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A minimal model for the mitochondrial rapid mode of Ca²+ uptake mechanism.

ABSTRACT: Mitochondria possess a remarkable ability to rapidly accumulate and sequester Ca²?. One of the mechanisms responsible for this ability is believed to be the rapid mode (RaM) of Ca²? uptake. Despite the existence of many models of mitochondrial Ca²? dynamics, very few consider RaM as a potential mechanism that regulates mitochondrial Ca²? dynamics. To fill this gap, a novel mathematical model of the RaM mechanism is developed herein. The model is able to simulate the available experimental data of rapid Ca²? uptake in isolated mitochondria from both chicken heart and rat liver tissues with good fidelity. The mechanism is based on Ca²? binding to an external trigger site(s) and initiating a brief transient of high Ca²? conductivity. It then quickly switches to an inhibited, zero-conductive state until the external Ca²? level is dropped below a critical value (?100-150 nM). RaM's Ca²?- and time-dependent properties make it a unique Ca²? transporter that may be an important means by which mitochondria take up Ca²? in situ and help enable mitochondria to decode cytosolic Ca²? signals. Integrating the developed RaM model into existing models of mitochondrial Ca²? dynamics will help elucidate the physiological role that this unique mechanism plays in mitochondrial Ca²?-homeostasis and bioenergetics.

SUBMITTER: Bazil JN

PROVIDER: S-EPMC3121760 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A minimal model for the mitochondrial rapid mode of Ca²+ uptake mechanism.

Bazil Jason N JN Dash Ranjan K RK

PloS one 20110623 6

Mitochondria possess a remarkable ability to rapidly accumulate and sequester Ca²⁺. One of the mechanisms responsible for this ability is believed to be the rapid mode (RaM) of Ca²⁺ uptake. Despite the existence of many models of mitochondrial Ca²⁺ dynamics, very few consider RaM as a potential mechanism that regulates mitochondrial Ca²⁺ dynamics. To fill this gap, a novel mathematical model of the RaM mechanism is developed herein. The model is able to simulate the available experimental data o ...[more]

PMID: 21731705

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Project description:BackgroundRadiation therapy strongly increases the risk of atherosclerotic vascular disease, such as carotid stenosis. Radiation induces DNA damage, in particular in mitochondria, but the upstream and downstream signaling events are poorly understood. The objective of this study was to define such mechanisms.MethodsEndothelial-specific MCU (mitochondrial Ca2+ uniporter) knockout and C57Bl6/J mice with or without a preinfusion of a mitoTEMPO (mitochondrial reactive oxygen species [ROS] scavenger) were exposed to a single dose of cranial irradiation. 24, and 240 hours postirradiation, vascular reactivity, endothelial function, and mitochondrial integrity were assessed ex vivo and in vitro.ResultsIn cultured human endothelial cells, irradiation with 4 Gy increased cytosolic Ca2+ transients and the mitochondrial Ca2+ concentration ([Ca2+]mt) and activated MCU. These outcomes correlated with increases in mitochondrial ROS (mtROS), loss of NO production, and sustained damage to mitochondrial but not nuclear DNA. Moreover, irradiation impaired activity of the ETC (electron transport chain) and the transcription of ETC subunits encoded by mitochondrial DNA (mtDNA). Knockdown or pharmacological inhibition of MCU blocked irradiation-induced mtROS production, mtDNA damage, loss of NO production, and impairment of ETC activity. Similarly, the pretreatment with mitoTEMPO, a scavenger of mtROS, reduced irradiation-induced Ca2+ entry, and preserved both the integrity of the mtDNA and the production of NO, suggesting a feed-forward loop involving [Ca2+]m and mtROS. Enhancement of DNA repair in mitochondria, but not in the nucleus, was sufficient to block prolonged mtROS elevations and maintain NO production. Consistent with the findings from cultured cells, in C57BL/6J mice, head and neck irradiation decreased endothelium-dependent vasodilation, and mtDNA integrity in the carotid artery after irradiation. These effects were prevented by endothelial knockout of MCU or infusion with mitoTEMPO.ConclusionsIrradiation-induced damage to mtDNA is driven by MCU-dependent Ca2+ influx and the generation of mtROS. Such damage leads to reduced transcription of mitochondrial genes and activity of the ETC, promoting sustained mtROS production that induces endothelial dysfunction. Our findings suggest that targeting MCU and mtROS might be sufficient to mitigate irradiation-induced vascular disease.

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A minimal model for the mitochondrial rapid mode of Ca²+ uptake mechanism.

Publications

A minimal model for the mitochondrial rapid mode of Ca²+ uptake mechanism.

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