Function of the outer mitochondrial compartment in regulation of energy metabolism.

Electron microscopy showed the organization of several kinases at the mitochondrial surface as complexes between outer membrane (porin), kinase, and inner membrane (presumably adenine nucleotide translocator?). The complexes were enriched in the isolated contact site fraction. Interaction of porin with the kinases in vitro led to formation of tetramers of hexokinase and active creatine kinase. Kinetic analyses of mitochondria with intact outer compartment showed separate ATP/ADP exchange between kinases and oxidative phosphorylation. Considering these results, we postulate that the mitochondrial metabolism in intact cells is not regulated by free ADP, but induced by substrates wf kinases such as glucose or creatine (Fig 1). Increased ATP turnover in muscle during contraction results in only a small change in the free ADP but causes a larger change of creatine because the equilibrium constant of the creatine kinase reaction at pH 7.2 favours ATP formation (ATP creatine/ADP phosphocreatine = 104.7) [38]. In addition, the level of phosphocreatine is roughly 10-times higher compared to ATP. Considering the higher concentration and the equilibrium constant, it can be calculated that a change of ADP between 40 and 70 microM results in creatine increasing from 8 to 12 mM. Thus creatine can be the signal that stimulates the mitochondrial metabolism transmitted by the mitochondrial creatine kinase [39]. Likewise, increased blood glucose in muscle at rest or in the liver stimulates the mitochondrial metabolism transmitted by the activity of bound hexokinase utilizing external ATP. The mitochondrial metabolism provides the UTP for glycogen synthesis through mitochondrial nucleoside-diphosphate kinase activity (Fig 1).