title: Tissue Specific Impacts of a Ketogenic Diet on Mitochondrial Dynamics in the BTBRT+tf/jMouse.
abstract: 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 mitochondrial 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 mitochondrial dynamics is energy availability. Therefore, the aim of this study was to examine the impact of a KD on mitochondrial dynamics in the liver and brain (prefrontal cortex) of the BTBR mouse model of ASD. Juvenile male C57Bl/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 mitochondrial gene expression but no correlation with protein levels. Unlike in the brain, KD led to decreased levels of mitochondrial proteins in the liver, despite increased gene expression. Consistent with decreased mitochondrial 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 mitochondrial 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 mitochondrial turnover in the liver, while gene and protein expression in the brain remaining tightly regulated.
authors.affiliation: Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary Calgary, AB, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newell
authors.affiliation: Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada; Department of Medical Genetics, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Shutt
authors.affiliation: Department of Pediatrics, Cumming School of Medicine, University of Calgary Calgary, AB, Canada.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary Calgary, AB, Canada.
authors.forename: Dustin S
authors.initials: DS
authors.lastname: Hittel
authors.affiliation: Department of Medical Genetics, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada; Department of Pediatrics, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada.
authors.forename: Aneal
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada.
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
authors.affiliation: Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada; Faculty of Kinesiology, University of CalgaryCalgary, AB, Canada.
authors.forename: Jane
authors.initials: J
authors.lastname: Shearer
keywords: ketogenic diet; liver metabolism; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial respiration; nutrient sensing