Regulation of oxidative phosphorylation through parallel activation

When the mechanical work intensity in muscle increases, the elevated ATP consumption rate must be matched by the rate of ATP production by oxidative phosphorylation in order to avoid a quick exhaustion of ATP. The traditional mechanism of the regulation of oxidative phosphorylation, namely the negative feedback involving [ADP] and [Pi] as regulatory signals, is not sufficient to account for various kinetic properties of the system in intact skeletal muscle and heart in vivo. Theoretical studies conducted using a dynamic computer model of oxidative phosphorylation developed previously strongly suggest the so-called each-step-activation (or parallel activation) mechanism, due to which all oxidative phosphorylation complexes are directly activated by some cytosolic factor/mechanism related to muscle contraction in parallel with the activation of ATP usage and substrate dehydrogenation by calcium ions. The present polemic article reviews and discusses the growing evidence supporting this mechanism and compares it with alternative mechanisms proposed in the literature. It is concluded that only the each-step-activation mechanism is able to explain the rich set of various experimental results used as a reference for estimating the validity and applicability of particular mechanisms.