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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    • "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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    ABSTRACT: Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and ageing.
    Experimental gerontology 08/2014; 56. DOI:10.1016/j.exger.2014.01.021 · 3.49 Impact Factor
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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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    ABSTRACT: Background Lewy bodies (LB) are a neuropathological hallmark of Parkinson’s disease (PD) and other synucleinopathies. The role their formation plays in disease pathogenesis is not well understood, in part because studies of LB have been limited to examination of post-mortem tissue. LB formation may be detrimental to neuronal survival or merely an adaptive response to other ongoing pathological processes. In a human cytoplasmic hybrid (cybrid) neural cell model that expresses mitochondrial DNA from PD patients, we observed spontaneous formation of intracellular protein aggregates (“cybrid LB” or CLB) that replicate morphological and biochemical properties of native, cortical LB. We studied mitochondrial morphology, bioenergetics and biogenesis signaling by creating stable sub-clones of three PD cybrid cell lines derived from cells expressing CLB. Results Cloning based on CLB expression had a differential effect on mitochondrial morphology, movement and oxygen utilization in each of three sub-cloned lines, but no long-term change in CLB expression. In one line (PD63CLB), mitochondrial function declined compared to the original PD cybrid line (PD63Orig) due to low levels of mtDNA in nucleoids. In another cell line (PD61Orig), the reverse was true, and cellular and mitochondrial function improved after sub-cloning for CLB expression (PD61CLB). In the third cell line (PD67Orig), there was no change in function after selection for CLB expression (PD67CLB). Conclusions Expression of mitochondrial DNA derived from PD patients in cybrid cell lines induced the spontaneous formation of CLB. The creation of three sub-cloned cybrid lines from cells expressing CLB resulted in differential phenotypic changes in mitochondrial and cellular function. These changes were driven by the expression of patient derived mitochondrial DNA in nucleoids, rather than by the presence of CLB. Our studies suggest that mitochondrial DNA plays an important role in cellular and mitochondrial dysfunction in PD. Additional studies will be needed to assess the direct effect of CLB expression on cellular and mitochondrial function.
    Molecular Neurodegeneration 01/2013; 8(1):6. DOI:10.1186/1750-1326-8-6 · 6.56 Impact Factor
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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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    ABSTRACT: Increased mitochondrial biogenesis by activation of PPAR- or AMPK/PGC-1α-dependent homeostatic pathways has been proposed as a treatment for mitochondrial disease. We tested this hypothesis on three recombinant mouse models characterized by defective cytochrome c-oxidase (COX) activity: a knockout (KO) mouse for Surf1, a knockout/knockin mouse for Sco2, and a muscle-restricted KO mouse for Cox15. First, we demonstrated that double-recombinant animals overexpressing PGC-1α in skeletal muscle on a Surf1 KO background showed robust induction of mitochondrial biogenesis and increase of mitochondrial respiratory chain activities, including COX. No such effect was obtained by treating both Surf1(-/-) and Cox15(-/-) mice with the pan-PPAR agonist bezafibrate, which instead showed adverse effects in either model. Contrariwise, treatment with the AMPK agonist AICAR led to partial correction of COX deficiency in all three models, and, importantly, significant motor improvement up to normal in the Sco2(KO/KI) mouse. These results open new perspectives for therapy of mitochondrial disease.
    Cell metabolism 07/2011; 14(1):80-90. DOI:10.1016/j.cmet.2011.04.011 · 17.57 Impact Factor
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