title: 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.
authors.affiliation: a Department of Physiology , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Moore
authors.affiliation: a Department of Physiology , Perelman School of Medicine, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D001343:Autophagy; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D011956:Receptors, Cell Surface