Ovarian Hormones increase Mitochondrial Efficiency and Biogenesis via Distinct Regulation of PGC1 Isoforms in Cerebral Blood Vessels

Ovarian hormones, and estrogen in particular, have long been associated with decreased vascular disease and improved stroke outcomes, but the mechanisms for these remarkable changes remained unclear. Mitochondrial function plays an integral role in an array of pathologies, including many of the vascular diseases positively impacted by estrogen action. Our laboratory has previously shown that in cerebrovascular tissue that estrogen suppresses mitochondrial reactive oxygen species (ROS) and increases activity of crucial mitochondrial enzymes involved with oxidative phosphorylation and detoxification of ROS. However, it was unclear how estrogen increases mitochondria efficiency and decreases mitochondrial ROS.;The PGC1 family of nuclear receptor coactivators has been described as master regulators of mitochondrial function and coactivators of the estrogen receptors. These coactivators not only increase mitochondrial biogenesis, but guide mitochondrial function to fit the needs of different cells. To better understand estrogen's actions, I examined transcriptional pathways that regulate mitochondrial function, beginning with these coactivators.;I demonstrate that endogenous ovarian hormones increase mitochondrial biogenesis and ROS protection through differential regulation of these coactivators. These studies link previous findings in our laboratory to classical findings regarding estrogen protection of numerous tissues. I found that in rodent cerebral blood vessels and the endothelial cells therein, ovarian hormones or estrogen alone, are able to differentially regulate PGC1&agr; and PGC1beta, increasing beta while decreasing &agr;, changing mitochondrial function to favor efficiency and ROS protection.;Estrogen also increased several mitochondrial biogenesis related transcription factors; specifically NRF1 and TFAM. Increases in this pathway translated into increases in mitochondrial DNA and electron transport chain proteins, a final demonstration that ovarian hormones can increase mitochondrial biogenesis in cerebral blood vessels.;Both PGC1 isoforms can initiate mitochondrial biogenesis, but it was surprising to see a decrease in PGC1&agr;, the most studied of the isoforms. One of the few in-depth studies of PGC1beta showed it promotes ROS protection better than PGC1&agr;. I found that estrogen increased, and ovariectomy decreased, the synthetic pathway for glutathione, an important detoxifier of mitochondrial ROS. The shift to PGC1beta by estrogen can explain why this hormone promotes ATP synthesis as well as decreasing mitochondrial ROS in cerebral blood vessels.