title: Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy.
abstract: Mitochondria can be degraded by autophagy in a process termed mitophagy. The Parkinson-disease-associated ubiquitin ligase Parkin can trigger mitophagy of depolarized mitochondria. However, it remains to be determined how the autophagy machinery is involved in this specific type of autophagy. It has been speculated that adaptor proteins such as p62 might mediate the interaction between the autophagosomal LC3 family of proteins and ubiquitylated proteins on mitochondria. Here, we describe our systematic analysis of the recruitment of Atg proteins in Parkin-dependent mitophagy. Structures containing upstream Atg proteins, including ULK1, Atg14, DFCP1, WIPI-1 and Atg16L1, can associate with depolarized mitochondria even in the absence of membrane-bound LC3. Atg9A structures are also recruited to these damaged mitochondria as well as to the autophagosome formation site during starvation-induced canonical autophagy. In the initial steps of Parkin-mediated mitophagy, the structures containing the ULK1 complex and Atg9A are independently recruited to depolarized mitochondria and both are required for further recruitment of downstream Atg proteins except LC3. Autophagosomal LC3 is important for efficient incorporation of damaged mitochondria into the autophagosome at a later stage. These findings suggest a process whereby the isolation membrane is generated de novo on damaged mitochondria as opposed to one where a preformed isolation membrane recognizes mitochondria.
authors.affiliation: Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519,  Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Itakura
authors.forename: Chieko
authors.initials: C
authors.lastname: Kishi-Itakura
authors.forename: Ikuko
authors.initials: I
authors.lastname: Koyama-Honda
authors.forename: Noboru
authors.initials: N
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D033921:Vesicular Transport Proteins
chemical_list: C549015:Atg9A protein, mouse; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse