Multiscale Modeling Of The Regulation Of Mitochondrial Function By Metabolites And Ultrastructur

Mitochondria are responsible for producing ATP, the energy currency in all living cells. To do this, the mitochondria have a complex micro-architecture upon which occur biomolecular processes that break down energy substrate to produce ATP. In heart which is constantly beating, mitochondrial energy metabolism is well regulated, allowing for increases during exercise. Energy metabolism is thought to be regulated both by changes in metabolite concentration as well as the micro-architecture of the cristae which are the folds in the mitochondrial inner membrane. The two questions addressed here are 1) how is calcium in the mitochondria regulated and what effect does this have on energy metabolism and 2) how does the cristae structure contribute to the regulation of energy metabolism. To this end, a multiscale computational modeling approach has been used to integrate experimental information across disparate scales and gain an understanding of the complex dynamics of this system.;Calcium activates three dehydrogenases in the mitochondria and the ATP synthase all of which are involved in energy metabolism. In the experimental literature there is disagreement upon whether calcium dynamics in the mitochondrial is fast or slow. Fast dynamics leads to large beat to beat changes in mitochondrial calcium. Slow dynamics results in a time averaging of the calcium transients similar to a low pass filter. The computational studies suggest that slow calcium dynamics are more efficient at stimulating ATP production than fast dynamics.;The cristae structure in mitochondria varies in different cells, under different physiological conditions, and during disease. We hypothesize that these changes might play role in the efficiency of energy metabolism. The computational studies suggest that there are gradients in the intercristae spaces of metabolites such as calcium, ATP, and ADP. These gradients change when mitochondria structure changes. The computational models also suggest that the changes in gradient affect the efficiency of energy metabolism and that these gradients can occur under different physiological and structural conditions. With greater accumulation of calcium in mitochondrial matrix, ATP synthase activation produces more ATP. However, mitochondria, which are known to be bounded by a double membrane, are structurally dynamic organelles with three subcompartments including the inter-membrane space between outer and inner membrane, inter-crista space between two adjacent invaginations of the inner membrane and the central matrix enveloped by the inner membrane. Calcium accumulation is much more rapid in the inter-membrane space and the crista region than in the matrix. Our model simulations suggest that depending on the structure, gradients across the length of mitochondrial crista change as does the matrix volume. Such variation in the localized concentrations of metabolites may dictate the overall function of mitochondria.