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Abstract
The mitochondrial calcium (Ca
2+
) uniporter (MCU) channel is responsible for mitochondrial Ca
2+
influx. Its expression was found to be upregulated in endothelial cells (ECs) under cardiovascular disease conditions. Since the role of MCU in regulating cytosolic Ca
2+
homeostasis in ECs exposed to shear stress (SS) is unknown, we studied mitochondrial Ca
2+
dynamics (that is known to decode cytosolic Ca
2+
signaling) in sheared ECs. To understand cause-and-effect, we ectopically expressed MCU in ECs. A higher percentage of MCU-transduced ECs exhibited mitochondrial Ca
2+
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 Ca
2+
uptake/mROS flashes/ΔΨ
m
flickers and endoplasmic reticulum Ca
2+
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.