Hypoxia-induced suppression of c-Myc by HIF-2α in human pulmonary endothelial cells attenuates TFAM expression

- Hypoxia causes reprogramming of mitochondria in pulmonary artery endothelial cells.
- The mitochondrial transcription factor, TFAM, is downregulated by HIF-2α pathways.
- HIF-2α decreases TFAM by suppressing c-Myc expression.
- HIF-2α-mediated mechanisms attenuate c-Jun activation to regulate c-Myc.

The adaptive response to hypoxia is mediated in large part by stabilization of the hypoxia-inducible factors, HIF-1α and HIF-2α. A hallmark of this response is the metabolic shift to decreased oxidative phosphorylation and increased glycolysis. We hypothesized that hypoxic responses would include a suppression of mitochondrial gene expression. We determined the effects of hypoxia on TFAM, a key mitochondrial transcription factor, in normal pulmonary artery endothelial cells. Hypoxia decreased gene expression of TFAM and that of its upstream regulator, the transcriptional co-activator PGC1β. Although HIF-1α and HIF-2α pathways both contributed to hypoxia-mediated PGC1β suppression, TFAM suppression was regulated solely by HIF-2α-dependent mechanisms. We found that HIF-2α suppresses TFAM by decreasing c-Myc expression. In addition, we show a role for c-Jun in this pathway, linking HIF-2α with attenuation of c-Jun activation. Taken together, these findings establish a new link between HIF-2α and MAPK-signaling that mediates the adaptive regulation of mitochondrial gene expression under low oxygen tension.