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Dev Cell. 2019 Jul 15. pii: S1534-5807(19)30569-6. doi: 10.1016/j.devcel.2019.06.016. [Epub ahead of print]

Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform.

Author information

1
Signalling Programme, Babraham Institute, Cambridge, UK.
2
Department of Biosciences, University of Helsinki, Helsingfors, Finland.
3
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
4
Institute of Biotechnology, University of Helsinki, Helsingfors, Finland.
5
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
6
Division of Medicine, University College London, London, UK.
7
Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsingfors, Finland.
8
Signalling Programme, Babraham Institute, Cambridge, UK. Electronic address: nicholas.ktistakis@babraham.ac.uk.

Abstract

The dynamics and coordination between autophagy machinery and selective receptors during mitophagy are unknown. Also unknown is whether mitophagy depends on pre-existing membranes or is triggered on the surface of damaged mitochondria. Using a ubiquitin-dependent mitophagy inducer, the lactone ivermectin, we have combined genetic and imaging experiments to address these questions. Ubiquitination of mitochondrial fragments is required the earliest, followed by auto-phosphorylation of TBK1. Next, early essential autophagy proteins FIP200 and ATG13 act at different steps, whereas ULK1 and ULK2 are dispensable. Receptors act temporally and mechanistically upstream of ATG13 but downstream of FIP200. The VPS34 complex functions at the omegasome step. ATG13 and optineurin target mitochondria in a discontinuous oscillatory way, suggesting multiple initiation events. Targeted ubiquitinated mitochondria are cradled by endoplasmic reticulum (ER) strands even without functional autophagy machinery and mitophagy adaptors. We propose that damaged mitochondria are ubiquitinated and dynamically encased in ER strands, providing platforms for formation of the mitophagosomes.

KEYWORDS:

autophagosome; autophagy; endoplasmic reticulum; mitophagy; super resolution microscopy; tomography

PMID:
31353311
DOI:
10.1016/j.devcel.2019.06.016
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