Abstract 12456: Mitochondrial Protein ES1 Deficiency Leads to Cardiac Hypertrophy Due to Disturbances in Mitochondrial Energy Metabolism
Defects in myocardial energy metabolism have been linked to pathological cardiac hypertrophy and congestive heart failure; however, the regulation of myocardial energy metabolism remains obscure. ATP synthase is an enzyme complex in the mitochondria and plays a central role in energy metabolism. In the present study, we identified ES1, a mitochondrial protein with unknown function, as a key determinant of myocardial energy metabolism via controlling ATP synthase activities. We uncovered that ES1 interacts with both α and β subunit of ATP synthase, and its expression levels in cultured H9c2 cardiomyocytes were directly correlated to ATP synthesis and inversely to ATP hydrolysis. Cellular energetic analysis revealed that ES1 levels in H9c2 cardiomyocytes were directly correlated with mitochondrial oxidative metabolism. We have generated an ES1 knockout mouse (ES1-/-) line. Echocardiography revealed substantially cardiac dysfunction with decreased ejection fraction (EF%) (55.3 ± 2.4 vs 46.1 ± 1.7) and fractional shortening (FS%) (28.6 ± 1.6 vs 22.8 ± 1.0) in 3-month-old ES1-/- mice compared with controlled littermates (ES1f/f) under a basal condition. As a result, ES1-/- mice showed increased left ventricular mass compared. Morphometric assessment confirmed that heart weight to body weight ratio was increased by 23% in ES1-/- vs controlled mice. Masson’s Trichrome blue and Sirius red staining on heart sections of ES1-/- mice showed markedly increased interstitial fibrosis. Transmission electron microscope (TEM) examination revealed substantial loss of mitochondrial cristae structure on ES1-/- knockout hearts. ATP synthase activity assays on isolated mitochondria revealed that ATP synthesis activities decreased and hydrolysis activities increased in cardiac mitochondria from ES1-/- mice compared with those of ES1f/f control mice. These results indicate that ES1 is a novel and important ATP synthase regulator and its deficiency causes mitochondrial energy metabolism dysfunction in the heart followed by cardiac pathology. Therefore, ES1 is a important determinant of cardiac pathophysiology and a potential therapeutic target in treating cardiac hypertrophy and heart failure.
- Mitochondrial energetics, heart failure, arrhythmias
- Energy metabolism
- Heart disease
Author Disclosures: Q. Long: Research Grant; Modest; AHA Postdoctoral Fellowship 13POST14180006. H. Yang: None. A. Wang: None. Y. Li: None. Y. Zhou: None. L. He: None. Y. Ding: None. T. Kim: None. K. Yang: None. L. Zhou: None. Q. Yang: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.