Tissue Specific Impacts of a Ketogenic Diet on Mitochondria! Dynamics in the BTBRT+tf/j Mouse

The ketogenic diet (KD) has been utilized as a dietary therapeutic for nearly a century. One experimental model particularly responsive to the KD is the BTBRT+tf/j (BTBR) mouse, which displays phenotypic characteristics of autism spectrum disorder (ASD) and insulin resistance. Recently, the study of impaired mitochondria' function has become a focal point of research investigating the pathophysiology of ASD. As highly dynamic organelles, mitochondria undergo constant fluctuations in morphology, biogenesis, and quality control in order to maintain cellular homeostasis. An important modifier of mitochondria' dynamics is energy availability. Therefore, the aim of this study was to examine the impact of a KD on mitochondria' dynamics in the liver and brain (prefrontal cortex) of the BTBR mouse model of ASD. Juvenile male C57BI/6 (B6) and BTBR mice were age-matched to 5 weeks of age before being fed standard chow (CD, 13% kcal fat) or a KD (75% kcal fat) for 10-14 days. Analysis of brain tissue identified differences in mitochondria' gene expression but no correlation with protein levels. Unlike in the brain, KD led to decreased levels of mitochondria' proteins in the liver, despite increased gene expression. Consistent with decreased mitochondria' proteins, we also observed decreased mtDNA for all mice on the KD, demonstrating that the KD reduces the total amount of mitochondria in the liver. In order to explain the discrepancy between protein levels and gene expression, we investigated whether mitochondria' turnover via mitophagy was increased. To this end, we examined expression levels of the mitophagy regulator BNIP3 (BCL2/adenovirus E1B 19 kd-interacting protein 3). BNIP3 gene and protein expression were significantly elevated in liver of KD animals (p < 0.05), indicating the potential activation of mitophagy. Therefore, consumption of a KD exerts highly tissue-specific effects, ultimately increasing mitochondria' turnover in the liver, while gene and protein expression in the brain remaining tightly regulated.