Regulation of electron transfer in the terminal step of the respiratory chain

In mitochondria, electrons are transferred along a series of enzymes and electron carriers that are referred to as the respiratory chain, leading to the synthesis of cellular ATP. The series of the interprotein electron transfer (ET) reactions is terminated by the reduction in molecular oxygen at Complex IV, cytochrome c oxidase (CcO) that is coupled with the proton pumping from the matrix to the inner membrane space. Unlike the ET reactions from Complex I to Complex III, the ET reaction to CcO, mediated by cytochrome c (Cyt c), is quite specific in that it is irreversible with suppressed electron leakage, which characterizes the ET reactions in the respiratory chain and is thought to play a key role in the regulation of mitochondrial respiration. In this review, we summarize the recent findings regarding the molecular mechanism of the ET reaction from Cyt c to CcO in terms of specific interaction between two proteins, a molecular breakwater, and the effects of the conformational fluctuation on the ET reaction, conformational gating. Both of these are essential factors, not only in the ET reaction from Cyt c to CcO, but also in the interprotein ET reactions in general. We also discuss the significance of a supercomplex in the terminal ET reaction, which provides information on the regulatory factors of the ET reactions that are specific to the mitochondrial respiratory chain.