Functional remodeling of the mitochondrial Ca2+ uniporter complex in metabolic cardiomyopathy

Abstract

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondation pour la Recherche Médicale ANR Background Calcium (Ca2+) uptake through the mitochondrial Ca2+ uniporter complex (MCUC) controls keys steps of the oxidative metabolism. In metabolic cardiomyopathy, myocardial mitochondrial Ca2+ uptake is impaired, but whether it is an early feature of the pathology remain unsolved. Purpose To establish whether mitochondrial Ca2+ dynamics and MCUC structure and function are affected at the early stage of the metabolic cardiomyopathy. Methods and Results Mice fed two weeks with a high fat sucrose diet display early features of metabolic disorders and diastolic dysfunction. Concomitantly, mitochondrial Ca2+-dependent pyruvate dehydrogenase activity and the beat-to-beat mitochondrial Ca2+ uptake are reduced. The impaired mitochondrial Ca2+ uptake was further confirmed by single channel recordings of the native MCUC incorporated in planar lipid bilayer demonstrating a reduction of the ion conductance and the open probability. The MCUC biochemical analysis showed an elevation of the EMRE subunit expression and an increase interaction of EMRE with the MICU1 subunits. Co-immunoprecipitation also revealed a deceased interaction of the pore forming subunits MCU with EMRE-MICU1 subcomplex. The displacement of the MCUC assembly was confirmed by the decrease in m-AAA protease-interacting protein 1 expression as well as its loss of binding with EMRE. Conclusions The remodeling of the MCUC integrity impacts mitochondrial Ca2+ homeostasis at the early stage of the metabolic cardiomyopathy and provides a novel post-translational paradigm of the MCUC regulation in pathophysiological context.