Alterations of Ca2+ handling in heart failure (2 of 4)

Dr. Christoph Maack

In chronic heart failure, oxidative stress is causally linked to the progression of the disease, and mitochondria were identified as critical sources of reactive oxygen species (ROS). Furthermore, disturbed excitation-contraction coupling (in particular, cytosolic Ca2+ and Na+ handling) and energy depletion contribute to contractile dysfunction in the failing heart. The aim of our research is to identify the underlying sources of oxidative stress and energetic deficit in heart failure. A key regulatory role is played by the mitochondrial Krebs cycle, which generates NADH for ATP production at the respiratory chain, but also NADPH, which is required for the elimination of ROS. Since Ca2+ activates key enzymes of the Krebs cycle, we will discuss the consequences of defective excitation-contraction coupling on energy supply-and-demand matching and the regulation of mitochondrial ROS production. Furthermore, the implications of a mitochondrial Ca2+ microdomain between the sarcoplasmic reticulum and mitochondria, governed by the close spatial association of these organelles, will be evaluated. Finally, the consequences of increased mitochondrial ROS production for left ventricular function in vivo will be addressed.