Sex differences in brain mitochondrial metabolism: influence of endogenous steroids and stroke

Abstract

Steroids are neuroprotective and a growing body of evidence indicates that mitochondria are a potential target of their effects. The mitochondria are the site of cellular energy synthesis, regulate oxidative stress and play a key role in cell death after brain injury and neurodegenerative diseases. After providing a summary of the literature on the general functions of mitochondria and the effects of sex steroid administrations on mitochondrial metabolism, we summarise and discuss our recent findings concerning sex differences in brain mitochondrial function under physiological and pathological conditions. To analyse the influence of endogenous sex steroids, the oxidative phosphorylation system, mitochondrial oxidative stress and brain steroid levels were compared between male and female mice, either intact or gonadectomised. The results obtained show that females have higher a mitochondrial respiration and lower oxidative stress compared to males and also that these differences were suppressed by ovariectomy but not orchidectomy. We have also shown that the decrease in brain mitochondrial respiration induced by ischaemia/reperfusion is different according to sex. In both sexes, treatment with progesterone reduced the ischaemia/reperfusioninduced mitochondrial alterations. Our findings indicate sex differences in brain mitochondrial function under physiological conditions, as well as after stroke, and identify mitochondria as a target of the neuroprotective properties of progesterone. Thus, it is necessary to investigate sex specificity in brain physiopathological mechanisms, especially when mitochondria impairment is involved. K E Y W O R D Smitochondria, oxidative phosphorylation, oxidative stress, progesterone, sex difference, stroke | INTRODUCTIONThe main function of mitochondria is energy production. Mitochondria play a major role in the nervous system because neurones have a high metabolic rate and do not have a high capacity with respect to energy storage. Mitochondrial dysfunction has devastating consequences because mitochondria are centrally involved in neural cells life. Indeed, mitochondrial energy production is vital to maintain membrane potential in neurones. Mitochondria also play a major role in regulating oxidative stress and in death/survival cell signalling. They are also the site of the first steps of steroidogenesis and increasing evidence indicates that mitochondria are an essential target of the neuroactive effects of steroids, especially oestradiol and progesterone. In this review, we describe the sex differences and the role of sex steroids in brain mitochondrial energy production and oxidative stress. In particular, we summarise our recent work on brain mitochondrial metabolism in both sexes under physiological conditions, as well as after stroke, a pathology characterised by both sexual dimorphism and mitochondrial bioenergetics impairment. | MITOCHONDRIA ARE THE SITE OF ENERGY PRODUCTIONThe energy production by the mitochondria is mediated by three major enzymatic systems: the pyruva...

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