title: Hexokinase II acts through UCP3 to suppress mitochondrial reactive oxygen species production and maintain aerobic respiration.
abstract: UCP3 (uncoupling protein-3) mitigates mitochondrial ROS (reactive oxygen species) production, but the mechanisms are poorly understood. Previous studies have also examined UCP3 effects, including decreased ROS production, during metabolic states when fatty acid oxidation is high (e.g. a fasting state). However, the role of UCP3 when carbohydrate oxidation is high (e.g. fed state) has remained largely unexplored. In the present study, we show that mitochondrial-bound HK (hexokinase) II curtails oxidative stress and enhances aerobic metabolism of glucose in the fed state in a UCP3-dependent manner. Genetic knockout or inhibition of UCP3 significantly decreased mitochondrial-bound HKII. Furthermore, UCP3 was required for the HKII-mediated decrease in mitochondrial ROS emission. Intriguingly, the UCP3-mediated modulation of mitochondria-associated HKII was only observed in cells cultured under high-glucose conditions. UCP3 was required to maintain high rates of aerobic metabolism in high-glucose-treated cells and in muscle of fed mice. Deficiency in UCP3 resulted in a metabolic shift that favoured anaerobic glycolytic metabolism, increased glucose uptake and increased sensitivity to oxidative challenge. PET (positron emission tomography) of [18F]fluoro-deoxyglucose uptake confirmed these findings in UCP3-knockout and wild-type mice. Collectively, our findings link the anti-oxidative and metabolic functions of UCP3 through a surprising molecular connection with mitochondrial-bound HKII.
authors.affiliation: Faculty of Medicine, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.forename: Tyler
authors.initials: T
authors.lastname: Dumouchel
authors.forename: Céline
authors.initials: C
authors.lastname: Aguer
authors.forename: Rob
authors.initials: R
authors.lastname: deKemp
authors.forename: Rob
authors.initials: R
authors.lastname: Beanlands
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects*; D005502:Food; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D057809:HEK293 Cells; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D006593:Hexokinase; D005947:Glucose