title: Impaired ubiquitin-proteasome-mediated PGC-1α protein turnover and induced mitochondrial biogenesis secondary to complex-I deficiency.
abstract: Most eukaryotic cells depend on mitochondrial OXidative PHOSphorylation (OXPHOS) in their ATP supply. The cellular consequences of OXPHOS defects and the pathophysiological mechanisms in related disorders are incompletely understood. Using a quantitative proteomics approach we provide evidence that a genetic defect of complex-I of the OXPHOS system may associate with transcriptional derangements of mitochondrial biogenesis through stabilization of the master transcriptional regulator PPARγ co-activator 1α (PGC-1α) protein. Chronic oxidative stress suppresses the gene expression of PGC-1α but concomitant inhibition of the ubiquitin-proteasome system (UPS) can stabilize this co-activator protein, thereby inducing its downstream metabolic gene expression programs. Thus, mitochondrial biogenesis, which lays at the heart of the homeostatic control of energy metabolism, can be deregulated by secondary impairments of the protein turnover machinery.
authors.affiliation: Nijmegen Center for Mitochondrial Disorders (NCMD), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.h.j.selman@lumc.nl
authors.forename: Murtada H
authors.initials: MH
authors.lastname: Farhoud
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Hans J C T
authors.initials: HJ
authors.lastname: Wessels
authors.forename: Edwin
authors.initials: E
authors.lastname: Lasonder
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: Janssen
authors.forename: Richard R J
authors.initials: RR
authors.lastname: Rodenburg
authors.forename: Lambert P
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
mesh_terms: D002478:Cells, Cultured; D042967:Electron Transport Complex I; D005347:Fibroblasts; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020543:Proteome; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020543:Proteome; D014157:Transcription Factors; D025801:Ubiquitin; D006861:Hydrogen Peroxide; D046988:Proteasome Endopeptidase Complex; D042967:Electron Transport Complex I