VDAC2 as a novel target for heart failure: Ca2+ at the sarcomere, mitochondria and SR

Abstract

Despite a growing number of successful therapies, heart failure remains the most common cause of death and disability worldwide. Thus, new and novel therapeutic strategies are urgently needed. Mitochondria of cardiomyocytes generate ATP that is needed to power cardiac contraction. Mitochondrial-derived ATP activate myosin ATPase at the sarcomere and the sarcoplasmic reticular (SR) ATPase Ca²⁺ pump, both which intersect with Ca²⁺ during contraction. Failure to maintain the relationship between mitochondria and SR can lead to cardiomyocyte dysfunction and heart failure. Here, we discuss recent discoveries that reveal Ca²⁺ transport via the voltage dependent anion channel (VDAC) into the mitochondria can favorably impact cardiac contraction and prevent cardiac arrhythmias. In a broader view, discussion of the opening of a new era for HF therapeutics that will address the sarcomere, SR and mitochondria as a functional unit.

Keywords: Calcium; Contractility; Excitation contraction coupling; Heart failure; Mitochondria; Mitochondrial Ca(2+) uptake transporter; Voltage dependent anion channels.