A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain

Abstract Mitochondrial genome maintenance plays a central role in preserving brain health. We previously demonstrated accumulation of mitochondrial DNA damage and severe neurodegeneration in transgenic mice inducibly expressing a mutated mitochondrial DNA repair enzyme (mutUNG1) selectively in foreb...

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Bibliographic Details
Published in:Neurobiology of aging 2016-12, Vol.48, p.34-47
Main Authors: Lauritzen, Knut H, Hasan-Olive, Md Mahdi, Regnell, Christine E, Kleppa, Liv, Scheibye-Knudsen, Morten, Gjedde, Albert, Klungland, Arne, Bohr, Vilhelm A, Storm-Mathisen, Jon, Bergersen, Linda H
Format: Article
Language:English
Subjects:
Animals
Biogenesis
Diet, Ketogenic - adverse effects
DNA Damage
DNA, Mitochondrial - metabolism
Internal Medicine
Ketogenic diet
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Electron
Mitochondria - genetics
Mitochondria - pathology
Mitochondrial Diseases - etiology
Mitochondrial Diseases - genetics
MtDNA damage
Neurodegeneration
Neurodegenerative Diseases - etiology
Neurodegenerative Diseases - genetics
Neurology
Neurons - ultrastructure
Organelle Biogenesis
Perylene
Prosencephalon - cytology
Prosencephalon - metabolism
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Summary:Abstract Mitochondrial genome maintenance plays a central role in preserving brain health. We previously demonstrated accumulation of mitochondrial DNA damage and severe neurodegeneration in transgenic mice inducibly expressing a mutated mitochondrial DNA repair enzyme (mutUNG1) selectively in forebrain neurons. Here, we examine whether severe neurodegeneration in mutUNG1 expressing mice could be rescued by feeding the mice a ketogenic diet, which is known to have beneficial effects in several neurological disorders. The diet increased the levels of superoxide dismutase 2 (SOD2), and mitochondrial mass, enzymes and regulators such as SIRT1 and FIS1, and appeared to downregulate NMDA receptor subunits NR2A/B and upregulate GABAA receptor subunits α1 . However, unexpectedly, the ketogenic diet aggravated neurodegeneration and mitochondrial deterioration. Electron microscopy showed structurally impaired mitochondria accumulating in neuronal perikarya. We propose that aggravation is caused by increased mitochondrial biogenesis of generally dysfunctional mitochondria. This study thereby questions the dogma that a ketogenic diet is unambiguously beneficial in mitochondrial disorders.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2016.08.005