Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence

https://doi.org/10.1016/j.bbagen.2010.06.002Get rights and content

Abstract

Background

We have previously demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic Alzheimer's (3xTgAD) mouse model. Herein, we sought to determine the impact of reproductive senescence on mitochondrial function in the normal non-transgenic (nonTg) and 3xTgAD female mouse model of AD.

Methods

Both nonTg and 3xTgAD female mice at 3, 6, 9, and 12 months of age were sacrificed and mitochondrial bioenergetic profile as well as oxidative stress markers were analyzed.

Results

In both nonTg and 3xTgAD mice, reproductive senescence paralleled a significant decline in PDH, and Complex IV cytochrome c oxidase activity and mitochondrial respiration. During the reproductive senescence transition, both nonTg and 3xTgAD mice exhibited greater individual variability in bioenergetic parameters suggestive of divergent bioenergetic phenotypes. Following transition through reproductive senescence, enzymes required for long-chain fatty acid (HADHA) and ketone body (SCOT) metabolism were significantly increased and variability in cytochrome c oxidase (Complex IV) collapsed to cluster at a ∼ 40% decline in both the nonTg and 3xTgAD brain which was indicative of alternative fuel generation with concomitant decline in ATP generation.

Conclusions

These data indicate that reproductive senescence in the normal nonTg female brain parallels the shift to ketogenic/fatty acid substrate phenotype with concomitant decline in mitochondrial function and exacerbation of bioenergetic deficits in the 3xTgAD brain.

General significance

These findings provide a plausible mechanism for increased life-time risk of AD in postmenopausal women and suggest an optimal window of opportunity to prevent or delay decline in bioenergetics during reproductive senescence.

Introduction

The essential role of mitochondria in cellular bioenergetics and survival has been well established [1], [2], [3]. Further, mitochondrial dysfunction has been suggested to play a pivotal role in neurodegenerative disorders, including Alzheimer's disease (AD) [1], [4], [5]. It has been shown that brain metabolism is declined in AD patients at least a decade before disease diagnosis [1], [6], [7], [8], [9]. Dysfunction in glucose metabolism, bioenergetics and mitochondrial function are consistent antecedents to development of Alzheimer pathology [10], [11], [12], [13], [14], [15], [16], [17], [18]. Recently we demonstrated that mitochondrial bioenergetic deficits precede Alzheimer's pathology in the female triple transgenic mouse model of Alzheimer's disease (3xTgAD) [7]. These antecedent declines in brain metabolism indicate a potential causal role of mitochondrial bioenergetics in AD pathogenesis and disease progression.

Basic science analyses indicate that the endogenous estrogen, 17β-estradiol (E2), significantly increased glucose uptake, glucose metabolism, insulin growth factor signaling and the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism) [1], [6], [19]. The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of AD [1], [6]. The ability of estrogen to sustain glucose as the primary fuel source in brain by enhancing glucose transport, uptake and aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism) is likely linked to its ability to prevent age-associated metabolic decline in brain and thus could be a key mechanism whereby estrogen reduces the risk of AD in postmenopausal women [1], [6], [19], [20], [21], [22], [23], [24].

Reproductive senescence is a multifactorial process with a high degree of interpersonal variability and subject to a host of beneficial or detrimental influences. As such, reproductive senescence is an illustrative example of both the aging process and of modifiers of aging, such as ovarian hormone status, which both contribute to alteration in brain metabolic profile. In the current study, we sought to determine the impact of loss of ovarian hormones associated with reproductive senescence on mitochondrial function, particularly mitochondrial bioenergetics. We further investigate the individual variability in metabolic profile during the reproductive senescence transition. The results presented demonstrate that loss of ovarian hormones during reproductive senescence parallels the accelerated decline in mitochondrial bioenergetics, linking the loss of ovarian hormones to the development of a hypometabolic brain phenotype which could be clinically relevant to the in prodromal phase of AD. Collectively current clinical findings and findings from this study provide a plausible mechanism of increased AD risk in menopausal women.

Section snippets

Transgenic mice

Colonies of 3xTgAD and nonTg mouse strain (C57BL6/129S;Gift from Dr. Frank Laferla, University of California, Irvine)[25] were bred and maintained at the University of Southern California (Los Angeles, CA) following National Institutes of Health guidelines on use of laboratory animals and an approved protocol by the University of Southern California Institutional Animal Care and Use Committee. Mice were housed on 12-h light/dark cycles and provided ad libitum access to food and water. Only

Results

In the process of conducting an analysis of bioenergetic changes in aging to determine if changes in mitochondrial preceded development of AD pathology, we observed that a decline in bioenergetics occurred after the development of AD pathology but which corresponded to the transition of reproductive senescence. Data presented in Fig. 1, Fig. 2, Fig. 4, Fig. 5 are derived from the quantitative data presented in Fig. 4 and Table 1 of the PNAS manuscript [7]. In the previous publication the

Discussion

Increasing evidence links mitochondrial dysfunction in multiple neurodegenerative disorders, such as Alzheimer's disease (AD) [11]. We previously demonstrated that mitochondrial bioenergetic deficits precede AD pathology in the female triple transgenic AD mouse model [7], suggesting a potential causal role of mitochondrial bioenergetic deficiency in AD pathogenesis. Clinically, Alzheimer's pathology is accompanied by a decrease in expression and activity of enzymes involved in mitochondrial

Acknowledgments

This study was supported by National Institute on Aging Grant 2R01AG032236 (to RDB; Project 1 EC), National Institute on Aging Grant 5P01AG026572 (to RDB) and the Kenneth T. and Eileen L. Norris Foundation (R.D.B.). We gratefully thank Dr. Ronald W. Irwin for contributions to mitochondrial isolation and Dr. Frank M Laferla for providing the triple-transgenic Alzheimer's disease mouse model.

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