Respiratory cytochrome supercomplexes

Evidence from several investigations demonstrates the existence of supramolecular units of Complex I, Complex III, and multiple copies of Complex IV in mitochondria and indicates that specific respiratory complexes may preferentially associate to form cytochrome-containing supercomplexes in the native membrane. There are now indications that cardiolipin, a distinctive mitochondrial lipid, stabilizes the respiratory assemblies. The isolated supercomplexes are active with respect to both their component individual complexes and the entire respiratory function that relies on Coenzyme Q and cytochrome c as intermediate substrates. The latter finding argues against previous models of a random distribution of the respiratory complexes in mitochondria. The supercomplex organization is compatible with electron transfer, but experimental evidence is scant for an effective mechanism via substrate channeling compared to free diffusion of substrates in accordance with the random collision model. The finding that Complex I is almost totally associated in a supercomplex with Complex III seems to exclude a role for the ubiquinone pool in physiological electron transfer between these two complexes, whereas it is certainly required for electron transfer from Complex II or from other dehydrogenases to Complex III; likely, only a small fraction of Complex IV forms a functional supercomplex with channeling of cytochrome c. Nevertheless, the supercomplexes may physiologically exist in equilibrium with free complexes (plasticity model). The supercomplex organization appears to prevent excessive generation of reactive oxygen species from the respiratory chain; accordingly, many pathological conditions and the mitochondrial aging phenotype characterized by a loss of supercomplex assembly correlate with mitochondrial dysfunction and increased oxidative stress. Specific metabolic signals may also arise in the cell in response to a tuned production of reactive oxygen species as a consequence of the controlled dynamics of supercomplex assembling/ disassembling at different physio-pathological conditions. The present review paper provides an updated and extensive discussion on the subject.