A Low‐carbohydrate, Ketogenic Diet Enhances Hippocampal Mitochondrial Bioenergetics and Efficiency

Mitochondrial dysfunction(definition) and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as in nonpathological aging. Ketones have been suggested as therapeutic for their relevance in epilepsy as well as other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Here we explored whether a low‐carbohydrate, ketogenic diet (KD) alters recognition memory, hippocampal mitochondrial bioenergetics, and expression of proteins involved in mitochondrial dynamics. Mature‐to‐middle‐aged adult male and female mice were placed on a lard‐based KD supplemented with an exogenous ketone ester for eight weeks. Changes in behavioral recognition memory were measured in a two‐object novel object recognition test. Hippocampal mitochondrial physiology was assessed using high‐resolution respirometry to measure changes in oxygen flux, biochemical assays to quantify ATP production, and western blot to measure changes in Drp1 expression. Here we demonstrate that the KD reduces hippocampal oxygen consumption (p=0.013), but does not alter ATP production (p=0.42) or Drp1 expression (p=0.51). These results indicate an enhancement of mitochondrial coupling and efficiency independent of mitochondrial dynamics, as changes in oxygen flux occurred without changes in Drp1 expression. Together, these findings add to growing support for the use of ketones and KDs in pathological brain states in which mitochondrial function is compromised, especially within the hippocampus.