MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous Ca
| Autor: | Shanna, Hamilton, Radmila, Terentyeva, Fruzsina, Perger, Benjamín, Hernández Orengo, Benjamin, Martin, Matthew W, Gorr, Andriy E, Belevych, Richard T, Clements, Sandor, Györke, Dmitry, Terentyev |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Microscopy Confocal Ventricular Remodeling Arrhythmias Cardiac Biosensing Techniques Adrenergic beta-Agonists Myocardial Contraction Mitochondria Heart Ventricular Function Left Up-Regulation Rats Sprague-Dawley Disease Models Animal Heart Rate Animals Calcium Hypertrophy Left Ventricular Myocytes Cardiac Calcium Channels Calcium Signaling Reactive Oxygen Species Cells Cultured Research Article |
| Zdroj: | Am J Physiol Heart Circ Physiol |
| ISSN: | 1522-1539 |
| Popis: | Cardiac dysfunction in heart failure (HF) and diabetic cardiomyopathy (DCM) is associated with aberrant intracellular Ca(2+) handling and impaired mitochondrial function accompanied with reduced mitochondrial calcium concentration (mito-[Ca(2+)]). Pharmacological or genetic facilitation of mito-Ca(2+) uptake was shown to restore Ca(2+) transient amplitude in DCM and HF, improving contractility. However, recent reports suggest that pharmacological enhancement of mito-Ca(2+) uptake can exacerbate ryanodine receptor-mediated spontaneous sarcoplasmic reticulum (SR) Ca(2+) release in ventricular myocytes (VMs) from diseased animals, increasing propensity to stress-induced ventricular tachyarrhythmia. To test whether chronic recovery of mito-[Ca(2+)] restores systolic Ca(2+) release without adverse effects in diastole, we overexpressed mitochondrial Ca(2+) uniporter (MCU) in VMs from male rat hearts with hypertrophy induced by thoracic aortic banding (TAB). Measurement of mito-[Ca(2+)] using genetic probe mtRCamp1h revealed that mito-[Ca(2+)] in TAB VMs paced at 2 Hz under β-adrenergic stimulation is lower compared with shams. Adenoviral 2.5-fold MCU overexpression in TAB VMs fully restored mito-[Ca(2+)]. However, it failed to improve cytosolic Ca(2+) handling and reduce proarrhythmic spontaneous Ca(2+) 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-[Ca(2+)], reduced mitochondria-derived reactive oxygen species (mito-ROS) and spontaneous Ca(2+) waves. Our findings emphasize the key role of elevated mito-ROS in disease-related proarrhythmic Ca(2+) mishandling. These data establish nonlinear mito-[Ca(2+)]/mito-ROS relationship, whereby partial restoration of mito-[Ca(2+)] in diseased VMs is protective, whereas further enhancement of MCU-mediated Ca(2+) uptake exacerbates damaging mito-ROS emission. NEW & NOTEWORTHY Defective intracellular Ca(2+) homeostasis and aberrant mitochondrial function are common features in cardiac disease. Here, we directly compared potential benefits of mito-ROS scavenging and restoration of mito-Ca(2+) uptake by overexpressing MCU in ventricular myocytes from hypertrophic rat hearts. Experiments using novel mito-ROS and Ca(2+) biosensors demonstrated that mito-ROS scavenging rescued both cytosolic and mito-Ca(2+) homeostasis, whereas moderate and high MCU overexpression demonstrated disparate effects on mito-ROS emission, with only a moderate increase in MCU being beneficial. |
| Databáze: | OpenAIRE |
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