Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model

Abstract

Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model.Methods: Bilateral ovariectomy was conducted in adult females C57BL/6J. Cognitive function was examined using the Morris water maze (MWM) test at 2 weeks, 1, 2, and 3 months after ovariectomy. Neurodegeneration was assessed using an immunofluorescence assay of microtubule-associated protein 2 (MAP2) in the hippocampus and immunoblotting against postsynaptic density-95 (PSD95). Mitochondrial function in the hippocampus was assessed using immunoblotting for NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A1. Mitochondrial biogenesis was examined using immunoblotting for PGC-1α, NRF1, and mtTFA. Mitochondrion fission was assessed with immunoblotting for Drp1, whereas mitochondrion fusion was analyzed with immunoblotting for OPA1 and Mfn2. Mitophagy was examined with immunoblotting for PINK1 and LC3B. Mice receiving sham surgery were used as controls.Results: Ovariectomy resulted in significant learning and memory deficits in the MWM test at 3 months, but not at any earlier time points. At 2 weeks after ovariectomy, levels of Drp1 phosphorylated at Ser637 decreased in the hippocampus. At 1 month after ovariectomy, hippocampal levels of NDUFB8, SDHB, PGC-1α, mtTFA, OPA1, and Mfn2 were significantly reduced. At 2 months after ovariectomy, hippocampal levels of MAP2, PSD95, MTCO1, NRF1, and Pink1 were also reduced. At 3 months, levels of LC3B-II were reduced.Conclusions: The cognitive decline associated with estrogen deficiency is preceded by mitochondrial dysfunction, abnormal mitochondrial biogenesis, irregular mitochondrial dynamics, and decreased mitophagy. Thus, mitochondrial damage may contribute to cognitive impairment associated with estrogen deficiency.

Estrogen fluctuations during the menopausal transition are a risk factor for depressive disorders

“…The loss of antioxidant homeostasis negatively affects the quality of mitochondria in many tissues, including the brain [ 125 ], and antioxidant production seems to depend on E2 levels. Recently, Zhao et al [ 126 ] showed mitochondrial dysfunction and cognitive decline in a mouse model of ovariectomy-induced E2 deprivation.…”

From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy

“…In female AD patients, mtERβ expression and mitochondrial cytochrome C oxidase activity were significantly reduced, which implies that the deficiency of mtERβ might be associated with the dysfunction of mitochondria in AD [161]. A recent study showed that mitochondrial damage, including abnormal mitochondrial function and biogenesis, occurs prior to cognitive decline in the hippocampus of ovariectomized mice [162]. Compared to a premenopausal control, post-and perimenopausal females displayed reduced platelet mitochondrial activity, which was highly correlated to cerebral glucose metabolism [163].…”

“…Interestingly, insulin-induced hypoglycemia significantly decreases GPER protein expression in A2 noradrenergic nerve cells in females but not males [227], which indicates a sex difference in GPER gene expression regulation. In addition, ERα and ERβ are also expressed in mitochondria and against mitochondrial-mediated oxidative stress via a non-genomic pathway [228], and estrogen deficiency causes mitochondrial dysfunction prior to cognitive decline in ovariectomized mice [162].…”

Oestrogenic Regulation of Mitochondrial Dynamics

“…Mitochondria are one of the essential cellular organelles for the induction of E2 effects [47]. Regulation of mitochondrial metabolism [24,48], cell death [49,50] and quality control [51,52] are a few examples by which E2 regulates cellular homeostasis. In this article, we discuss the mechanisms of E2 actions and its effects on mitochondrial function.…”