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Hormone Deprivation Alters Mitochondrial Function and Lipid Profile in the Hippocampus

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Hormone Deprivation Alters Mitochondrial Function and Lipid Profile in the Hippocampus 233 1 S ZÁRATE and others Ovariectomy alters mitochondrial 233:1 1–14 Research function and lipids Hormone deprivation alters mitochondrial function and lipid profile in the hippocampus Sandra Zárate1,2, Mariana Astiz3,†, Natalia Magnani4,‡, Mercedes Imsen1, Florencia Merino1, Silvia Álvarez4, Analía Reinés5 and Adriana Seilicovich1,2 1Instituto de Investigaciones Biomédicas (INBIOMED, UBA-CONICET), Buenos Aires, Argentina 2Departamento de Histología, Embriología, Biología Celular y Genética, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina 3Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP, UNLP-CONICET) and Cátedra de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Nacional de La Plata, La Plata, Argentina 4Instituto de Bioquímica y Medicina Molecular (IBIMOL, UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina 5Instituto de Biología Celular y Neurociencias ‘Prof. E. De Robertis’ (IBCN, UBA-CONICET), Facultad de Medicina and Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Correspondence Aires, Buenos Aires, Argentina should be addressed †(M Astiz is now at University of Lübeck, Medical Department I, Lübeck, Germany) to S Zárate ‡(N Magnani is now at Division of Pulmonary and Critical Care Medicine, Northwestern University Email Feinberg School of Medicine, Chicago, Illinois, USA) [email protected] Abstract Endocrinology of Mitochondrial dysfunction is a common hallmark in aging. In the female, reproductive Key Words senescence is characterized by loss of ovarian hormones, many of whose neuroprotective f mitochondria Journal effects converge upon mitochondria. The functional integrity of mitochondria is f ovariectomy dependent on membrane fatty acid and phospholipid composition, which are also f hippocampus affected during aging. The effect of long-term ovarian hormone deprivation upon f PUFAs mitochondrial function and its putative association with changes in mitochondrial f cardiolipin membrane lipid profile in the hippocampus, an area primarily affected during aging f aging and highly responsive to ovarian hormones, is unknown. 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 and respiratory complex activities) as well as membrane phospholipid content and composition were evaluated in hippocampal mitochondria. 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 showed no changes in cholesterol levels but higher levels of unsaturated fatty acids and a higher peroxidizability index in mitochondria from ovariectomized rats. Interestingly, ovariectomy also reduced cardiolipin content and altered cardiolipin fatty acid profile leading to a lower peroxidizability index. In conclusion, chronic ovarian hormone deprivation induces mitochondrial dysfunction and changes in the mitochondrial membrane lipid profile comparable to an aging phenotype. Our study provides insights into ovarian hormone loss-induced early lipidomic changes with bioenergetic deficits in the hippocampus that may contribute to the increased risk of Alzheimer’s disease and other age-associated Journal of Endocrinology disorders observed in postmenopause. (2017) 233, 1–14 http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0451 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 08:25:13PM via free access 10.1530/JOE-16-0451 Research S ZÁRATE and others Ovariectomy alters mitochondrial 233:1 2 function and lipids Introduction Mitochondria are key organelles for cellular bioenergetics is more evident in specific brain areas, among which the and survival. They are the main source of ATP hippocampus emerges as an early target of both aging and production through oxidative phosphorylation by the ovarian hormone loss (Navarro et al. 2008, Paradies et al. mitochondrial respiratory chain and also the primary 2011, Hara et al. 2015). sites for cellular reactive oxygen species (ROS) generation. The accumulation of oxidative products leading to As an organ with a high demand of energy and low changes in mitochondrial macromolecules has been antioxidant capacity, the brain is particularly vulnerable proposed as a plausible mechanism underlying the to mitochondria dysfunction and oxidative stress, aforementioned alterations induced by ovarian hormone interdependent mechanisms that play a central role in loss and in aging (Paradies et al. 2011, Viña et al. 2011, brain aging (Chakrabarti et al. 2011). Aging is an inevitable