TY - JOUR
T1 - Impaired ubiquitin-proteasome-mediated PGC-1α protein turnover and induced mitochondrial biogenesis secondary to complex-I deficiency
AU - Farhoud, Murtada H.
AU - Nijtmans, Leo G.
AU - Wanders, Ronald J.A.
AU - Wessels, Hans J.C.T.
AU - Lasonder, Edwin
AU - Janssen, Antoon J.M.
AU - Rodenburg, Richard R.J.
AU - van den Heuvel, Lambert P.
AU - Smeitink, Jan A.M.
N1 - Funding information: This work was supported in part by the Sixth Framework Program Priority 1, project titled “Rational treatment strategies com-bating mitochondrial oxidative phosphorylation (OXPHOS) dis-orders (EUMITOCOMBAT).”
PY - 2012/5
Y1 - 2012/5
N2 - 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.
AB - 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.
KW - Cell biology
KW - NADH:ubiquinone oxidoreductase
KW - OXPHOS
KW - PGC-1α
KW - SILAC
KW - Ubiquitin-proteasome system
UR - http://www.scopus.com/inward/record.url?scp=84861136640&partnerID=8YFLogxK
U2 - 10.1002/pmic.201100326
DO - 10.1002/pmic.201100326
M3 - Article
C2 - 22589185
AN - SCOPUS:84861136640
SN - 1615-9853
VL - 12
SP - 1349
EP - 1362
JO - Proteomics
JF - Proteomics
IS - 9
ER -