Ca2+ signals:
Molecular Mechanisms and Integrative Functions Collaborative Research Center 894

Project A13 - Christoph Maack

Role of mitochondrial Ca2+ uptake during physiological and pathological workloads

The heart consumes high amounts of energy in the form of ATP. Mitochondria are the major cellular source of ATP, but also of reactive oxygen species (ROS). The Krebs cycle produces NADH, which is required for ATP production at the electron transport chain, but also NADPH, which is required for anti-oxidative defense mechanisms. Ca2+ activates the Krebs cycle and thus, adapts ATP supply to demand, but also regenerates the anti-oxidative capacity. This Ca2+ is taken up into mitochondria via a Ca2+ uniporter (MCU) whose molecular identity was revealed only recently.

The aim of the present project is to reveal the role of mitochondrial Ca2+ uptake via the MCU during a physiological or pathological increase of workload in the heart, in particular of cardiac afterload. In this regard, also the interplay between neuronal nitric oxide synthase (nNOS) and mitochondrial ROS production on cytosolic and mitochondrial Ca2+ transients will be analyzed in more detail. These studies should reveal the precise regulation of mitochondrial redox state and ROS production during physiological and pathological load conditions in the heart. Since mitochondrial ROS production plays a causal role during the development of heart failure, these results have major pathophysiological and possibly therapeutical implications.