FIGURE 1.

Model for mitochondrial energetic stress in skeletal muscle with exercise between healthy and unhealthy regions of the mitochondrial reticulum. (A). Repeated muscle contraction with prolonged exercise requires sustained hydrolysis of ATP and donation of phosphates from creatine phosphate (CP), creating free creatine that is turned back to CP by mitochondrial creatine kinase (mCK) through the donation of a phosphate from intramitochondrial ATP. (B). In healthy regions of the mitochondrial reticulum, accumulation of intramitochondrial ADP promotes generation of ATP from nutrient substrates via TCA cycle and ß-oxidation and through the ETC to meet energy demand, without undue accumulation in function altering intermediates (e.g., ROS). (C). In spatially distinct unhealthy regions of the mitochondrial reticulum, ATP production does not keep pace with energetic demand, resulting in accumulation of intra and extramitochondrial ADP and excessive generation of ROS, potentially acting as energetic signals for removal via mitophagy.