Mitochondrial Ca²⁺ transport in the endothelium: regulation by ions, redox signalling and mechanical forces

Calcium (Ca²⁺) transport by mitochondria is an important component of the cell Ca²⁺ homeostasis machinery in metazoans. Ca²⁺ uptake by mitochondria is a major determinant of bioenergetics and cell fate. Mitochondrial Ca²⁺ uptake occurs via the mitochondrial Ca²⁺ uniporter (MCU) complex, an inner mitochondrial membrane protein assembly consisting of the MCU Ca²⁺ channel, as its core component, and the MCU complex regulatory/auxiliary proteins. In this review, we summarize the current knowledge on the molecular nature of the MCU complex and its regulation by intra- and extramitochondrial levels of divalent ions and reactive oxygen species (ROS). Intracellular Ca²⁺ concentration ([Ca²⁺]_i), mitochondrial Ca²⁺ concentration ([Ca²⁺]_m) and mitochondrial ROS (mROS) are intricately coupled in regulating MCU activity. Here, we highlight the contribution of MCU activity to vascular endothelial cell (EC) function. Besides the ionic and oxidant regulation, ECs are continuously exposed to haemodynamic forces (either pulsatile or oscillatory fluid mechanical shear stresses, depending on the precise EC location within the arteries). Thus, we also propose an EC mechanotransduction-mediated regulation of MCU activity in the context of vascular physiology and atherosclerotic vascular disease.