Fig. 1.

Proposed model for how a ketogenic diet aggravates neurodegenerative effects of mtDNA toxicity in mutUNG1-expressing mice. A ketogenic diet induces mitochondrial biogenesis, which enhances the energy metabolism and energy reserves in neural tissues. It thereby makes the neurons better equipped to deal with cellular stress and increases cellular viability. In mutUNG1-expressing mice, the mutUNG1 protein is targeted to all mitochondria, generating high levels of mtDNA damage, which causes dysfunctional mitochondria. We propose that in this scenario, an increase in mitochondrial biogenesis will lead to an energetic cost that is higher than the gain and that this ultimately leads to an energy deficit. This together with the harmful effects of increased ROS levels, resulting from a greater number of dysfunctional mitochondria, leads to increased neurodegeneration rather than an alleviating effect. Abbreviation: mtDNA, mitochondrial DNA.