Crucial yet divergent roles of mitochondrial redox state in skeletal muscle vs. brown adipose tissue energetics

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 approximate to 46), and this was associated with fairly high (similar to 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 (similar to 20% in situ). BAT mitochondria were found to have a much more oxidized status (GSH/GSSG approximate to 13) and had basal reactive oxygen species emission that was higher (similar to 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.-Mailloux, R. J., Adjeitey, C. N.-K., Xuan, J. Y., and Harper, M.-E. Crucial yet divergent roles of mitochondrial redox state in skeletal muscle vs. brown adipose tissue energetics. FASEB J. 26, 363-375 (2012). www.fasebj.org