Spatiotemporal dynamics of autophagy receptors in selective mitophagy.

ABSTRACT: Damaged mitochondria are turned over through a process of selective autophagy termed mitophagy. In mitophagy, unhealthy mitochondria are recognized and ubiquitinated by Parkinson disease-linked proteins PINK1 and PARK2. The subsequent recruitment of ubiquitin-binding autophagy receptors leads in turn to the sequestration of the damaged organelles into LC3-positive phagophores, precursors to autophagosomes. The precise identity of these receptors and how they are regulated has been the focus of considerable attention. Our recent work uses live-cell imaging to explore the dynamics and regulation of autophagy receptor recruitment. Utilizing multiple paradigms to induce mitochondrial damage, we identified the rapid, 2-step recruitment of autophagy receptors OPTN, CALCOCO2/NDP52, and TAX1BP1. All 3 receptors are recruited to damaged mitochondria with similar kinetics; however, only OPTN is necessary for efficient formation of a phagophore sequestering damaged mitochondria from the cytosol. OPTN is co-recruited to damaged mitochondria along with its upstream kinase TBK1. Depletion of OPTN or TBK1, or expression of amyotrophic lateral sclerosis (ALS)-linked mutations in either protein, interfere with efficient autophagic engulfment of depolarized mitochondria. These observations suggest that insufficient autophagy of damaged mitochondria may contribute to neurodegenerative disease.

SUBMITTER: Moore AS 

PROVIDER: S-EPMC5079667 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature