Impaired mitochondrial function often results in excessive production of
reactive oxygen species (ROS) and is involved in the etiology of many
chronic diseases, including
cardiovascular disease, diabetes,
neurodegenerative disorders, and
cancer. Moderate levels of mitochondrial ROS, however, can protect against
chronic disease by inducing upregulation of mitochondrial capacity and
endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional
ketosis is a safe and physiological metabolic state induced through a
ketogenic diet low in
carbohydrate and moderate in
protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the
ketone β-hydroxybutyrate (BHB), which is elevated during nutritional
ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional
ketosis beyond
carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and
endogenous antioxidant defense in response to nutritional
ketosis, as well as the potential mechanisms leading to these adaptations.