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PGC-1alpha/beta upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations.

ABSTRACT: We have studied the functional effects of nonsense mitochondrial DNA (mtDNA) mutations in the COXI and ND5 genes in a colorectal tumor cell line. Surprisingly, these cells had an efficient oxidative phosphorylation (OXPHOS); however, when mitochondria from these cells were transferred to an osteosarcoma nuclear background (osteosarcoma cybrids), the rate of respiration markedly declined suggesting that the phenotypic expression of the mtDNA mutations was prevented by the colorectal tumor nuclear background. We found that there was a significant increase in the steady-state levels of PGC-1alpha and PGC-1beta transcriptional coactivators in these cells and a parallel increase in the steady-state levels of several mitochondrial proteins. Accordingly, adenoviral-mediated overexpression of PGC-1alpha and PGC-1beta in the osteosarcoma cybrids stimulated mitochondrial respiration suggesting that an upregulation of PGC-1alpha/beta coactivators can partially rescue an OXPHOS defect. In conclusion, upregulation of PGC-1alpha and PGC-1beta in the colorectal tumor cells can be part of an adaptation mechanism to help overcome the severe consequences of mtDNA mutations on OXPHOS.

SUBMITTER: Srivastava S

PROVIDER: S-EPMC2652746 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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PGC-1alpha/beta upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations.

Srivastava Sarika S Barrett John N JN Moraes Carlos T CT

Human molecular genetics 20070306 8

We have studied the functional effects of nonsense mitochondrial DNA (mtDNA) mutations in the COXI and ND5 genes in a colorectal tumor cell line. Surprisingly, these cells had an efficient oxidative phosphorylation (OXPHOS); however, when mitochondria from these cells were transferred to an osteosarcoma nuclear background (osteosarcoma cybrids), the rate of respiration markedly declined suggesting that the phenotypic expression of the mtDNA mutations was prevented by the colorectal tumor nuclear ...[more]

PMID: 17341490

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Project description:Prolonged cardiac overexpression of the mitochondrial biogenesis regulatory transcriptional coactivator PGC-1alpha disrupts cardiac contractile function and its genetic ablation limits cardiac capacity to enhance workload. In contrast, transient induction of PGC-1alpha alleviates neuronal cell oxidative stress and enhances skeletal myotube anti-oxidant defenses. We explored whether transient upregulation of PGC-1alpha in the heart protects against ischemia-reperfusion injury. The transient induction of PGC-1alpha in the cardiac-restricted inducible PGC-1alpha transgenic mouse, increased PGC-1alpha protein levels 5-fold. Following 25 min of ischemia and 2h of reperfusion on a Langendorff perfusion apparatus, contractile recovery and the rate pressure product was significantly blunted in mice overexpressing PGC-1alpha vs. controls. Affymetrix gene array analysis showed a 3-fold PGC-1alpha-mediated upregulation of adenine nucleotide translocase 1 (ANT1). As ANT1 upregulation induces cardiomyocyte cell death we investigated whether the induction of ANT1 by PGC-1alpha contributes to this enhanced ischemia-stress susceptibility. Infection with adenovirus harboring PGC-1alpha into cardiac-derived H9c2 cells significantly upregulates ANT1 without changing basal cell viability. In response to anoxia-reoxygenation injury cell death is significantly increased following PGC-1alpha overexpression. This detrimental effect is abolished following siRNA knockdown of ANT1. Similarly, the attenuation of ANT-1 in the presence of PGC-1alpha overexpression preserves the mitochondrial membrane potential in response to hydrogen-peroxide stress. Interestingly, the isolated knockdown of ANT1 also protects H9c2 cells from anoxia-reoxygenation injury. Taken together these data suggest that transient induction of PGC-1alpha in the murine heart decreases ischemia-reperfusion contractile recovery and diminishes anoxia-reoxygenation tolerance in H9c2 cells. These adverse phenotypes appear to be mediated, in part, by PGC-1alpha induced upregulation of ANT1.

Dataset Information

PGC-1alpha/beta upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations.

Publications

PGC-1alpha/beta upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations.

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