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

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 iverm...

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Published in:Developmental cell Vol. 50; no. 5; p. 627
Main Authors: Zachari, Maria, Gudmundsson, Sigurdur R, Li, Ziyue, Manifava, Maria, Cugliandolo, Fiorella, Shah, Ronak, Smith, Matthew, Stronge, James, Karanasios, Eleftherios, Piunti, Caterina, Kishi-Itakura, Chieko, Vihinen, Helena, Jokitalo, Eija, Guan, Jun-Lin, Buss, Folma, Smith, Andrew M, Walker, Simon A, Eskelinen, Eeva-Liisa, Ktistakis, Nicholas T
Format: Journal Article
Language:English
Published: United States 09.09.2019
Subjects:
Animals
Apoptosis Regulatory Proteins - metabolism
Autophagy-Related Proteins - metabolism
Baculoviral IAP Repeat-Containing 3 Protein - metabolism
Cells, Cultured
Endoplasmic Reticulum - metabolism
HEK293 Cells
Humans
Inhibitor of Apoptosis Proteins - metabolism
Mice
Mitophagy
Mouse Embryonic Stem Cells - metabolism
TNF Receptor-Associated Factor 2 - metabolism
Ubiquitination
mitophagy
autophagy
autophagosome
tomography
endoplasmic reticulum
super resolution microscopy
ISSN:1878-1551, 1878-1551
Online Access:Get more information
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Summary: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.
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ISSN:1878-1551
1878-1551
DOI:10.1016/j.devcel.2019.06.016