A substrate cycle between citric acid cycle (CAC) intermediates isocitrate and 2-oxoglutarate, involving NAD+- and NADP+-linked isocitrate dehydrogenase (NAD-IDH and NADP-IDH, respectively) and mitochondrial transhydrogenase (H+-Thase), has recently been proposed. This cycle has been hypothesized to enhance mito-chondrial respiratory control by increasing the sensitivity of NAD-IDH to its modulators and allowing for enhanced increases in flux through this step of the CAC during periods of increased ATP demand. The activities of the enzymes comprising the substrate cycle: NAD-IDH, forward and reverse NADP-IDH, and forward and reverse H+-Thase, along with the activity of a marker of mitochondrial content, citrate synthase (CS) were measured in mitochondria isolated from rabbit Type I and Type IIb muscles and in whole muscle homogenates, representing the various fiber types, from rats. In isolated rabbit muscle mitochondria, NAD-IDH had significantly higher (1.6 X) activity in white muscle while forward NADP-IDH, forward and reverse H+-Thase, and CS all had significantly higher (1.2-1.6 X) activities in red muscle. There was no difference in reverse NADP-IDH between fiber types. Similarly, in rat whole muscle enzyme activities normalized to CS, NAD-IDH had significantly higher activity in fast-twitch glycolytic (FG) fibers, while forward NADP-IDH and forward H+-Thase had significantly higher activities in slow-twitch oxidative (SO) fibers. These results suggest that differences in the activities of the substrate cycle enzymes between skeletal muscle fiber types could contribute to differences in respiratory control due to differential cycling rates and/or loci of control.
Howlett, R. A., & Willis, W. T. (1998). Fiber-type-related differences in the enzymes of a proposed substrate cycle. Biochimica et Biophysica Acta - Bioenergetics, 1363(3), 224–230. https://doi.org/10.1016/S0005-2728(98)00002-4