Control of mitochondrial respiration in the heart in vivo.

After reviewing the controversies in the literature surrounding the regulation of oxidative phosphorylation, a unifying theory to integrate the disparate results would be welcome. Following the traditional biochemical approach to identifying sites of control, one searches for the rate-limiting step in a series of reactions (i.e. a biochemical pathway) that, presumably, will not be at equilibrium. This approach has not succeeded in locating a reaction in cardiac respiratory control that is singularly rate-limiting and may actually be contributing to, rather than clarifying, the problem. There are two major criticisms of this approach. First, even if the step is in disequilibrium, it does not prove that it is rate-limiting (26). Second, a reaction near equilibrium can contribute to regulation of a system (37). In a complex, multiple-reaction integrated pathway such as mitochondrial respiration there are many steps that could potentially share the control of the overall system. Thus this pathway easily lends itself to the possibility of multiple sites of control, each of which could contribute by varying degrees to regulation. In Figure 3 we present one possible network (undoubtedly incomplete) for the distributed control of respiration, which incorporates contributions by the cellular redox state (supply), phosphate metabolite concentrations (either kinetic or thermodynamic), and oxygen. The coordination of the dehydrogenases, phosphate metabolites, and myosin ATPase activity (work) may be orchestrated by a second messenger. Calcium is an attractive candidate for this role (15) as it simultaneously can modulate reducing equivalent supply via the dehydrogenases and ATP use by the myofibrils. The theory of shared control along the path of respiration is not new (37), and has been gaining support from a variety of laboratories (3, 9, 26). Applying this concept to the experimental setting, the relative control strengths for various steps in oxidative phosphorylation have been reported for isolated mitochondria (26). The control coefficients for respiration in isolated myocytes or hearts in vivo remain unknown at this time. If control of respiration occurs at multiple sites, it could account for much of the disagreement in the literature. Experimental conditions, whether intentional or inadvertent, that saturate one or more control mechanisms will increase the relative effect of the other regulatory sites on the remaining range of mitochondrial function. If, for example, the medium surrounding isolated myocytes is such that the cytosolic redox state and pO2 are very high, the phosphate metabolite concentrations could logically be expected to be a major factor influencing the observed rate of oxidative phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)