An in-silico study to determine whether changes to mitochondria organization through engineered mitochondrial dynamics can enhance bioenergetics in cardiomyocytes

Abstract

SUMMARYMitochondria are the powerhouse of the cell and owing to their unique energetic demands, heart muscles contain a high density of mitochondria. In conditions such as heart failure and diabetes-induced heart disease, changes in the organization of cardiac mitochondria are common. While recent studies have also shown that cardiac mitochondria split and fuse throughout the cell, a mechanistic understanding of how mitochondrial dynamics may affect energy output is lacking. Using a mathematical model that has been fitted to experimental data, we test if briefly altering fission or fusion rates improves ATP production and supply in cardiomyocytes. Unexpectedly, we found that cardiac bioenergetics, e.g., the ADP/ATP ratio, were robust to changes in fusion and fission rates and consequently mitochondria organization. Our study highlights complex nonlinear feedback loops that are at play in the cross-talk between mitochondrial dynamics and bioenergetics. The study motivate further in-silico and experimental investigations to determine the mechanistic basis for new therapies that target mitochondrial dynamics.