title: Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice.
abstract: Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17β-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function.
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gaignard
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Savouroux
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Pianos
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Thérond
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Slama
authors.affiliation: U1195 Inserm and University Paris-Sud (P.G., P.L., A.P., M.S., R.G.), 94276 Le Kremlin-Bicêtre Cedex, France; and Biochemistry Laboratory (P.G., S.S., P.T., A.S.), Bicêtre Hospital, Assistance Publique - Hôpitaux de Paris, University Paris-Sud, 94275 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Rachida
authors.initials: R
authors.lastname: Guennoun
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D019069:Cell Respiration / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D009243:NAD / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000502:physiology; D012727:Sex Characteristics
chemical_list: D009243:NAD; D005182:Flavin-Adenine Dinucleotide; C058805:1,5-dihydro-FAD; D004958:Estradiol