Parkin coordinates mitochondrial lipid remodeling to execute mitophagy

Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubi...

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Bibliographic Details
Published in:EMBO reports 2022-12, Vol.23 (12), p.e55191-n/a
Main Authors: Lin, Chao‐Chieh, Yan, Jin, Kapur, Meghan D, Norris, Kristi L, Hsieh, Cheng‐Wei, Huang, De, Vitale, Nicolas, Lim, Kah‐Leong, Guan, Ziqiang, Wang, Xiao‐Fan, Chi, Jen‐Tsan, Yang, Wei‐Yuan, Yao, Tso‐Pang
Format: Article
Language:English
Subjects:
Assembly
Autophagy
Binding
Destruction
diacylglycerol
Diglycerides
Golgi apparatus
Lipids
Lipin‐1
Mitochondria
Mitophagy
Parkin
Parkin protein
Phagosomes
Phosphatidic acid
Phospholipase
Phospholipase D2
PLD2
Quality control
Receptors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitination
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Summary:Autophagy has emerged as the prime machinery for implementing organelle quality control. In the context of mitophagy, the ubiquitin E3 ligase Parkin tags impaired mitochondria with ubiquitin to activate autophagic degradation. Although ubiquitination is essential for mitophagy, it is unclear how ubiquitinated mitochondria activate autophagosome assembly locally to ensure efficient destruction. Here, we report that Parkin activates lipid remodeling on mitochondria targeted for autophagic destruction. Mitochondrial Parkin induces the production of phosphatidic acid (PA) and its subsequent conversion to diacylglycerol (DAG) by recruiting phospholipase D2 and activating the PA phosphatase, Lipin‐1. The production of DAG requires mitochondrial ubiquitination and ubiquitin‐binding autophagy receptors, NDP52 and optineurin (OPTN). Autophagic receptors, via Golgi‐derived vesicles, deliver an autophagic activator, EndoB1, to ubiquitinated mitochondria. Inhibition of Lipin‐1, NDP52/OPTN, or EndoB1 results in a failure to produce mitochondrial DAG, autophagosomes, and mitochondrial clearance, while exogenous cell‐permeable DAG can induce autophagosome production. Thus, mitochondrial DAG production acts downstream of Parkin to enable the local assembly of autophagosomes for the efficient disposal of ubiquitinated mitochondria. Synopsis Parkin orchestrates mitophagy by coordinating mitochondrial lipid remodeling and sequential production of mitochondrial phosphatic acid and diacylglycerol. Parkin engages phospholipase D2 (PLD2) to generate mitochondrial phosphatidic acid. Parkin‐mediated mitochondrial ubiquitination recruits the ubiquitin‐binding autophagic receptors, optineurin and NDP52, which promote mitochondrial diacylglycerol production via Lipin‐1. Mitochondrial diacylglycerol production stimulates autophagosome assembly and mitophagy. Parkin orchestrates mitophagy by coordinating mitochondrial lipid remodeling and sequential production of mitochondrial phosphatic acid and diacylglycerol.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.202255191