Ca 2+ -Dependent Interaction of S100A1 with F 1 -ATPase Leads to an Increased ATP Content in Cardiomyocytes

Abstract

ABSTRACT S100A1, a Ca 2+ -sensing protein of the EF-hand family that is expressed predominantly in cardiac muscle, plays a pivotal role in cardiac contractility in vitro and in vivo. It has recently been demonstrated that by restoring Ca 2+ homeostasis, S100A1 was able to rescue contractile dysfunction in failing rat hearts. Myocardial contractility is regulated not only by Ca 2+ homeostasis but also by energy metabolism, in particular the production of ATP. Here, we report a novel interaction of S100A1 with mitochondrial F 1 -ATPase, which affects F 1 -ATPase activity and cellular ATP production. In particular, cardiomyocytes that overexpress S100A1 exhibited a higher ATP content than control cells, whereas knockdown of S100A1 expression decreased ATP levels. In pull-down experiments, we identified the α- and β-chain of F 1 -ATPase to interact with S100A1 in a Ca 2+ -dependent manner. The interaction was confirmed by colocalization studies of S100A1 and F 1 -ATPase and the analysis of the S100A1-F 1 -ATPase complex by gel filtration chromatography. The functional impact of this association is highlighted by an S100A1-mediated increase of F 1 -ATPase activity. Consistently, ATP synthase activity is reduced in cardiomyocytes from S100A1 knockout mice. Our data indicate that S100A1 might play a key role in cardiac energy metabolism.