Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function.

We hypothesized the coordinate induction of mitochondrial regulatory genes in the hypertrophied right ventricle to sustain mitochondrial respiratory capacity and contractile function in response to increased load. Wistar rats were exposed to hypobaric hypoxia (11% O(2)) or normoxia for 2 wk. Cardiac contractile and mitochondrial respiratory function were separately assessed for the right and left ventricles. Transcript levels of several mitochondrial regulators were measured. A robust hypertrophic response was observed in the right (but not left) ventricle in response to hypobaric hypoxia. Mitochondrial O(2) consumption was increased in the right ventricle, while proton leak was reduced vs. normoxic controls. Citrate synthase activity and mitochondrial DNA content were significantly increased in the hypertrophied right ventricle, suggesting higher mitochondrial number. Transcript levels of nuclear respiratory factor-1, peroxisome proliferator-activated receptor-gamma-coactivator-1alpha, cytochrome oxidase (COX) subunit II, and uncoupling protein-2 (UCP2) were coordinately induced in the hypertrophied right ventricle following hypoxia. UCP3 transcript levels were significantly reduced in the hypertrophied right ventricle vs. normoxic controls. Exposure to chronic hypobaric hypoxia had no significant effects on left ventricular mitochondrial respiration or contractile function. However, COXIV and UCP2 gene expression were increased in the left ventricle in response to chronic hypobaric hypoxia. In summary, we found coordinate induction of several genes regulating mitochondrial function and higher mitochondrial number in a model of physiological right ventricular hypertrophy, linking the efficiency of mitochondrial oxidative phosphorylation and respiratory function to sustained contractile function in response to the increased load.

Skeletal muscle of female rats exhibit higher mitochondrial mass and oxidative-phosphorylative capacities compared to males.

The effect of gender and caloric restriction on mitochondrial content and oxidative-phosphorylative capacities has been investigated in rat gastrocnemius muscle. Muscle protein, mitochondrial protein and DNA contents, enzymatic activities of mitochondrial oxidative and phosphorylative system, mitochondrial antioxidant enzymes, protein levels of complex IV (subunit I and IV) and ATPase, and the gene and protein expression of mitochondrial transcription factor A (TFAM), involved in mitochondrial replication and transcription, were measured in rats of both genders fed ad libitum and subjected to three months of 40% caloric restriction. Compared to males, gastrocnemius muscle of female rats showed higher mitochondrial DNA and protein contents, TFAM protein level, oxidative and phosphorylative machinery and activities, and glutathione peroxidase activity. In conclusion, the present data show a clear gender dimorphism in rat muscle mitochondrial features, which could explain the higher facility of females to adapt to altered metabolic energy situations.

Mitochondrial transcription factor A (TFAM) is increased in rat embryo during placentation and associated with mitochondrial differentiation.

In the current study, the mitochondrial proliferationdifferentiation process was investigated in rat embryo during the placentation process, straight after organogenesis, when there is an important oxidative metabolism activation. For this purpose, on gestational days 11, 12 and 13 we studied the mitochondrial DNA (mtDNA) content and the relative gene expression of proteins involved in mtDNA replication (mitochondrial single strand DNA binding protein (mtSSB)), mtDNA transcription (mitochondrial transcription factor A (TFAM)), as well as in mitochondrial function (cytochrome c oxidase subunit I (COXI)). The results indicated that during placentation important changes in mitochondrial proliferation-differentiation process take place in rat embryo. There is a great decrease in cellular mtDNA content and a rise in the ratio between TFAM and mtDNA accompanied by an increase in COXI gene expression. Thus, we can conclude that on gestational day 13 mitochondrial differentiation predominates over mitochondrial proliferation in embryo cells. Besides, our work reveals that in a physiological condition such as embryonic development the TFAM levels change in order to regulate the transcriptional activity of mtDNA.