Developmental Sex Differences in the Metabolism of Cardiolipin in Mouse Cerebral Cortex Mitochondria

Acaz‐Fonseca, Estefanía; Ortiz-Rodriguez, Ana; López-Rodríguez, Ana Belén; Garcia-Segura, Luis Miguel; Astiz, Mariana

doi:10.1038/srep43878

Cited by 24 publications

(18 citation statements)

References 91 publications

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“…Functional sex differences in brain subcellular organelle, including the mitochondria (Acaz-Fonseca et al, 2017;Gaignard et al, 2018;Giatti et al, 2018), or in the action of sex hormones on these organelle (Grimm et al, 2016b), may also contribute to divergent neuroprotective outcomes of estrogen therapy. For instance, mitochondria contribute to sex differences in oxidative stress under neurodegenerative conditions (Ruszkiewicz et al, 2019) and may generate sex differences in the neuroprotective actions of estradiol.…”

Section: Subcellular and Cellular Contributions To Sex Differences Inmentioning

confidence: 99%

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Azcoitia

Barreto

García‐Segura

2019

Frontiers in Neuroendocrinology

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100

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Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca 2+ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference.

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Section: Subcellular and Cellular Contributions To Sex Differences Inmentioning

confidence: 99%

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Azcoitia

Barreto

García‐Segura

2019

Frontiers in Neuroendocrinology

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100

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“…It can be speculated that alterations in CL remodeling, which uses PC or PE as substrates for FA transacylation, could explain the altered phospholipid FA profiles found in long-term hormone-deprived animals. Despite that sequences of estrogen-responsive elements have been found in the promoters of enzymes involved in CL remodeling (Acaz-Fonseca et al 2017), further analysis of these pathways should be performed to test this hypothesis.…”

Section: Figurementioning

confidence: 99%

Hormone deprivation alters mitochondrial function and lipid profile in the hippocampus

Zárate

Astiz

Magnani

et al. 2017

Journal of Endocrinology

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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. The functional integrity of mitochondria is dependent on membrane fatty acid and phospholipid composition, which are also affected during aging. The effect of long-term ovarian hormone deprivation upon mitochondrial function and its putative association with changes in mitochondrial membrane lipid profile in the hippocampus, an area primarily affected during 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 (O 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 O 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 disorders observed in postmenopause.

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“…Until now, few studies have focused on the role of mitochondrial CL metabolism and the possible impact of sex hormones during brain development. However, recent findings indicate that the dynamic CL molecular profile observed during brain development, at least in a narrower temporal window of 10 days after birth, is sex dimorphic . At birth, mitochondrial CL had more than twice the proportion of unsaturated fatty acids in the brain of male mice than in the brain of females.…”

Section: Regulation Of Brain CL Metabolism By Sex Hormonesmentioning

confidence: 97%

“…Depending on the differential expression of the enzymes involved in CL de novo synthesis and the remodelling pathways, as well as on the availability of fatty acids, CL content and acyl chain composition differ from one tissue or cell type to another . For example, heart mitochondria contain almost exclusively tetralinoleoyl‐CL, whereas brain CL species are highly heterogeneous . Moreover, the amount of CL and its composition are region‐specific within the brain, which may be attributed to regional differences in mitochondrial metabolism.…”

Section: Cardiolipin Synthesismentioning

confidence: 99%

“…Both oestradiol and progesterone have been shown to protect brain mitochondria in aged animals and both ovarian hormones are likely responsible for the changes in CL content and composition in the brain of ovariectomised rats. Indeed, in silico analyses predict the presence of binding sites for oestrogen receptors in the promoters of the enzymes involved in both de novo and remodelling CL synthesis pathways . The effects of oestradiol on neuronal CL levels were directly assessed via an in vitro study using neuronal cultures from male rat brains at embryonic day 18, as well as at 9 months and 24 months old.…”

Section: Regulation Of Brain CL Metabolism By Sex Hormonesmentioning

confidence: 99%

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Sex differences and gonadal hormone regulation of brain cardiolipin, a key mitochondrial phospholipid

Acaz‐Fonseca

Ortiz-Rodriguez

García‐Segura

et al. 2019

J Neuroendocrinology

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Cardiolipin (CL) is a phospholipid that is almost exclusively located in the inner mitochondrial membrane of eukaryotic cells. As a result of its unique structure and distribution, CL establishes non‐covalent bonds with a long list of proteins involved in ATP production, mitochondria biogenesis, mitophagy and apoptosis. Thus, the amount of CL, as well as its fatty acid composition and location, strongly impacts upon mitochondrial‐dependent functions and therefore the metabolic homeostasis of different tissues. The brain is particularly sensitive to mitochondrial dysfunction as a result of its high metabolic demand. Several mitochondrial related‐neurodegenerative disorders, as well as physiological ageing, show altered CL metabolism. Furthermore, mice lacking enzymes involved in CL synthesis show cognitive impairments. CL content and metabolism are regulated by gonadal hormones in the developing and adult brain. In neuronal cultures, oestradiol increases CL content, whereas adult ovariectomy decreases CL content and alters CL metabolism in the hippocampal mitochondria. Transient sex differences in brain CL metabolism have been detected during development. At birth, brain CL has a higher proportion of unsaturated fatty acids in the brain of male mice than in the brain of females. In addition, the expression of enzymes involved in CL de novo and recycling synthetic pathways is higher in males. Most of these sex differences are abolished by the neonatal androgenisation of females, suggesting a role for testosterone in the generation of sex differences in brain CL. The regulation of brain CL by gonadal hormones may be linked to their homeostatic and protective actions in neural cells, as well as the manifestation of sex differences in neurodegenerative disorders.

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Developmental Sex Differences in the Metabolism of Cardiolipin in Mouse Cerebral Cortex Mitochondria

Cited by 24 publications

References 91 publications

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Hormone deprivation alters mitochondrial function and lipid profile in the hippocampus

Sex differences and gonadal hormone regulation of brain cardiolipin, a key mitochondrial phospholipid

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