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

Knut H. Lauritzen, Md Mahdi Hasan-Olive, Christine E. Regnell, Liv Kleppa, Morten Scheibye-Knudsen, Albert Gjedde, Arne Klungland, Vilhelm A. Bohr, Jon Storm-Mathisen, Linda H. Bergersen

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)34-47
Number of pages14
JournalNeurobiology of aging
StatePublished - Dec 1 2016


  • Biogenesis
  • Ketogenic diet
  • MtDNA damage
  • Neurodegeneration

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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