title: Crucial yet divergent roles of mitochondrial redox state in skeletal muscle vs. brown adipose tissue energetics.
abstract: Reduced glutathione (GSH) is the major determinant of redox balance in mitochondria and as such is fundamental in the control of cellular bioenergetics. GSH is also the most important nonprotein antioxidant molecule in cells. Surprisingly, the effect of redox environment has never been examined in skeletal muscle and brown adipose tissue (BAT), two tissues that have exceptional dynamic range and that are relevant to the development of obesity and related diseases. Here, we show that the redox environment plays crucial, yet divergent, roles in modulating mitochondrial bioenergetics in skeletal muscle and BAT. Skeletal muscle mitochondria were found to naturally have a highly reduced environment (GSH/GSSG≈46), and this was associated with fairly high (∼40%) rates of state 4 (nonphosphorylating) respiration and decreased reactive oxygen species (ROS) emission. The deglutathionylation of uncoupling protein 3 (UCP3) following an increase in the reductive potential of mitochondria results in a further increase in nonphosphorylating respiration (∼20% in situ). BAT mitochondria were found to have a much more oxidized status (GSH/GSSG≈13) and had basal reactive oxygen species emission that was higher (∼250% increase in ROS generation) than that in skeletal muscle mitochondria. When redox status was subsequently increased (i.e., more reduced), UCP1-mediated uncoupling was more sensitive to GDP inhibition. Surprisingly, BAT was found to be devoid of glutaredoxin-2 (Grx2) expression, while there was abundant expression in skeletal muscle. Taken together, these findings reveal the importance of redox environment in controlling bioenergetic functions in both tissues, and the highly unique characteristics of BAT in this regard.
authors.affiliation: University of Ottawa, Department of Biochemistry, Microbiology, and Immunology, Ottawa, ON, Canada.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mailloux
authors.forename: Cyril Nii-Klu
authors.initials: CN
authors.lastname: Adjeitey
authors.forename: Jian Ying
authors.initials: JY
authors.lastname: Xuan
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D003080:Cold Temperature; D004229:Dithiothreitol / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009928:Organ Specificity; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000502:physiology; D011522:Protons; D022722:Thermogenesis / Q000502:physiology; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D011522:Protons; C000604393:Ucp3 protein, mouse; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D005978:Glutathione; D004229:Dithiothreitol; D019803:Glutathione Disulfide