Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca 2+ Signals is Controlled by the Stoichiometry of MICU1/2 and MCU

Paillard, Mélanie; Csordás, György; Szanda, Gergö; Golenár, Tünde; Debattisti, Valentina; Bartók, Ádám; Moffat, Cynthia; Seifert, Erin L.; Spät, András; Hajnóczky, György

doi:10.1016/j.bpj.2016.11.2905

Cited by 15 publications

(29 citation statements)

References 27 publications

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“…MICU1 controls the allosteric activation of the uniporter by Ca 2+ , on its cytosolic side [17]. In agreement with the assumption of Paillard et al [16], a decrease of both K 2 measuring the level of Ca 2+ required to activate the channel and V MCU to simulate the lower expression level of the uniporter in cardiac cells leads to a larger flux J MCU at low Ca 2+ and a smaller one at high Ca 2+ (Fig. 4B).…”

Section: Different Activities Of the Mitochondrial Ca 2+ Uniporter Insupporting

confidence: 88%

“…This large decrease time observed in experiments could be reproduced in our simulations when considering other dissociation constants for Ca 2+ binding to the MCU than those used in our study of intact cells. More specifically, if these values were increased up to 25 and 1.6 lM for the transport and activation site, respectively, the model predicts a decrease time of 14.3 s. Interestingly, these latter values for K 1 and K 2 are in agreement with the kinetic characterisation of the MCU reported in the literature [16][17][18]. Indeed, the red curve in Fig.…”

Section: Ca 2+ Dynamics In a Suspension Of Hepatocyte Mitochondriasupporting

confidence: 86%

“…4A shows the activity of the MCU computed with K 1 = 25 lM and K 2 = 1.6 lM. It can be seen that the half-maximal activity occurs at~3 lM cytosolic Ca 2+ , which lies in the range of experimentally reported values (3.4 lM in HeLa cells [17], 4.0 lM in hepatocytes [16]). Thus, agreement between experimentally observed and simulated kinetics of Ca 2+ entry into mitochondria can be obtained with realistic values for the Ca 2+ binding to the MCU.…”

Section: Ca 2+ Dynamics In a Suspension Of Hepatocyte Mitochondriamentioning

confidence: 69%

“…4B). The change in cooperativity suggested by Paillard et al [16] was found to be unnecessary to account for their observations in the framework of the Monod-Wyman-Changeux description of the uniporter regulation used in Eqn S2.…”

Section: Different Activities Of the Mitochondrial Ca 2+ Uniporter Inmentioning

confidence: 92%

“…This observation had early suggested that the Ca 2+ uptake capacity of the MCU is smaller in cardiac cells than in electrically non-excitable cells such as hepatocytes [30,31]. It has been shown recently that such tissuespecificity of the MCU relies on different relative abundances of the pore-forming protein of the uniporter and its Ca 2+ -sensing regulator MICU1 [16]. As the heart cells express a relatively lower level of MICU1, the MCU has a larger Ca 2+ transporting capacity at low Ca 2+ than in other cell types such as hepatocytes.…”

Section: Different Activities Of the Mitochondrial Ca 2+ Uniporter Inmentioning

confidence: 99%

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Mitochondrial Ca²⁺ dynamics in cells and suspensions

Wacquier

Campos²,

González‐Vélez³

et al. 2017

The FEBS Journal

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Mitochondria play a significant role in shaping cytosolic Ca signals. Thus, transfer of Ca across the mitochondrial membrane is much studied, not only in intact cells but also in artificial systems such as mitochondrial suspensions or permeabilised cells. Observed rates of Ca changes vary by at least one order of magnitude. In this work, we investigate the relationship between the Ca dynamics observed in various experimental conditions using a computational model calibrated on experimental data. Results confirm that mitochondrial Ca exchange fluxes through the mitochondrial Ca uniporter (MCU) and the Na /Ca exchanger obey the same basic kinetics in cells and in suspensions, and emphasise the important role played by the high Ca levels reached in mitochondria-associated endoplasmic reticulum membranes in intact cells. Tissue specificity can be ascribed to the different modes of regulation of the MCU by Ca , probably related to the specific levels of expression of the Ca sensing regulator subunit of this channel. The model emphasises the importance of mitochondrial density and buffering in controlling the rate of Ca exchanges with mitochondria, as verified experimentally. Finally, we show that heterogeneity between individual mitochondria can explain the large range of amplitudes and rates of rise in mitochondrial Ca concentration that have been observed experimentally.

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Section: Different Activities Of the Mitochondrial Ca 2+ Uniporter Insupporting

confidence: 88%

Section: Ca 2+ Dynamics In a Suspension Of Hepatocyte Mitochondriasupporting

confidence: 86%

Section: Ca 2+ Dynamics In a Suspension Of Hepatocyte Mitochondriamentioning

confidence: 69%

Section: Different Activities Of the Mitochondrial Ca 2+ Uniporter Inmentioning

confidence: 92%

Section: Different Activities Of the Mitochondrial Ca 2+ Uniporter Inmentioning

confidence: 99%

See 3 more Smart Citations

Mitochondrial Ca²⁺ dynamics in cells and suspensions

Wacquier

Campos²,

González‐Vélez³

et al. 2017

The FEBS Journal

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A High-Throughput Screening Identifies MICU1 Targeting Compounds

et al. 2020

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Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

Groten

MacVicar

2022

Commun Biol

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Neuronal activation is fundamental to information processing by the brain and requires mitochondrial energy metabolism. Mitochondrial Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) has long been implicated in the control of energy metabolism and intracellular Ca2+ signalling, but its importance to neuronal function in the brain remains unclear. Here, we used in situ electrophysiology and two-photon imaging of mitochondrial Ca2+, cytosolic Ca2+, and NAD(P)H to test the relevance of MCU activation to pyramidal neuron Ca2+ signalling and energy metabolism during action potential firing. We demonstrate that mitochondrial Ca2+ uptake by the MCU is tuned to enhanced firing rate and the strength of this relationship varied between neurons of discrete brain regions. MCU activation promoted electron transport chain activity and chemical reduction of NAD+ to NADH. Moreover, Ca2+ buffering by mitochondria attenuated cytosolic Ca2+ signals and thereby reduced the coupling between activity and the slow afterhyperpolarization, a ubiquitous regulator of excitability. Collectively, we demonstrate that the MCU is engaged by accelerated spike frequency to facilitate neuronal activity through simultaneous control of energy metabolism and excitability. As such, the MCU is situated to promote brain functions associated with high frequency signalling and may represent a target for controlling excessive neuronal activity.

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Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca 2+ Signals is Controlled by the Stoichiometry of MICU1/2 and MCU

Cited by 15 publications

References 27 publications

Mitochondrial Ca²⁺ dynamics in cells and suspensions

Mitochondrial Ca²⁺ dynamics in cells and suspensions

A High-Throughput Screening Identifies MICU1 Targeting Compounds

Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

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Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca 2+ Signals is Controlled by the Stoichiometry of MICU1/2 and MCU

Cited by 15 publications

References 27 publications

Mitochondrial Ca2+ dynamics in cells and suspensions

Mitochondrial Ca2+ dynamics in cells and suspensions

A High-Throughput Screening Identifies MICU1 Targeting Compounds

Mitochondrial Ca2+ uptake by the MCU facilitates pyramidal neuron excitability and metabolism during action potential firing

Contact Info

Product

Resources

About

Mitochondrial Ca²⁺ dynamics in cells and suspensions

Mitochondrial Ca²⁺ dynamics in cells and suspensions