PGC-1 / induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders

Department of Neurology, University of Miami School of Medicine, Miami, FL 33136, USA.
Human Molecular Genetics (Impact Factor: 6.39). 04/2009; 18(10):1805-12. DOI: 10.1093/hmg/ddp093
Source: PubMed


Members of the peroxisome proliferator-activated receptor gamma coactivator (PGC) family are potent inducers of mitochondrial biogenesis. We have tested the potential effect of increased mitochondrial biogenesis in cells derived from patients harboring oxidative phosphorylation defects due to either nuclear or mitochondrial DNA mutations. We found that the PGC-1alpha and/or PGC-1beta expression improved mitochondrial respiration in cells harboring a complex III or IV deficiency as well as in transmitochondrial cybrids harboring mitochondrial encephalomyopathy lactic acidosis and stroke A3243G tRNA((Leu)UUR) gene mutation. The respiratory function improvement was found to be associated with increased levels of mitochondrial components per cell, although this increase was not homogeneous. These results reinforce the concept that increased mitochondrial biogenesis is a promising venue for the treatment of mitochondrial diseases.

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Available from: Francisca Diaz
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    • "Studies in mouse models of mitochondrial diseases indicate that overexpression of PGC-1α alleviates mitochondrial defects and triggers mitochondrial proliferation (Viscomi et al., 2011). Additionally, studies in human cells with complex III or IV deficiency showed that expression of PGC- 1α, and/or its homologue PGC-1β, improves mitochondrial respiration (Srivastava et al., 2009). Therefore, PGC-1α is characterized as the master regulator of mitochondrial biogenesis and function. "
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    • "Overexpression of PGC-1α in neurons was found to be protective in a neurotoxin mouse model of PD [56]. In cell culture, primary fibroblasts and cybrids generated using mtDNA from patients with mitochondrial diseases showed improved respiration after increased PGC1-α expression [57]. PPAR (peroxisome proliferator-activated receptor) agonists, such as bezafibrate (an agonist of PPARα), have also been shown to improve mitochondrial function in patient fibroblasts and myoblasts [58] and in a mouse model of mitochondrial disease [59]. "
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    • "These observations have suggested the hypothesis that the deleterious effects of either mtDNA-or nuclear-gene mutations could be overcome, at least partially, by increasing the total amount of mitochondria and/or of functionally active " MRC units, " via activation of the mitochondrial biogenesis program in critical tissues (Bastin et al., 2008; Wenz et al., 2008). This idea has first been tested in cells from mitochondrial disease patients, by overexpressing recombinant PGC-1α or by adding bezafibrate in the medium (Bastin et al., 2008; Srivastava et al., 2009). Both treatments showed mutant cells to partially recover MRC activities and increase ATP production. "
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