Unconventional initiation of PINK1/Parkin mitophagy by Optineurin

Thanh Ngoc Nguyen, Justyna Sawa-Makarska, Grace Khuu, Wai Kit Lam, Elias Adriaenssens, Dorotea Fracchiolla, Stephen Shoebridge, Daniel Bernklau, Benjamin Scott Padman, Marvin Skulsuppaisarn, Runa S.J. Lindblom, Sascha Martens, Michael Lazarou

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an “autophagosome” on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.

Original languageEnglish
Pages (from-to)1693-1709.e9
Number of pages26
JournalMolecular Cell
Volume83
Issue number10
DOIs
Publication statusPublished - 18 May 2023

Keywords

  • autophagosome
  • autophagy
  • OPTN
  • Parkin
  • PINK1
  • selective autophagy
  • TBK1

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