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

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.

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

“…Hypometabolism can be observed in several brain areas, especially in the hippocampus [60,61] as well as impaired mitochondrial function [62]. There is a shift in brain metabolism as an early event in AD pathology, which results in decreased cerebral glucose utilization, while changing from utilization of glucose to increased ketogenesis during aging [63,64]. Providing ketone bodies as an alternative fuel for neurons has been suggested to bypass such metabolic deficits present in the AD brain.…”

Neuroprotection in Perimenopausal Women

“…The model on female rat brain aging revealed that bioenergetic decline is starting from perimenopausal transition, which is followed by the decrease of brain synaptic plasticity [39]. The mouse female transgenic model of familial AD revealed that ovariectomy induces a shift in fuel availability and metabolism in the hippocampus, with an increase of enzymes required for long-chain fatty acid and ketone body metabolism, to obtain brain energy [46,60]. Glucose hypometabolism associated to cerebral hypoperfusion initiated with perimenopausal atherosclerosis [61], hypercholesterolemia, nitric oxide, and impairment of redox homeostasis is considered as the key pathophysiologic promoter of neurodegeneration [59], and the known differences in regional brain metabolism make some women prone to AD [62].…”

“…It was demonstrated how during reproductive ages the estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance aerobic glycolysis coupled to the citric acid cycle, mitochondrial respiration, and ATP generation, and in senescence when estrogens are missing, it is a chronic oxidative stress due to the shift from an aerobic glycolytic to a ketogenic profile/phenotype/ [35,60], and this shift is preceded by the early, already mentioned decline in glucose transport and metabolism [46]. In mouse model, the mitochondrial bioenergetic deficit precedes AD [92].…”

Global metabolic effect of manipulating pyruvate dehydrogenase complex activity in mammalian cells

“…This may contribute to development of type 2 diabetes mellitus as insulin secretion requires a coupled PDC-OXPHOS system and increasing PDC activity in patients had a glucose and lactate lowering effect (Stacpoole, Moore & Kornhauser 1978). In brain, an age-related decrease in glucose oxidation and oxygen consumption was observed (Kalpouzos et al 2009;Martin et al 1991) together with an increase of aerobic glycolysis and ketone body oxidation (Ross et al 2010;Yao et al 2010). Many neurodegenerative diseases, particularly Alzheimer's disease, are associated with abnormal brain oxidative metabolism and data implicate a reduced PDC activity and up-regulation of aerobic glycolysis (reviewed in (Coskun et al 2012;Green, Galluzzi & Kroemer 2011)).…”

“…Decreased PDC activity reduces glucose carbon flux into the TCA cycle and is linked to various age-related diseases such as glucose intolerance (Stacpoole, Moore & Kornhauser 1978), heart failure (Bersin & Stacpoole 1997), neurodegeneration (Stacpoole 1997), and cancer (reviewed in (Stacpoole 2012). An age-related decrease in glucose oxidation and oxygen consumption was observed in the brain (Kalpouzos et al 2009;Martin et al 1991) together with increased ketone body formation and aerobic glycolysis (Ross et al 2010;Yao et al 2010). Many neurodegenerative diseases, such as Alzheimer's disease, are associated with abnormal brain oxidative metabolism and data implicate up-regulated aerobic glycolysis and reduced PDC activity (reviewed in (Coskun et al 2012;Green, Galluzzi & Kroemer 2011).…”