Impaired ubiquitin-proteasome-mediated PGC-1α protein turnover and induced mitochondrial biogenesis secondary to complex-I deficiency

Murtada H. Farhoud*, Leo G. Nijtmans, Ronald J.A. Wanders, Hans J.C.T. Wessels, Edwin Lasonder, Antoon J.M. Janssen, Richard R.J. Rodenburg, Lambert P. van den Heuvel, Jan A.M. Smeitink

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1349-1362
Number of pages14
JournalProteomics
Volume12
Issue number9
Early online date16 May 2012
DOIs
Publication statusPublished - May 2012
Externally publishedYes

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