Hypoxia induced alteration of mitochondrial genes in cardiomyocytes- role of Bnip3 and Pdk1

The hypoxic conditions induced by reduced blood flow decreases oxygen availability in target tissues. Cellular hypoxia leads to mitochondrial dysfunction, decreased energy production and increased production of reactive oxygen species. In order to determine the alteration in expression of mitochondrial genes following hypoxia in cardiomyocytes, we developed a rodent mitochondrial gene chip (RoMitoChip). The chip had 1088 probesets including 46 probesets representing 37 mouse mitochondrial DNA (mtDNA) transcripts and the remaining probesets representing mouse nuclear genes contributing to the mitochondrial structure and function. Mouse cardiomyocytes isolated from neonatal C57BL/6 mice were subjected to hypoxia (1% oxygen) for different time intervals demonstrated a dichotomy in the expression profile of tRNA and mRNA transcripts. We report a total of 483 signature genes that were altered by hypoxia in the cardiac myocytes, and related to mitochondrial structure and function. This includes 23 transcripts on mtDNA. Pathway analysis demonstrated predominant changes in the expression of genes involved in oxidative phosphorylation, glucose and fatty acid metabolism and apoptosis. The most upregulated genes following 24 hr hypoxia included HIF-1α inducible genes Bnip3, Pdk1 and Aldoc. While Bnip3 is important in the cardiomyocyte death pathway, Pdk1 enzyme is critical in conserving mitochondrial function by diverting metabolic intermediates to glycolysis. This study identifies the participation of two important pathways, cell death and glycolytic, and two key proteins, Bnip3 and Pdk1, playing critical role in these pathways in cardiomyocytes following severe hypoxia.