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Landscape of the PARKIN‐dependent ubiquitin modified proteome in response to mitochondrial depolarization defined through quantitative proteomics
Author(s) -
Sarraf Shireen A,
Raman Malavika,
GuaraniPereira Virginia,
Sowa Mathew E,
Huttlin Edward L,
Gygi Steven P,
Harper J Wade
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.553.17
Subject(s) - parkin , pink1 , mitophagy , ubiquitin ligase , ubiquitin , biology , microbiology and biotechnology , mitochondrion , proteome , proteasome , biochemistry , parkinson's disease , autophagy , apoptosis , medicine , disease , pathology , gene
Parkinson's Disease (PD) results from loss of dopaminergic neurons of the substantia nigra, in part due to mitochondrial malfunction. The protein kinase PINK1 and E3 ubiquitin ligase PARKIN, found mutated in hereditary and sporadic forms of PD, are thought to control mitochondrial homeostasis. Upon mitochondrial damage, activation of PINK1 on the mitochondrial outer membrane (MOM) recruits PARKIN to ubiquitylate Porin, Mitofusin, and Miro proteins on the MOM; however, the full repertoire of PARKIN substrates and how their ubiquitylation alters mitochondrial homeostasis via mitophagy is poorly understood. Large‐scale quantitative diGLY capture proteomics identified hundreds of ubiquitylation sites in dozens of proteins upon mitochondrial depolarization, with strong enrichment for mitochondrial proteins. Physical association of PARKIN with a cohort of ubiquitylation targets and the proteasome was dependent upon mitochondrial depolarization. Structural and evolutionary analysis of PARKIN‐dependent ubiquitylation events revealed conservation of target sites in vertebrate and D. melanogaster MOM proteins. These studies provide a resource for elucidating how the PINK1‐PARKIN pathway re‐sculpts the mitochondrial proteome via ubiquitylation to maintain mitochondrial homeostasis. Supported by NIH grants GM070565 to JWH, GM067945 to SPG, and a grant from the Michael J Fox Foundation to JWH.