Long term ovarian hormone deprivation induces mitochondrial bioenergetic decay as well as changes in mitochondrial membrane lipid profile and DNA repair mechanisms in the hippocampus

ZÁRATE SANDRA

Congreso; Simposio Satélite IUBMB: Transducción de Señales, LXI Reunión de la Sociedad Argentina de Investigación Clínica; 2016

Mitochondrial dysfunction is a common hallmark in aging. In the female, reproductive senescence is characterized by loss of ovarian hormones, many of whose neuroprotective effects converge upon mitochondria. Mitochondria functional integrity is dependent on membrane fatty acid andphospholipid composition as well as mitochondrial DNA (mtDNA) stability, parameters also affected during aging. The aim of this work was to study the effect of long-term ovarian hormone deprivation upon mitochondrial function and its putative association with changes in mitochondrialmembrane lipid profile and in mtDNA repair mechanisms the hippocampus, an area primarily affected during aging and highly responsive to ovarian hormones. To this aim, Wistar adult female rats were ovariectomized or sham-operated. Twelve weeks later, different parameters of mitochondrial function (O2 uptake, ATP production, membrane potential, respiratory complex activities), membrane phospholipid content and composition as well as single steps in the main mtDNA repair pathway were evaluated in hippocampal mitochondria. Our results show that chronic ovariectomy reduced mitochondrial O2 uptake and ATP production rates and induced membrane depolarization during active respiration without altering the activity of respiratory complexes. Mitochondrial membrane lipid profile from ovariectomized rats showed no changes in cholesterol levels but higher levels of unsaturated fatty acids, rendering them more proneto peroxidation. Interestingly, chronic ovariectomy also reduced cardiolipin content and altered cardiolipin fatty acid profile. mtDNA repair pathway was also altered in hippocampal mitochondria from ovariectomized rats. Our results show that chronic ovarian hormone deprivation induces mitochondrial bioenergetic dysfunction and changes in the mitochondrial membrane lipid profile and mtDNA repair mechanisms comparable to an aging phenotype. The maintenance of membrane properties and mtDNA integrity emerge as putative therapeutic targets worth exploring to avoid early impairments in mitochondrial energy expenditure that affects the high-energy demanding brain after ovarian hormone natural or surgical loss.