Altered mitochondrial sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice

Voltage-dependent anion channels (VDACs) form the main pathway for metaboli tes across the mitochondrial outer membrane. The mouse vdac1 gene has been disrupted by gene targeting, and the resulting mutant mice have been examin ed for defects in muscle physiology, To test the hypothesis that VDAC1 cons titutes a pathway for ADP translocation into mitochondria, the apparent mit ochondrial sensitivity for ADP (k(m(ADP))) and the calculated rate of respi ration in the presence of the maximal ADP concentration (V-max) have been a ssessed using skinned fibers prepared from two oxidative muscles (ventricle and soleus) and a glycolytic muscle (gastrocnemius) in control and vdac1(- /-) mice. We observed a significant increase in the apparent K-m(ADP) in he art and gastrocnemius, whereas the V-max remained unchanged in both muscles . In contrast, a significant decrease in both the apparent K-m(ADP) and V-m ax was observed in soleus, To test whether VDAC1 is required for creatine s timulation of mitochondrial respiration in oxidative muscles, the apparent K-m(ADP) and V-max were determined in the presence of 25 mM creatine. The c reatine effect on mitochondrial respiration was unchanged in both heart and soleus, These data, together with the significant increase in citrate synt hase activity in heart, but not in soleus and gastrocnemius, suggest that d istinct metabolic responses to altered mitochondrial outer membrane permeab ility occur in these different striated muscle types.