Ca2+ -dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes.
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 alpha- and beta-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.
Boerries
Melanie
M
Maurice E Mueller Institute for Structural Biology, Biozentrum, University of Basel, Basel, Switzerland.
Most
Patrick
P
Gledhill
Jonathan R
JR
Walker
John E
JE
Katus
Hugo A
HA
Koch
Walter J
WJ
Aebi
Ueli
U
Schoenenberger
Cora-Ann
CA
D000255:Adenosine Triphosphate / Q000032:analysis*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D019084:Fluorescent Antibody Technique, Indirect; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism* / Q000648:ultrastructure
D011993:Recombinant Fusion Proteins; D009418:S100 Proteins; C110294:S100A1 protein; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D008156:Luciferases; D005982:Glutathione Transferase; D006180:Proton-Translocating ATPases; D002118:Calcium