To understand the control and regulation of mitochondrial energy metabolism a generalized matrix method of Metabolic Control Analysis has been applied to a computational model of mitochondrial energetics. The computational model of Cortassa et al. (2003) encompasses oxidative phosphorylation, the tricarboxylic acid (TCA) cycle, and ion dynamics across the inner mitochondrial membrane. Control of respiration and ATP synthesis fluxes were found to be distributed among various mitochondrial processes. Control is shared by processes associated with ATP synthesis and ATP/ADP transport, as well as by Ca(2+) dynamics. The analysis of flux control coefficients and response coefficients has led to the notion of control by diffuse loops, that points to the regulatory interactions exerted by processes that are mechanistically only indirectly related with each other. The approach we have utilized demonstrates how properties of integrated systems may be understood through applications of computational modeling and control analysis.