The mitochondrial Ca²⁺ uniporter channel synergizes with fluid shear stress to induce mitochondrial Ca²⁺ oscillations

The mitochondrial calcium (Ca²⁺) uniporter (MCU) channel is responsible for mitochondrial Ca²⁺ influx. Its expression was found to be upregulated in endothelial cells (ECs) under cardiovascular disease conditions. Since the role of MCU in regulating cytosolic Ca²⁺ homeostasis in ECs exposed to shear stress (SS) is unknown, we studied mitochondrial Ca²⁺ dynamics (that is known to decode cytosolic Ca²⁺ signaling) in sheared ECs. To understand cause-and-effect, we ectopically expressed MCU in ECs. A higher percentage of MCU-transduced ECs exhibited mitochondrial Ca²⁺ transients/oscillations, and at higher frequency, under SS compared to sheared control ECs. Transients/oscillations correlated with mitochondrial reactive oxygen species (mROS) flashes and mitochondrial membrane potential (ΔΨ_m) flickers, and depended on activation of the mechanosensitive Piezo1 channel and the endothelial nitric oxide synthase (eNOS). A positive feedback loop composed of mitochondrial Ca²⁺ uptake/mROS flashes/ΔΨ_m flickers and endoplasmic reticulum Ca²⁺ release, in association with Piezo1 and eNOS, provided insights into the mechanism by which SS, under conditions of high MCU activity, may shape vascular EC energetics and function.