Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy – an in-silico study

Abstract

SummaryDiabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy and computational modelling to understand the impact of diabetes induced ultrastructural changes on cardiac bioenergetics.We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using electron microscopy. Micrographs were converted to finite element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation and creatine kinase reactions to simulate diabetes induced mitochondrial dysfunction.Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with depressed activity of mitochondrial creatine kinase enzymes, leads to large spatial variation in ADP/ATP profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% due to lower mitochondrial area fraction and dysfunction in oxidative phosphorylation. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy.

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“…This is because we are always faced with a chicken-egg question: is the structural change a cause of growth/disease or an effect of growth/disease? Similar to Holmes et al [7] with regard to calcium signalling, Ghosh et al [13] offer a possible solution to the chicken-egg question by creating an in silico model that royalsocietypublishing.org/journal/rstb Phil. Trans.…”

“…[7] with regard to calcium signalling, Ghosh et al . [13] offer a possible solution to the chicken-egg question by creating an in silico model that integrates electron microscopy data with independent mitochondrial functional measurements in the literature to predict the explicit effects of structural disorganization on bioenergetics. With their model, they find that mitochondrial organization affects the homogeneity of energy supply across the cardiac myocyte.…”