Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport

Trenker, Michael; Malli, Roland; Fertschai, Ismene; Levak-Frank, Sanja; Graier, Wolfgang F.

doi:10.1038/ncb1556

Cited by 307 publications

(350 citation statements)

References 33 publications

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“…59 In addition, the uncoupling proteins 2 and 3 have been implicated in mitochondrial Ca 2þ uptake, but their roles remain controversial. 60 Our data indicate that hydroxyl CoQs are generated under physiological conditions and that they are able to bind and transport Ca 2þ across artificial biomembranes. As compared to MCU, the mitochondrial Ca 2þ accumulation mediated by hydroxyl CoQs is expected to be slower; however, the affinity is very high, and thus the transport is able to operate at cytosolic Ca 2þ concentrations lower than 0.5 μM and potentially even at resting Ca 2þ levels.…”

Section: ' Discussionmentioning

confidence: 70%

Calcium Binding and Transport by Coenzyme Q

et al. 2011

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Coenzyme Q10 (CoQ10) is one of the essential components of the mitochondrial electron-transport chain (ETC) with the primary function to transfer electrons along and protons across the inner mitochondrial membrane (IMM). The concomitant proton gradient across the IMM is essential for the process of oxidative phosphorylation and consequently ATP production. Cytochrome P450 (CYP450) monoxygenase enzymes are known to induce structural changes in a variety of compounds and are expressed in the IMM. However, it is unknown if CYP450 interacts with CoQ10 and how such an interaction would affect mitochondrial function. Using voltammetry, UV–vis spectrometry, electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), fluorescence microscopy and high performance liquid chromatography–mass spectrometry (HPLC–MS), we show that both CoQ10 and its analogue CoQ1, when exposed to CYP450 or alkaline media, undergo structural changes through a complex reaction pathway and form quinone structures with distinct properties. Hereby, one or both methoxy groups at positions 2 and 3 on the quinone ring are replaced by hydroxyl groups in a time-dependent manner. In comparison with the native forms, the electrochemically reduced forms of the new hydroxylated CoQs have higher antioxidative potential and are also now able to bind and transport Ca2+ across artificial biomimetic membranes. Our results open new perspectives on the physiological importance of CoQ10 and its analogues, not only as electron and proton transporters, but also as potential regulators of mitochondrial Ca2+ and redox homeostasis.

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Section: ' Discussionmentioning

confidence: 70%

Calcium Binding and Transport by Coenzyme Q

et al. 2011

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“…Although mitochondrial calcium channels have been studied extensively using a range of biochemical approaches and by electrophysiology [6,10], their molecular identity remains unknown. The uncoupling proteins UCP2 and UCP3 have been shown to be essential for mitochondrial Ca 2+ uptake, suggesting that these molecules might be part of the Ca 2+ uniporter of mitochondria [11]. However, this claim is disputed and awaits confirmation [12,13].…”

Section: Introductionmentioning

confidence: 97%

SLP-2 negatively modulates mitochondrial sodium–calcium exchange

et al. 2010

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a b s t r a c tMitochondria play a major role in cellular calcium homeostasis. Despite decades of studies, the molecules that mediate and regulate the transport of calcium ions in and out of the mitochondrial matrix remain unknown. Here, we investigate whether SLP-2, an inner membrane mitochondrial protein of unknown function, modulates the activity of mitochondrial Ca 2+ transporters. In HeLa cells depleted of SLP-2, the amplitude and duration of mitochondrial Ca 2+ elevations evoked by agonists were decreased compared to control cells. SLP-2 depletion increased the rates of calcium extrusion from mitochondria. This effect disappeared upon Na + removal or addition of CGP-37157, an inhibitor of the mitochondrial Na + /Ca 2+ exchanger, and persisted in permeabilized cells exposed to a fixed cytosolic Na + and Ca 2+ concentration. The rates of mitochondrial Ca 2+ extrusion were prolonged in SLP-2 over-expressing cells, independently of the amplitude of mitochondrial Ca 2+ elevations. The amplitude of cytosolic Ca 2+ elevations was increased by SLP-2 depletion and decreased by SLP-2 over-expression. These data show that SLP-2 modulates mitochondrial calcium extrusion, thereby altering the ability of mitochondria to buffer Ca 2+ and to shape cytosolic Ca 2+ signals.

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“…Although the tissue distribution and electrophysiological properties seem to exclude RyR1 as the MCU, the possibility that RyR is an additional uptake pathway cooperating with MCU in the heart is still open. More recently, Graier and co-workers (76) proposed that UCP2 and UCP3 are essential components of the MCU machinery. These results, which were questioned on theoretical grounds and based on experiments carried out in mitochondria from UCP2 Ϫ/Ϫ and UCP3 Ϫ/Ϫ mice (77), have recently been ascribed to an indirect effect on ATP production and hence ER Ca 2ϩ loading (78).…”

Section: The Discovery Of the Mcu: Finding The Needle In The Mitochonmentioning

confidence: 99%

The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

Patrón

Raffaello

Granatiero

et al. 2013

Journal of Biological Chemistry

152

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The direct measurement of mitochondrial [Ca 2؉ ] with highly specific probes demonstrated that major swings in organellar [Ca 2؉ ] parallel the changes occurring in the cytosol and regulate processes as diverse as aerobic metabolism and cell death by necrosis and apoptosis. Despite great biological relevance, insight was limited by the complete lack of molecular understanding. The situation has changed, and new perspectives have emerged following the very recent identification of the mitochondrial Ca 2؉ uniporter, the channel allowing rapid Ca 2؉ accumulation across the inner mitochondrial membrane.

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Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport

Cited by 307 publications

References 33 publications

Calcium Binding and Transport by Coenzyme Q

Calcium Binding and Transport by Coenzyme Q

SLP-2 negatively modulates mitochondrial sodium–calcium exchange

The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

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