Mitochondrial calcium (m Ca2+ ) uptake occurs via the Mitochondrial Ca2+ Uniporter (MCU) complex and plays a critical role in mitochondrial dynamics, mitophagy, and apoptosis. MCU complex activity is in part modulated by the expression of its regulatory subunits. Cardiovascular disease models demonstrated altered gene/protein expression of one or multiple subunits in different cells, including vascular endothelial cells (ECs). MCU complex activity was found necessary for stable flow (s-flow)-induced mitophagy and promotion of an atheroprotective EC phenotype. Disturbed flow (d-flow) is known to lead to an atheroprone phenotype. Despite the role of MCU in flow-regulated EC function, flow-induced alterations in MCU complex subunit expression are currently unknown. We exposed cultured human ECs to atheroprotective (steady shear stress, SS) or atheroprone flow (oscillatory shear stress, OS) and measured mRNA and protein levels of the MCU complex members. SS and OS differentially modulated subunit expression at gene/protein levels. Protein expression changes of the core MCU, m Ca2+ uptake 1 (MICU1) and MCU regulator 1 (MCUR1) subunits in SS- and OS-exposed, compared to static, ECs suggested an enhanced m Ca2+ influx under each flow and a potential contribution to EC dysfunction under OS. In silico analysis of a single-cell RNA-sequencing dataset was employed to extract transcript values of MCU subunits in mouse carotid ECs from regions exposed to s-flow or d-flow. Mcu and Mcur1 genes showed significant differences in expression after prolonged exposure to each flow. The differential expression of MCU complex subunits indicated a tight regulation of the complex activity under physiological and pathological hemodynamic conditions.
Keywords: calcium signaling; endothelial dysfunction; hemodynamics; mitochondrial dynamics; oxidative stress.
© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.