Influence of mitochondrial content on the sensitivity of respiratory control

This study evaluated the sensitivity of mitochondrial respiratory control as a function of tissue oxidative capacity. The mitochondrial content of rat skeletal muscle was increased by exercise training or decreased by hypothyroidism. Muscles of the lower hindlimb were stimulated to tetanically contract in situ for 3 min at one of four frequencies to elicit a 30-fold range of oxygen consumption rates. Freeze-clamped sections of fast-twitch red gastrocnemius muscle were extracted and analyzed for metabolite levels. The sensitivity of respiratory control was examined for three models of cytosolic respiratory control (ADPf, ATP/ADPf, and ATP/(ADPf X Pi]; for each proposed model, sensitivity went up as mitochondrial content increased. Thus, a smaller change in cytosolic modulator (e.g., ADPf) is required as oxidative capacity increases. Increases in the sensitivity of cytosolic respiratory control resulted in lower flux through the near-equilibrium energy exchange reactions of creatine kinase and myokinase such that calculated free concentrations of ADP and AMP were less. Other energetically important reactions/pathways were also affected. Accumulation of lactate and the deamination of AMP to IMP were lower in tissues with higher mitochondrial content. In summary, changes in oxidative capacity directly influence the sensitivity of cytosolic respiratory control and this, in turn, has important consequences for maintenance of cellular energy balance.