MITOCHONDRIAL OXYGEN-AFFINITY, RESPIRATORY FLUX CONTROL AND EXCESS CAPACITY OF CYTOCHROME-C-OXIDASE

The oxygen affinity of the enzyme system involved in mitochondrial res piration indicates, in relation to intracellular oxygen levels and int erpreted with the aid of flux control analysis, a significant role of oxygen supply in limiting maximum exercise. This implies that the flux control coefficient of mitochondria is not excessively high, based on a capacity of mitochondrial oxygen consumption that is slightly highe r than the capacity for oxygen supply through the respiratory cascade. Close matching of the capacities and distribution of flux control is consistent with the concept of symmorphosis. Within the respiratory ch ain, however, the large excess capacity of cytochrome c oxidase, COX, appears to be inconsistent with the economic design of the respiratory cascade. To address this apparent discrepancy, we used three model sy stems: cultured endothelial cells and mitochondria isolated from heart and liver. Intracellular oxygen gradients increase with oxygen flux, explaining part of the observed decrease in oxygen affinity with incre asing metabolic rate in cells. In addition, mitochondrial oxygen affin ities decrease from the resting to the active state. The oxygen affini ty in the active ADP-stimulated state is higher in mitochondria from h eart than in those from liver, in direct relationship to the higher ex cess capacity of COX in heart. This yields, in turn, a lower turnover rate of COX even at maximum flux through the respiratory chain, which is necessary to prevent a large decrease in oxygen affinity in the act ive state, Upregulation of oxygen affinity provides a functional expla nation of the excess capacity of COX. The concept of symmorphosis, a m atching of capacities in the respiratory cascade, is therefore complem ented by 'synkinetic' considerations on optimum enzyme ratios in the r espiratory chain. Accordingly, enzymatic capacities are matched in ter ms of optimum ratios, rather than equal levels, to meet the specific k inetic and thermodynamic demands set by the low-oxygen environment in the cell.