@article{12bbb05444944a3e85976e8ba5e9df20,
title = "Unconventional initiation of PINK1/Parkin mitophagy by Optineurin",
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.",
keywords = "autophagosome, autophagy, OPTN, Parkin, PINK1, selective autophagy, TBK1",
author = "Nguyen, {Thanh Ngoc} and Justyna Sawa-Makarska and Grace Khuu and Lam, {Wai Kit} and Elias Adriaenssens and Dorotea Fracchiolla and Stephen Shoebridge and Daniel Bernklau and Padman, {Benjamin Scott} and Marvin Skulsuppaisarn and Lindblom, {Runa S.J.} and Sascha Martens and Michael Lazarou",
note = "Funding Information: This work was supported by the National Health and Medical Research Council (NHMRC) ( GNT1106471 to M.L.), the Australian Research Council (ARC) Discovery Project ( DP200100347 to M.L.), the Human Frontiers Science Program RGP0026/2017 (to S.M.), a research and travel grant from the Flanders Fund for Scientific Research (FWO-Flanders to E.A.), and a Marie Sk{\l}odowska-Curie MSCA Postdoctoral Fellowship ( 101062916 to E.A.). This research was also funded in whole or in part by Aligning Science Across Parkinson{\textquoteright}s ( ASAP-000350 to S.M. and M.L.) through the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research (MJFF). For the purpose of open access, the author has applied a CC BY public copyright license to all author-accepted manuscripts arising from this submission. Funding Information: We thank members of the Larazou Lab and others in Aligning Science Across Parkinson's (ASAP) Team mito911 for their advice and discussions. We thank the laboratory of Noboru Mizushima (The University of Tokyo) for sharing FIP200 KO/penta KO cells and the laboratory of Mike Ryan (Monash Biomedicine Discovery Institute, Monash University) for sharing anti-B17.2L antibodies. We also thank the Monash Flow Cytometry Platform (FlowCore), the Monash Micro Imaging Platform, the Ramaciotti Centre for Cryo-Electron Microscopy, and the Max Perutz Labs BioOptics and Mass Spectrometry facilities for their technical support. This work was supported by the National Health and Medical Research Council (NHMRC) (GNT1106471 to M.L.), the Australian Research Council (ARC) Discovery Project (DP200100347 to M.L.), the Human Frontiers Science Program RGP0026/2017 (to S.M.), a research and travel grant from the Flanders Fund for Scientific Research (FWO-Flanders to E.A.), and a Marie Sk{\l}odowska-Curie MSCA Postdoctoral Fellowship (101062916 to E.A.). This research was also funded in whole or in part by Aligning Science Across Parkinson's (ASAP-000350 to S.M. and M.L.) through the Michael J. Fox Foundation for Parkinson's Research (MJFF). For the purpose of open access, the author has applied a CC BY public copyright license to all author-accepted manuscripts arising from this submission. T.N.N. and M.L. conceived the projects. T.N.N. J.S.-M. S.M. and M.L. designed the experiments. T.N.N. J.S.-M. G.K. W.K.L. E.A. D.F. S.S. D.B. B.S.P. M.S. and R.S.J.L. performed the experiments. T.N.N. and M.L. wrote the manuscript, and all authors contributed to preparing and editing the manuscript. S.M. is a member of the scientific advisory board of Casma Therapeutics. M.L. is a member of the scientific advisory board and co-founder of Automera. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = may,
day = "18",
doi = "10.1016/j.molcel.2023.04.021",
language = "English",
volume = "83",
pages = "1693--1709.e9",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "10",
}