Mitochondria, Estrogen and Female Brain Aging

Lejri, Imane; Grimm, Amandine; Eckert, Anne

doi:10.3389/fnagi.2018.00124

Cited by 89 publications

(57 citation statements)

References 124 publications

(156 reference statements)

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“…At respiratory complexes I and III of the ETC, mitochondria produce reactive oxygen species (ROS) [45]. Therefore, close to the menopause or at the pre-menopause state, estrogen decline may affect the functional state of mitochondria, causing declines of cellular functions and aging [46]. Our findings suggest that the initial effects of lack of trancription factor TFAM in MitoPark DA neurons can be partially counteracted by estrogen.…”

Section: Discussionmentioning

confidence: 78%

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice

Chen

Wang

Huang

et al. 2019

IJMS

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This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson's disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.Int. J. Mol. Sci. 2019, 20, 6251 2 of 17 in nigral neurons in aged humans with sharp elevations starting shortly before age 70. This correlates with age being a known major risk factor for PD. A better understanding of the progressive cellular events that precede the appearance of behavioral symptoms will be critical for the early diagnosis of PD and development of more effective treatment strategies.It has been suggested that gender is an important factor in the development of PD. The disease is more common in men than in woman by an approximate ratio of 1.5-2:1 [18,19]. In addition to prevalence, several other PD-coupled parameters differ between men and women, including onset of symptoms, types of motor and non-motor symptoms, medication use, the effect size of PD risk factors, levodopa bioavailability, neuropsychiatric, and cognitive changes, development of hallucinations, caregiver utilization and reliance, and the quality of life [20,21]. In women, the age of PD onset has shown a positive correlation with fertility. Sex hormones, especially estrogen, may thus influence PD pathogenesis and be an important gender differentiation factor [22,23]. Here we use the MitoPark (MP) mouse model of PD where the mitochondrial transcription factor, TFAM, is specifically deleted in midbrain dopamine (DA) neurons. There is subsequent progressive degeneration of midbrain DA neurons which project to both striatum and extrastriatal telencephalic sites. Since the TFAM deletion is driven by the DAT promoter, neurons that do not express DAT are spared. Ovariectomy was used to address gender differences and the possible protective effects of estrogen on the time course of degeneration of DA neurons. ResultsDA release rate was measured by fast scan cyclic voltammetry (FSCV) in ex vivo (in vitro) brain slices. The capacity of axon terminals to release DA was assessed by using one single pulse (for tonic) or 10 pulses (for phasic) stimulation delivered at 25 Hz under 10 volts stimulation intensities....

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Section: Discussionmentioning

confidence: 78%

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice

Chen

Wang

Huang

et al. 2019

IJMS

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“…In this conceptual framework, ER agonists could restore metabolic activity in the brain cortex simply by preventing the mitochondrial dysfunction induced by CIH. Other mechanisms linking estradiol receptors, CIH and mitochondrial functions in the brain might depend on molecular metabolic sensors such as the AMPK‐mTOR pathway (which is responsive to ATP/ADP ratio), the sirtuin family pathway (responsive to NAD+/NADH ratio) both of which are modulated by CIH, estradiol, or brain oxygen levels . Finally, it is worth mentioning that complex I of the electron transport chain can switch between an activated form and a deactivated form, and that hypoxia or hypoxic/ischemia “deactivates” complex I within minutes, but the effects of intermittent hypoxia, or estradiol receptors on this process are so far unknown …”

Section: Discussionmentioning

confidence: 99%

Roles of oestradiol receptor alpha and beta against hypertension and brain mitochondrial dysfunction under intermittent hypoxia in female rats

et al. 2019

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Aim Chronic intermittent hypoxia (CIH) induces systemic (hypertension) and central alterations (mitochondrial dysfunction underlying cognitive deficits). We hypothesized that agonists of oestradiol receptors (ER) α and β prevent CIH‐induced hypertension and brain mitochondrial dysfunction. Methods Ovariectomized female rats were implanted with osmotic pumps delivering vehicle (Veh), the ERα agonist propylpyraoletriol (PPT — 30 μg/kg/day) or the ERβ agonist diarylpropionitril (DPN — 100 μg/kg/day). Animals were exposed to CIH (21%‐10% FIO2 — 10 cycles/hour – 8 hours/day – 7 days) or normoxia. Arterial blood pressure was measured after CIH or normoxia exposures. Mitochondrial respiration and H2O2 production were measured in brain cortex with high‐resolution respirometry, as well as activity of complex I and IV of the electron transport chain, citrate synthase, pyruvate, and lactate dehydrogenase (PDH and LDH). Results Propylpyraoletriol but not DPN prevented the rise of arterial pressure induced by CIH. CIH exposures decreased O2 consumption, complex I activity, and increased H2O2 production. CIH had no effect on citrate synthase activity, but decreased PDH activity and increased LDH activity indicating higher anaerobic glycolysis. Propylpyraoletriol and DPN treatments prevented all these alterations. Conclusions We conclude that in OVX female rats, the ERα agonist prevents from CIH‐induced hypertension while both ERα and ERβ agonists prevent the brain mitochondrial dysfunction and metabolic switch induced by CIH. These findings may have implications for menopausal women suffering of sleep apnoea regarding hormonal therapy.

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“…In most mammals, including humans, life expectancy differs between sexes. Females show lower incidence of some age-related pathologies linked with oxidative stress conditions and this sex-difference disappears after menopause, which led to the conclusion that this protection is attributed to the effect of sex hormones (rev in [5]). The important approach to study ageing and age-linked pathologies is to investigate sex dimorphism in defense to metabolic stressors.…”

Section: Introductionmentioning

confidence: 99%

Role of Sirt3 in Differential Sex-Related Responses to a High-Fat Diet in Mice

et al. 2020

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Metabolic homeostasis is differently regulated in males and females. Little is known about the mitochondrial Sirtuin 3 (Sirt3) protein in the context of sex-related differences in the development of metabolic dysregulation. To test our hypothesis that the role of Sirt3 in response to a high-fat diet (HFD) is sex-related, we measured metabolic, antioxidative, and mitochondrial parameters in the liver of Sirt3 wild-type (WT) and knockout (KO) mice of both sexes fed with a standard or HFD for ten weeks. We found that the combined effect of Sirt3 and an HFD was evident in more parameters in males (lipid content, glucose uptake, pparγ, cyp2e1, cyp4a14, Nrf2, MnSOD activity) than in females (protein damage and mitochondrial respiration), pointing towards a higher reliance of males on the effect of Sirt3 against HFD-induced metabolic dysregulation. The male-specific effects of an HFD also include reduced Sirt3 expression in WT and alleviated lipid accumulation and reduced glucose uptake in KO mice. In females, with a generally higher expression of genes involved in lipid homeostasis, either the HFD or Sirt3 depletion compromised mitochondrial respiration and increased protein oxidative damage. This work presents new insights into sex-related differences in the various physiological parameters with respect to nutritive excess and Sirt3.

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Mitochondria, Estrogen and Female Brain Aging

Cited by 89 publications

References 124 publications

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice

Roles of oestradiol receptor alpha and beta against hypertension and brain mitochondrial dysfunction under intermittent hypoxia in female rats

Role of Sirt3 in Differential Sex-Related Responses to a High-Fat Diet in Mice

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