Non-uniform Distribution of Inner Mitochondrial Membrane Calcium Transport Mechanisms in the Cardiac Muscle

Abstract

Energy homeostasis in the cardiac muscle is critical to assure uninterrupted circulation. The primary energy source of the adult cardiomyocyte is the mitochondrial oxidative ATP production. Metabolic feedback loops and the ATP buffering creatine kinase-phosphocreatine system serve to replenish the ATP levels consumed at each heartbeat; however, they may not sufficiently support the abrupt performance increase needed during fight-or-flight or similar stress responses. To that end, a feed-forward loop has evolved that stimulates the electron donor generators for the respiratory chain, the calcium sensitive mitochondrial matrix dehydrogenases, via mitochondrial calcium uptake during the excitation-contraction coupling. This feed-forward loop, also referred as ‘excitation-bioenergetics coupling’, involves local calcium transfer at the membrane contacts formed between the sarcoplasmic reticulum calcium release units and intermyofibrillar mitochondria. These contacts are secured by protein tethers and our recent studies suggest that they are also areas with strong distribution anomalies of the primary mitochondrial calcium uptake and extrusion mechanisms of the inner mitochondrial membrane. Namely, while the contact area is a hotspot for the mitochondrial calcium uniporter complex (MCUC), the Na+/Ca2+ exchanger NCLX is largely excluded from there, even though it is abundant outside the contact area. In this talk, I will present our ideas why such a biased distribution is a favorable arrangement for effective mitochondrial matrix calcium signal generation. Furthermore, potential molecular mechanisms that are responsible for the non-uniform distribution of the MCUC components will be discussed.