Mitochondrial Metabolic Function is Affected by Inner Membrane Morphology

Abstract

The mitochondrial inner membrane (IM) has a dynamic and complex structure that plays a significant role in mitochondrial function and energy metabolism. The folds in the IM called cristae have different size and morphology which influence the surface area of the inner membrane, home of critical membrane proteins including ATP synthase and electron transport chain complexes; metabolite and ion transporters including the adenine nucleotide translocase, the calcium uniporter (MCU), the sodium/calcium exchanger (NCLX); and many more. Our multiscale modeling seeks to develop a fundamental understanding of the interplay of the mitochondrial cristae organization and mitochondrial metabolic function. Our previously published model (Nguyen et al., 2007) for mitochondrial energy metabolism was upgraded to take account of our new data on both activity-dependent regulation of ATP production, calcium handling, and new information on cristae structure. This spatiotemporal model of the mitochondrion was developed using the Virtual Cell platform in two and three-dimensional representations. The studies examine the effect of inner membrane morphology and protein localization on metabolic function and specifically ATP production and Ca uptake. In this study various aspects of crista structure in two and three dimensions, including shape, junctions and fenestrations were targeted. The model predicts spatial gradients of ion and metabolite concentrations for observed (tubular, lamellar), conformations of cristae and within the mitochondrial matrix. The existence of these gradients affects mitochondrial ATP fluxes across the inner membrane. The model suggests that mitochondrial crista geometry alters the gradients of ion and metabolite concentrations in the intracristal space and the matrix. These results provide new insight about metabolic modeling in 2D and 3D structures which can be useful for identifying structural features of mitochondria that influence function in modeling and experiment as well.