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Mitochondrial Biogenesis in Hypoxic Rat Pulmonary Artery Endothelial Cells (PAECs): Possible Involvement of DNA Oxidation

Like many stimuli promoting cell growth and proliferation, hypoxia uses reactive oxygen species (ROS) as signaling molecules. There is emerging evidence that for nuclear genes, controlled ROS‐mediated DNA damage and repair in specific promoter sequences is necessary for normal transcriptional regulation. Mitochondrial (mt) biogenesis in hypoxia requires mtDNA transcription and replication, but the specific mechanisms are unknown. Here we tested the idea that, in PAECs, these key events in hypoxia‐induced mitochondrial biogenesis, similar to hypoxia‐regulated nuclear gene expression, are associated with oxidative base modifications in the mtDNA D‐loop region involved in mtDNA transcriptional control. Using Fpg‐sensitive qPCR and quantitative Southern blot analyses, we found that although hypoxia did not cause alkali‐sensitive lesions in either the D‐loop or coding regions of mtDNA, Fpg‐sensitive modifications were present exclusively in the D‐loop sequence, with the coding region devoid of oxidative base modifications. Slot blot and real time RT‐PCR analyses revealed increased mtDNA copy number and mitochondrial mRNA transcripts after hypoxic exposure. Hypoxia also increased TFAM binding to D‐loop region as shown by ChIP assay. These observations support the concept that controlled oxidative DNA damage in the D‐loop region may be involved in mitochondrial biogenesis. Supported by NIH.