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

ABSTRACT: 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.

SUBMITTER: Patel A

PROVIDER: S-EPMC9729216 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Patel Akshar A Simkulet Matthew M Maity Soumya S Venkatesan Manigandan M Matzavinos Anastasios A Madesh Muniswamy M Alevriadou B Rita BR

Scientific reports 20221207 1

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 ...[more]

PMID: 36476944

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Project description:Mitochondrial Ca(2+) uniporter is the primary influx pathway for Ca(2+) into respiring mitochondria, and hence plays a key role in mitochondrial Ca(2+) homeostasis. Though the mechanism of extra-matrix Ca(2+) dependency of mitochondrial Ca(2+) uptake has been well characterized both experimentally and mathematically, the mechanism of membrane potential (ΔΨ) dependency of mitochondrial Ca(2+) uptake has not been completely characterized. In this paper, we perform a quantitative reevaluation of a previous biophysical model of mitochondrial Ca(2+) uniporter that characterized the possible mechanism of ΔΨ dependency of mitochondrial Ca(2+) uptake. Based on a model simulation analysis, we show that model predictions with a variant assumption (Case 2: external and internal Ca(2+) binding constants for the uniporter are distinct), that provides the best possible description of the ΔΨ dependency, are highly sensitive to variation in matrix [Ca(2+)], indicating limitations in the variant assumption (Case 2) in providing physiologically plausible description of the observed ΔΨ dependency. This sensitivity is attributed to negative estimate of a biophysical parameter that characterizes binding of internal Ca(2+) to the uniporter. Reparameterization of the model with additional nonnengativity constraints on the biophysical parameters showed that the two variant assumptions (Case 1 and Case 2) are indistinguishable, indicating that the external and internal Ca(2+) binding constants for the uniporter may be equal (Case 1). The model predictions in this case are insensitive to variation in matrix [Ca(2+)] but do not match the ΔΨ dependent data in the domain ΔΨ≤120 mV. To effectively characterize this ΔΨ dependency, we reformulate the ΔΨ dependencies of the rate constants of Ca(2+) translocation via the uniporter by exclusively redefining the biophysical parameters associated with the free-energy barrier of Ca(2+) translocation based on a generalized, non-linear Goldman-Hodgkin-Katz formulation. This alternate uniporter model has all the characteristics of the previous uniporter model and is also able to characterize the possible mechanisms of both the extra-matrix Ca(2+) and ΔΨ dependencies of mitochondrial Ca(2+) uptake. In addition, the model is insensitive to variation in matrix [Ca(2+)], predicting relatively stable physiological operation. The model is critical in developing mechanistic, integrated models of mitochondrial bioenergetics and Ca(2+) handling.

Dataset Information

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

Publications

The mitochondrial Ca<sup>2+</sup> uniporter channel synergizes with fluid shear stress to induce mitochondrial Ca<sup>2+</sup> oscillations.

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