    (University of Oslo
    University of Oslo
    BioPharmaceuticals R&D, AstraZeneca)

  • Benan J. Mathai

    (University of Oslo
    University of Oslo)

  • Matthew Yoke Wui Ng

    (University of Oslo
    University of Oslo)

  • Laura Trachsel-Moncho

    (University of Oslo
    University of Oslo)

  • Laura R. Ballina

    (University of Oslo
    University of Oslo)

  • Sebastian W. Schultz

    (University of Oslo
    The Norwegian Radium Hospital Montebello)

  • Yahyah Aman

    (University of Oslo and Akershus University Hospital)

  • Alf H. Lystad

    (University of Oslo
    University of Oslo)

  • Sakshi Singh

    (University of Oslo
    University of Oslo)

  • Sachin Singh

    (University of Oslo
    The Norwegian Radium Hospital Montebello)

  • Jørgen Wesche

    (University of Oslo
    The Norwegian Radium Hospital Montebello)

  • Evandro F. Fang

    (University of Oslo and Akershus University Hospital)

  • Anne Simonsen

    (University of Oslo
    University of Oslo
    The Norwegian Radium Hospital Montebello)

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.

Suggested Citation

  • 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 , 2021. "GAK and PRKCD are positive regulators of PRKN-independent mitophagy," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26331-7
    DOI: 10.1038/s41467-021-26331-7
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    References listed on IDEAS

    as
    1. Petter Holland & Helene Knævelsrud & Kristiane Søreng & Benan J. Mathai & Alf Håkon Lystad & Serhiy Pankiv & Gunnveig T. Bjørndal & Sebastian W. Schultz & Viola H. Lobert & Robin B. Chan & Bowen Zhou , 2016. "HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    2. Michael Lazarou & Danielle A. Sliter & Lesley A. Kane & Shireen A. Sarraf & Chunxin Wang & Jonathon L. Burman & Dionisia P. Sideris & Adam I. Fogel & Richard J. Youle, 2015. "The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy," Nature, Nature, vol. 524(7565), pages 309-314, August.
    3. Matthew Y. Tang & Marta Vranas & Andrea I. Krahn & Shayal Pundlik & Jean- François Trempe & Edward A. Fon, 2017. "Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    4. Konstantinos Palikaras & Eirini Lionaki & Nektarios Tavernarakis, 2015. "Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans," Nature, Nature, vol. 521(7553), pages 525-528, May.
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    Cited by:

    1. Matthew Yoke Wui Ng & Chara Charsou & Ana Lapao & Sakshi Singh & Laura Trachsel-Moncho & Sebastian W. Schultz & Sigve Nakken & Michael J. Munson & Anne Simonsen, 2022. "The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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