Abstract
Cardiomyocyte hypertrophy induced by phenylephrine (PE) is accompanied by suppression of cytochrome c oxidase (CCO) activity, and copper (Cu) supplementation restores CCO activity and reverses the hypertrophy. The present study was aimed to understand the mechanism of PE-induced decrease in CCO activity. Primary cultures of neonatal rat cardiomyocytes were treated with PE at a final concentration of l00 µM in cultures for 72 h to induce cell hypertrophy. The CCO activity was determined by enzymatic assay and changes in CCO subunit COX-IV as well as copper chaperones for CCO (COX17, SCO2, and COX11) were determined by Western blotting. PE treatment increased both intracellular and extracellular homocysteine concentrations and decreased intracellular Cu concentrations. Studies in vitro found that homocysteine and Cu form complexes. Inhibition of the intracellular homocysteine synthesis in the PE-treated cardiomyocytes prevented the increase in the extracellular homocysteine concentration, retained the intracellular Cu concentration, and preserved the CCO activity. PE treatment decreased protein concentrations of the COX-IV, and the Cu chaperones COX17, COX11, and SCO2. These PE effects were prevented by either inhibition of the intracellular homocysteine synthesis or Cu supplementation. Therefore, PE-induced elevation of homocysteine restricts Cu availability through its interaction with Cu and suppression of Cu chaperones, leading to the decrease in CCO enzyme activity.
Highlights
Disturbance in the mitochondrial structure and metabolism makes a critical contribution to the pathogenesis of hypertrophic cardiomyopathy [1,2,3]
The results presented here addressed the mechanism by which PE treatment suppresses the cytochrome c oxidase (CCO) activity in cardiomyocytes
Cu is required for the CCO activity, and Cu deficiency leads to the suppression of the CCO activity [11,12,13]
Summary
Disturbance in the mitochondrial structure and metabolism makes a critical contribution to the pathogenesis of hypertrophic cardiomyopathy [1,2,3]. Among the essential components involved in the mitochondrial integrity and function, cytochrome c oxidase (CCO) is the last of the three proton-pumping assembles of the mitochondrial respiratory chain, catalyzing the transfer of electron from reduced cytochrome c to molecular oxygen, the final electron acceptor. Both experimental and clinical studies demonstrated the determinant role of CCO depression in the initiation and progression of cardiac hypertrophy and dysfunction [4,5,6]. CCO is composed of 13 subunits, three of which (COX-I, -II, and -III) are encoded by the mitochondrial DNA and the rest are encoded by the nuclear DNA [7,8,9]. Mutations in COX11 suppress the CCO activity [22]
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