A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis

Abstract

A ketogenic diet (KD; high-fat, low-carbohydrate) can benefit refractory epilepsy, but underlying mechanisms are unknown. We used mice inducibly expressing a mutated form of the mitochondrial DNA repair enzyme UNG1 (mutUNG1) to cause progressive mitochondrial dysfunction selectively in forebrain neurons. We examined the levels of mRNAs and proteins crucial for mitochondrial biogenesis and dynamics. We show that hippocampal pyramidal neurons in mutUNG1 mice, as well as cultured rat hippocampal neurons and human fibroblasts with HO induced oxidative stress, improve markers of mitochondrial biogenesis, dynamics and function when fed on a KD, and when exposed to the ketone body β-hydroxybutyrate, respectively, by upregulating PGC1α, SIRT3 and UCP2, and (in cultured cells) increasing the oxygen consumption rate (OCR) and the NAD/NADH ratio. The mitochondrial level of UCP2 was significantly higher in the perikarya and axon terminals of hippocampus CA1 pyramidal neurons in KD treated mutUNG1 mice compared with mutUNG1 mice fed a standard diet. The β-hydroxybutyrate receptor GPR109a (HCAR2), but not the structurally closely related lactate receptor GPR81 (HCAR1), was upregulated in mutUNG1 mice on a KD, suggesting a selective influence of KD on ketone body receptor mechanisms. We conclude that progressive mitochondrial dysfunction in mutUNG1 expressing mice causes oxidative stress, and that exposure of animals to KD, or of cells to ketone body in vitro, elicits compensatory mechanisms acting to augment mitochondrial mass and bioenergetics via the PGC1α-SIRT3-UCP2 axis (The compensatory processes are overwhelmed in the mutUNG1 mice by all the newly formed mitochondria being dysfunctional).

Functional and therapeutic potential of mitochondrial SIRT3 deacetylase in disease conditions

“…Report by Olive et al showed that mitochondrial dysfunction model of mouse expressing a mutated form of the mitochondrial DNA repair enzyme UNG1 (mutUNG1) improved SIRT3 levels when fed with ketogenic diet. This further improved oxygen consumption rate and the NAD + /NADH ratio through compensatory mechanism which increased mitochondrial mass and bioenergetics acting via PGC1α-SIRT3-UCP2 axis [21]. The relationship between SIRT3 and PGC1α has already been well discussed in previous studies [22][23][24].…”

Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer&rsquo;s Disease<strong> </strong>

“…Notably, the ketogenic diet improves mitochondrial biogenesis and bioenergetics via an increase in PGC1α-SIRT3 [157]. This seem driven increased NAD+ within a couple of days [158], with these authors showing the ketogenic diet to elevate the mRNA and protein levels of nuclear sirtuins.…”

Ketogenic Diet for Weight Loss and Its Implication on Health: A Literature Study

“…Ketogenic diet is currently used for weight loss (Kirkpatrick et al, 2019), diet therapy for cancer (Weber et al, 2019), mitochondrial dysfunction (Hasan-Olive et al, 2019), alzheimer (Rusek et al, 2019, infl ammation, oxidative stress (Pinto et al, 2018), and movement disorders and severe or traumatic brain injury (McDougall et al, 2018).…”