López-Grueso et al. 2014). Mitochondrial membranes, biological process characterized by a progressive decline mostly composed of phospholipids, are main targets of in physiological functions and increased susceptibility oxidative damage due to their physicochemical properties to disease. It is now accepted that normal aging and and the chemical reactivity of their fatty acid (FA) double several aging-related diseases, such as Alzheimer’s and bonds (Pamplona 2008, Paradies et al. 2011). In fact, Parkinson’s, are related to mitochondrial dysfunction membrane phospholipid unsaturation degree has been (Chakrabarti et al. 2011, Johri & Beal 2012). Sex steroid suggested to play a causal role in aging by modulating hormones, especially estrogens, have been widely oxidative stress and molecular integrity of the membrane, investigated in relation to brain aging. Multiple lines of which is particularly important for the proper activity evidence point to brain mitochondria as targets of steroid of proteins involved in oxidative phosphorylation hormone action (Jones & Brewer 2009, Arnold et al. 2012). (Pamplona 2008, Schenkel & Bakovic 2014). In fact, a link between sex-dependent susceptibility and Similar to other subcellular membranes, phos- mitochondrial dysfunction has been identified in normal phatidylcholine (PC) and phosphatidylethanolamine (PE) aging as well as in neurodegenerative diseases both in are the major phospholipids in mitochondrial membranes, Endocrinology preclinical animal studies and in women after menopause comprising 40% and 30% of total mitochondrial of (Rasgon et al. 2005, Yao et al. 2010, Johri & Beal 2012). phospholipids, respectively (Schenkel & Bakovic 2014). Collectively, data from animal studies indicate that the Unlike the plasma membrane, mitochondria contain high Journal decline in whole brain mitochondrial function associated levels of cardiolipin (CL), a phospholipid localized almost with reproductive senescence is due to loss of ovarian exclusively in the inner mitochondrial membrane (IMM) hormones (Yao et al. 2009, 2010, 2012). Unlike primates, that is essential for several mitochondrial processes such the loss of reproductive cycles during aging in rats does as oxidative phosphorylation, apoptosis, mitochondrial not occur concomitant with ovarian follicular atresia protein import and supercomplex formation (Claypool & and its associated decline in estradiol levels. Rather, Koehler 2012). Due to its location near the site of ROS middle-aged acyclic rats are in a state of persistent estrus production and to the fact that it is particularly rich in with chronically high estradiol levels and thus are not unsaturated FAs, brain CL is highly prone to oxidative considered a good model for reproductive aging. Instead, attack (Pamplona 2008). During aging, both an increase ovariectomy has been widely used as a more appropriate in the levels of oxidized CL together with a reduction in model for reproductive aging in rats (Morrison et al. 2006). CL content in brain mitochondria have been reported Detrimental effects of ovarian hormone deprivation upon (Sen et al. 2007, Petrosillo et al. 2008, Jones & Brewer mitochondrial bioenergetics include reduced respiration 2009), conditions that have been suggested to contribute and ATP production rates, increased oxidative stress, and to mitochondrial dysfunction in multiple aged tissues decreased expression and/or activity of metabolic enzymes (Paradies et al. 2011). Studies on the putative association within this organelle (Irwin et al. 2011, Shi et al. 2011, between ovarian hormone loss and alterations in Yao et al. 2012, Gaignard et al. 2015). The vast majority mitochondrial membrane lipid profile, especially in CL, of animal studies about steroid hormone modulation are still lacking. of mitochondrial function have been performed in the In this context, the aim of this work was to whole brain, without the dissection of different brain assess bioenergetic alterations and mitochondrial areas that have dissimilar response to ovarian hormones. membrane lipid profile induced by long-term ovarian Indeed, brain mitochondrial dysfunction in aged animals hormone deprivation in the hippocampus, a highly http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0451 Printed in Great Britain Downloaded from Bioscientifica.com at 09/25/2021 08:25:13PM via free access Research S ZÁRATE and others Ovariectomy alters mitochondrial 233:1 3 function and lipids hormone-responsive area primarily affected during aging. all four paws (crossings). After each animal was tested, the By doing so, we
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