Mitochondrial NHE1 and NCLX in the diabetic cardiomyopathy

DE FAZIO R; CARRIZO VELÁSQUEZ FE; COSTANTINI N; CIARROCCHI S; AIELLO EA; JAQUENOD DE GIUSTI C

Santiago de Chile

Congreso; Congreso de la Asociación Latinoamericana de Ciencias Fisiológicas (ALACF).; 2020

Introduction: Heart failure is the leading cause of death among diabetic people. Cellular and molecular entities leading to diabetic cardiomyopathy (DCM) are poorly understood. Na+/H+ exchanger (NHE) is a ubiquitous ion exchanger responsible for intracellular pH maintenance. NHE1 is the heart isoform. Our previous results show increased NHE1 activity in the heart from obese anddiabetic mice (ob-/-) compared to the control heterozygous littermates (ob+/-). Mitochondrial dysfunction has been related to the development of heart failure and NHE1 has been detected in rat mitochondria, where its inhibition resulted in decreased mitochondrial swelling. Altered mitochondrial Ca2+ may result in mitochondrial dysfunction. The role of mitochondrial NHE1 and Na+/Ca2+ exchanger (NLCX) in DCM has not been yet studied. Objective to study the role of NHE1 and NLCX in the mitochondria of ob-/- mice. Methodology: Left ventricle mitochondria were isolated by differential centrifugation. NHE1 inhibition was obtained using 10 μM HOE. Data were expressed as mean ± SE. Statistical analysis was performed by one-way ANOVA followed by Tukey´s test. The experimental protocol was approved by the Animal Welfare Committee of La Plata School of Medicine. Results: Our results showed increased NHE1 expression in the mitochondria from ob-/- mice. Preliminary results also show increased NCLX expression. These mitochondria also presented altered swelling, mPTP opening, CRC, and ΔΨm, while NHE1 blockade partially reverted this phenotype. Finally, mitochondria from ob-/- mice present reduced calcium content and increased NCLX expression. Conclusions: The role of mitochondrial NHE1 is not completely understood however, NHE1 activity could not directly result in ΔΨm alteration considering its electroneutral exchange. However, alterations in mitochondrial Na+ concentration could influenceNCLX activity. Considering that NHE1 inhibition partially reverses mitochondrial alterations and that our preliminary data indicates increased NCLX, our results indicate that both mitochondrial NHE1 and NCLX are involved in the development of mitochondrial dysfunction in DCM.