Ovarian hormone deprivation and hormone replacement therapy effects on mitochondrial DNA repair processes in the brain

ZÁRATE, SANDRA

Congreso; II Reunión Conjunta de Sociedades de Biociencias; 2017

Sex steroids exert pleiotropic effects in the brain, preserving neural function and promoting neuronal survival. Not surprisingly, loss of ovarian hormones during natural or induced reproductive senescence in the female is characterized by synaptic and cognitive impairments and increased risk of neurodegeneration, processes that are now recognized to be highly associated with mitochondrial dysfunction. Multiple lines of evidence point for brain mitochondria as targets of steroid hormone action. In fact, a link between sex-dependent susceptibility and decline in brain mitochondrial function has been identified in normal aging as well as in neurodegenerative diseases both in preclinical animal studies as well as in women after natural or surgical menopause. Mitochondria are key players in cellular bioenergetics and survival, they are the main source of ATP production and also the primary sites for cellular reactive oxygen species (ROS) generation. These organelles are unique in terms of having their own genome, which is more prone to oxidative damage than the nuclear genome in part due to its close proximity to the source of ROS production. Accumulative damage in mitochondrial DNA (mtDNA) over time, if not properly repaired, leads to mitochondrial dysfunction and disease. As an organ with a high demand of energy and low antioxidant capacity, the brain is particularly vulnerable to mitochondria dysfunction and oxidative stress. Base excision repair (BER) is the major DNA repair pathway in mitochondria, thereby constituting an important mechanism to avoid accumulation of mtDNA mutations. Still, little is known about how hormonal status affects mtDNA repair mechanisms in the brain. Moreover, the heterogeneity of organization, function, and biochemical mechanisms in the brain implies that some regions may be particularly vulnerable to ovarian hormone loss and accumulation of mtDNA damage. In this context, we are studying the effects of long-term ovarian hormone deprivation and early hormone-replacement treatments on BER pathway in mitochondria from rat cortex and hippocampus, areas primarily affected in aging and neurodegenerative diseases and highly responsive to ovarian hormones. Our data suggest that hormonal status regulate BER pathway in a region-specific manner and poises the hippocampus as a highly vulnerable area to ovarian hormone loss regarding impaired BER capacity. Considering the importance of preserving mtDNA integrity for normal cell function, this study provides insights into the role of early hormone replacement therapy in mtDNA repair capacity and could help find new therapeutic targets to promote a healthier lifespan for women after natural or induced menopause.