MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous Ca^{2 þ} release in hypertrophic rat cardiomyocytes

Authors

Shanna Hamilton, Dorothy M. Davis Heart and Lung Research Institute
Radmila Terentyeva, Dorothy M. Davis Heart and Lung Research Institute
Fruzsina Perger, Dorothy M. Davis Heart and Lung Research Institute
Benjamín Hernández Orengo, Dorothy M. Davis Heart and Lung Research Institute
Benjamin Martin, Dorothy M. Davis Heart and Lung Research Institute
Matthew W. Gorr, Dorothy M. Davis Heart and Lung Research Institute
Andriy E. Belevych, Dorothy M. Davis Heart and Lung Research Institute
Richard T. Clements, University of Rhode Island
Sandor Gyorke, Dorothy M. Davis Heart and Lung Research Institute
Dmitry Terentyev, Dorothy M. Davis Heart and Lung Research Institute

Document Type

Article

Date of Original Version

10-1-2021

Abstract

Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca2 þ handling and impaired mitochondrial function accompanied with reduced mitochondrial calcium concentration (mito-[Ca2 þ ]). Pharmacological or genetic facilitation of mito-Ca2 þ uptake was shown to restore Ca2 þ transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca2 þ uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca2 þ release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia. To test whether chronic recovery of mito-[Ca2 þ ] restores systolic Ca2 þ release without adverse effects in diastole, we overexpressed mitochondrial Ca2 þ uniporter (MCU) in VMs from male rat hearts with hypertrophy induced by thoracic aortic banding (TAB). Measurement of mito-[Ca2 þ ] using genetic probe mtRCamp1h revealed that mito-[Ca2 þ ] in TAB VMs paced at 2 Hz under b-adrenergic stimulation is lower compared with shams. Adenoviral 2.5-fold MCU overexpression in TAB VMs fully restored mito-[Ca2 þ ]. However, it failed to improve cytosolic Ca2 þ handling and reduce proarrhythmic spontaneous Ca2 þ waves. Furthermore, mitochondrial-targeted genetic probes MLS-HyPer7 and OMM-HyPer revealed a significant increase in emission of reactive oxygen species (ROS) in TAB VMs with 2.5-fold MCU overexpression. Conversely, 1.5-fold MCU overexpression in TABs, that led to partial restoration of mito-[Ca2 þ ], reduced mitochondria-derived reactive oxygen species (mito-ROS) and spontaneous Ca2 þ waves. Our findings emphasize the key role of elevated mito-ROS in disease-related proarrhythmic Ca2 þ mishandling. These data establish nonlinear mito-[Ca2 þ ]/mito-ROS relationship, whereby partial restoration of mito-[Ca2 þ ] in diseased VMs is protective, whereas further enhancement of MCU-mediated Ca2 þ uptake exacerbates damaging mito-ROS emission.

Publication Title, e.g., Journal

American Journal of Physiology - Heart and Circulatory Physiology

Volume

321

Issue

4

Citation/Publisher Attribution

Hamilton, Shanna, Radmila Terentyeva, Fruzsina Perger, Benjamín H. Orengo, Benjamin Martin, Matthew W. Gorr, Andriy E. Belevych, Richard T. Clements, Sandor Gyorke, and Dmitry Terentyev. "MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous Ca^{2 þ} release in hypertrophic rat cardiomyocytes." American Journal of Physiology - Heart and Circulatory Physiology 321, 4 (2021): H615-H632. doi: 10.1152/ajpheart.00126.2021.