Supercomplexes and subcomplexes of mitochondrial oxidative phosphorylation

Abstract

Dimerization or oligomerization of ATP synthase has been proposed to play an important role for mitochondrial cristae formation and to be involved in regulating ATP synthase activity. We found comparable oligomycin-sensitive ATPase activity for monomeric and oligomeric ATP synthase suggesting that oligomerization/monomerization dynamics are not directly involved in regulating ATP synthase activity. Binding of the natural IF 1 inhibitor protein has been shown to induce dimerization of F 1-subcomplexes. This suggested that binding of IF 1 might also dimerize holo ATP synthase, and possibly link dimerization and inhibition. Analyzing mitochondria of human rho zero cells that contain mitochondria but lack mitochondrial DNA, we identified three subcomplexes of ATP synthase: (i) F 1 catalytic domain, (ii) F 1-domain with bound IF 1, and (iii) F 1-c subcomplex with bound IF 1 and a ring of subunits c. Since both IF 1 containing subcomplexes were present in monomeric state and exhibited considerably reduced ATPase activity as compared to the third subcomplex lacking IF 1, we postulate that inhibition and induction of dimerization of F 1-subcomplexes by IF 1 are independent events. F 1-subcomplexes were also found in mitochondria of patients with specific mitochondrial disorders, and turned out to be useful for the clinical differentiation between various types of mitochondrial biosynthesis disorders. Supramolecular associations of respiratory complexes, the “respirasomes”, seem not to be the largest assemblies in the structural organization of the respiratory chain, as suggested by differential solubilization of mitochondria and electron microscopic analyses of whole mitochondria. We present a model for a higher supramolecular association of respirasomes into a “respiratory string”.