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

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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 H2O2 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).

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Acknowledgements

This study was supported by research Grants from the Research Council of Norway, the Norwegian Health Association, and the Lundbeck Foundation (Denmark).

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Authors and Affiliations

  1. Synaptic Neurochemistry and Amino Acid Transporter Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Center, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Md Mahdi Hasan-Olive, Knut H. Lauritzen, Jon Storm-Mathisen & Linda H. Bergersen

  2. Brain and Muscle Energy Group, Electron Microscopy Laboratory, Institute of Oral Biology, University of Oslo, Oslo, Norway

    Md Mahdi Hasan-Olive & Linda H. Bergersen

  3. Center for Healthy Aging, Department of Neurosciences and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Md Mahdi Hasan-Olive, Lene Juel Rasmussen & Linda H. Bergersen

  4. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway

    Knut H. Lauritzen

  5. Department of Biochemistry, Sir Salimullah Medical College & Mitford Hospital, Dhaka, Bangladesh

    Mohammad Ali

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  1. Md Mahdi Hasan-Olive
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  2. Knut H. Lauritzen
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Hasan-Olive, M.M., Lauritzen, K.H., Ali, M. et al. A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis. Neurochem Res 44, 22–37 (2019). https://doi.org/10.1007/s11064-018-2588-6

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