Electron Transport in the Mitochondrial Respiratory Chain

The metabolic capacity of the eukaryotic cell to convert free energy contained in nutrients into ATP is a process accomplished by a multistep system: the mitochondrial respiratory chain. This chain involves a series of electron-transferring enzymes and redox co-factors, whose biochemical characterization is the collective result of more than 50 years of scientists’ endeavors. The current knowledge describes in detail the structure and function of the individual proton-translocating “core” complexes of the respiratory chain (Complex I, III, IV). However, a holistic approach to the study of electrons transport from NADdependent substrates to oxygen has recently directed our attention to the existence of specific albeit dynamic interactions between the respiratory complexes. In this context, the respiratory complexes are envisaged to be either in form of highly ordered assemblies (i.e. supercomplexes) or as individual enzymes randomly distributed in the mitochondrial membrane. Either model of organization has functional consequences, which can be discussed in terms of the structural stability of the protein complexes and the kinetic efficiency of inter-complex electron transfer. Available experimental evidence suggests that Complex I and Complex III behave as assembled supercomplexes (ubiquinone channeling) or as individual enzymes (ubiquinone-pool), depending on the lipid environment of the membrane. On the contrary, a strict association of Complexes III and Complex IV is not required for electron transfer via cytochrome c, although there are supercomplexes in bovine heart mitochondria, known as the respirasomes, that also include some molecules of Complex IV. Our recent experimental results demonstrate that the disruption of the supercomplex I1–III2 enhances the propensity of Complex I to generate the superoxide anion; we propose that any primary source of oxidative stress in mitochondria may perpetuate generation of reactive oxygen species by a vicious cycle involving supercomplex dissociation as a major determinant.