title: Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi.
abstract: We report here that blocking the activity of the 26 S proteasome results in drastic changes in the morphology of the mitochondria and accumulation of intermembrane space (IMS) proteins. Using endonuclease G (endoG) as a model IMS protein, we found that accumulation of wild-type but to a greater extent mutant endoG leads to changes in the morphology of the mitochondria similar to those observed following proteasomal inhibition. Further, we show that wild-type but to a greater extent mutant endoG is a substrate for ubiquitination, suggesting the presence of a protein quality control. Conversely, we also report that wild-type but not mutant endoG is a substrate for the mitochondrial protease Omi but only upon inhibition of the proteasome. These findings suggest that although elimination of mutant IMS proteins is strictly dependent on ubiquitination, elimination of excess or spontaneously misfolded wild-type IMS proteins is monitored by ubiquitination and as a second checkpoint by Omi cleavage when the proteasome function is deficient. One implication of our finding is that in the context of attenuated proteasomal function, accumulation of IMS proteins would contribute to the collapse of the mitochondrial network such as that observed in neurodegenerative diseases. Another implication is that such collapse could be accelerated either by mutations in IMS proteins or by mutations in Omi itself.
authors: Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors: Susanne
authors: S
authors: Radke
authors: Harish
authors: H
authors: Chander
authors: Patrick
authors: P
authors: Schäfer
authors: Gregor
authors: G
authors: Meiss
authors: Rejko
authors: R
authors: Krüger
authors: Jörg B
authors: JB
authors: Schulz
authors: Doris
authors: D
authors: Germain
mesh_terms: D002460:Cell Line; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008854:Microscopy, Electron; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021381:Protein Transport; D054875:Ubiquitination
chemical_list: D024101:Mitochondrial Proteins; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D046988:Proteasome Endopeptidase Complex