Flux-balance analysis of mitochondrial energy metabolism: consequences of systemic stoichiometric constraints

Mitochondrial metabolism is a critical component in the functioning and mai ntenance of cellular organs. The stoichiometry of biochemical reaction netw orks imposes constraints on mitochondrial function. A modeling framework, f lux-balance analysis (FBA), was used to characterize the optimal flux distr ibutions for maximal ATP production in the mitochondrion. The model predict ed the expected ATP yields for glucose, lactate, and palmitate. Genetic def ects that affect mitochondrial functions have been implicated in several hu man diseases. FBA can characterize the metabolic behavior due to genetic de letions at the metabolic level, and the effect of mutations in the tricarbo xylic acid (TCA) cycle on mitochondrial ATP production was simulated. The m itochondrial ATP production is severely affected by TCA-cycle mutations. In addition, the model predicts the secretion of TCA-cycle intermediates, whi ch is observed in clinical studies of mitochondriopathies such as those ass ociated with fumarase deficiency. The model provides a systemic perspective to characterize the effect of stoichiometric constraints and specific meta bolic fluxes on mitochondrial function.