title: Temporal dynamics of PARK2/parkin and OPTN/optineurin recruitment during the mitophagy of damaged mitochondria.
abstract: Damaged mitochondria are selectively degraded via autophagy in a regulated pathway known as mitophagy. Parkinson disease-linked proteins PINK1 (PTEN induced putative kinase 1) and PARK2 (parkin RBR E3 ubiquitin protein ligase) are recruited to the outer mitochondrial membrane upon mitochondrial damage, leading to the PARK2-mediated ubiquitination of mitochondrial proteins. Here, we discuss our recent work demonstrating that OPTN (optineurin) is recruited to damaged mitochondria, serving as an autophagy receptor for autophagosome formation around mitochondria. Using high-resolution live-cell imaging, we find that OPTN is recruited to ubiquitinated mitochondria downstream of PARK2, and induces autophagosome assembly around mitochondria via its LC3-interacting region. Mutations in OPTN are linked to both glaucoma and ALS (amyotrophic lateral sclerosis), and an ALS-associated E478G mutation in OPTN's ubiquitin binding domain leads to defective mitophagy and accumulation of damaged mitochondria. Importantly, our results highlight a role for mitophagy defects in ALS pathogenesis, and demonstrate that defects in the same pathway for mitochondrial homeostasis are causal for both familial Parkinson disease and ALS.
authors: a Department of Physiology ; Perelman School of Medicine ; University of Pennsylvania ; Philadelphia , PA USA.
authors: Yvette C
authors: YC
authors: Wong
authors: Erika L F
authors: EL
authors: Holzbaur
mesh_terms: D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D006367:HeLa Cells; D006801:Humans; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D035582:Transcription Factor TFIIIA / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Parkinson disease; amyotrophic lateral sclerosis (ALS); autophagy receptor; glaucoma; mitochondria; mitophagy; optineurin; parkin