Sex Hormone Modulation of Mitochondrial Function: A Possible Mechanism for Neuroprotection

Abstract

There is increasing evidence for the central role of reactive oxygen species (ROS) as a unifying mechanism underlying the development of age-related diseases such as stroke. As fundamental energy-producing units, mitochondria play an important role in ROS production. We have shown that the gonadal steroids, estrogen (E) and testosterone (T), have opposing effects on function of brain blood vessels, but knowledge of the impact of these sex hormones on mitochondrial function is sparse. In female rat brain blood vessels E increases levels of respiratory chain proteins and mitochondrial enzyme activities while decreasing mitochondrial ROS production. Here we compare effects of E and T on mitochondrial function in brains and cerebral blood vessels isolated from four groups of male rats: intact, orchiectomized (ORX), testosterone-treated (ORX+T), and estrogen-treated (ORX+E). After four weeks of hormone treatment, we isolated whole brain and cerebral blood vessel mitochondria and performed biochemical analyses. In contrast to the effect of E to increase cytochrome c protein, cerebral vessels from ORX+T showed no significant change in cytochrome c. Mitochondrial ROS inactivate aconitase, but have no effect on fumarase. Therefore, the ratio of activities of aconitase to fumarase (A/F) is an indicator of mitochondrial ROS production. We found that E increased the A/F ratio, demonstrating decreased ROS production, but that the ratio was unchanged in ORX+T. Thus, modulation of mitochondrial function and ROS production by E, but not T, may contribute to neuroprotection. NIH HL-50775.