Mitochondria, providing most of ATP needed for cell work, realizing numerous specific functions as biosyntheses or degradations, contributing to Ca2+ signalling also play a key role in the pathways to cell death. Impairment of mitochondrial functions caused by mutations of mt-genome and by acute processes are responsible for numerous diseases. The relations between changes on the level of molecules and the clinical state are rather complex, and the prediction of thresholds is difficult. Therefore investigations on different levels of an organismus (genome, metabolites, enzymes, mitochondrial function in vivo and in vitro) are necessary (multi level approach). Metabolic control theory is a valuable tool for understanding the different effects of mutations on the level of enzyme activities and mitochondrial function. Decreased concentrations of adenine nucleotides, leaky outer and inner mitochondrial membranes, decreased rates of mitochondrial linked pathways and decreased activities of respiratory chain enzymes contribute to depression of cellular energy metabolism characterized by decreased cytosolic phosphorylation potentials as one of the most important consequences of mitochondrial impairments. This review regards classical bioenergetic mechanisms of mitochondrial impairment which contribute to energetic depression.