title: 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 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, and mitochondrial mass, enzymes, and regulators such as SIRT1 and FIS1, and appeared to downregulate N-methyl-D-aspartic acid (NMDA) receptor subunits NR2A/B and upregulate γ-aminobutyric acid A (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.
authors.affiliation: Synaptic Neurochemistry Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Brain and Muscle Energy Group, Electron Microscopy Laboratory, Institute of Oral Biology, University of Oslo, Oslo, Norway.
authors.forename: Knut H
authors.initials: KH
authors.lastname: Lauritzen
authors.affiliation: Synaptic Neurochemistry Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Brain and Muscle Energy Group, Electron Microscopy Laboratory, Institute of Oral Biology, University of Oslo, Oslo, Norway.
authors.forename: Md Mahdi
authors.initials: MM
authors.lastname: Hasan-Olive
authors.affiliation: Synaptic Neurochemistry Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Brain and Muscle Energy Group, Electron Microscopy Laboratory, Institute of Oral Biology, University of Oslo, Oslo, Norway; Center for Healthy Aging and Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Regnell
authors.affiliation: Synaptic Neurochemistry Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Brain and Muscle Energy Group, Electron Microscopy Laboratory, Institute of Oral Biology, University of Oslo, Oslo, Norway.
authors.forename: Liv
authors.initials: L
authors.lastname: Kleppa
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.affiliation: Center for Healthy Aging and Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Albert
authors.initials: A
authors.lastname: Gjedde
authors.affiliation: Institute of Medical Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: Synaptic Neurochemistry Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Jon
authors.initials: J
authors.lastname: Storm-Mathisen
authors.affiliation: Synaptic Neurochemistry Laboratory, Division of Anatomy and CMBN/SERTA Healthy Brain Ageing Centre, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Brain and Muscle Energy Group, Electron Microscopy Laboratory, Institute of Oral Biology, University of Oslo, Oslo, Norway; Center for Healthy Aging and Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: l.h.bergersen@odont.uio.no.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Bergersen
mesh_terms: D000818:Animals; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D055423:Diet, Ketogenic / Q000009:adverse effects*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000209:etiology / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000235:genetics*; D009474:Neurons / Q000648:ultrastructure; D001678:Organelle Biogenesis; D010569:Perylene; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D010569:Perylene
keywords: Biogenesis; Ketogenic diet; MtDNA damage; Neurodegeneration