Parkin coordinates mitochondrial lipid remodeling to execute mitophagy.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lin, C-C; Yan, J; Kapur, MD; Norris, KL; Hsieh, C-W; Huang, D; Vitale, N; Lim, K-L; Guan, Z; Wang, X-F; Chi, J-T; Yang, W-Y; Yao, T-P

Published Date

  • December 6, 2022

Published In

Volume / Issue

  • 23 / 12

Start / End Page

  • e55191 -

PubMed ID

  • 36256516

Pubmed Central ID

  • PMC9724658

Electronic International Standard Serial Number (EISSN)

  • 1469-3178

Digital Object Identifier (DOI)

  • 10.15252/embr.202255191

Language

  • eng

Conference Location

  • England