Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases

Metabolic control analysis has often been used for quantitative studies of the regulation of mitochondrial oxidative phosphorylations (OXPHOS). The ma in contribution of this work has been to show that the control of mitochond rial metabolic fluxes can be shared among several steps of the oxidative ph osphorylation process, and that this distribution can vary according to the steady state and the tissue. However, these studies do not show whether th is observed variation in the OXPHOS control is due to the experimental cond itions or to the nature of the mitochondria. To find out if there actually exists a tissue variation in the distribution of OXPHOS control coefficient s, we determined the control coefficients of seven OXPHOS complexes on the oxygen-consumption flux in rat mitochondria isolated from five different ti ssues under identical experimental conditions. Thus in this work, only the nature of the mitochondria can be responsible for any variation detected in the control coefficient values between different tissues. The analysis of control coefficient distribution shows two tissue groups: (i) the muscle an d the heart, controlled essentially at the level of the respiratory chain; and (ii) the liver, the kidney and the brain, controlled mainly at the phos phorylation level by ATP synthase and the phosphate carrier. We propose tha t this variation in control coefficient according to the tissue origin of t he mitochondria can explain part of the tissue specificity observed in mito chondrial cytopathies.