“Allosteric Regulation” of Calcium-Uptake in Rat Liver Mitochondria

Kröner, H.

doi:10.1515/bchm3.1986.367.1.483

Cited by 23 publications

(11 citation statements)

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“…In the high [Ca 2+ ] c range, the role of MICU1 in the allosteric control of mtCU may have been missed previously because the transport assay was performed in the absence of physiological [Mg 2+ ] (Mallilankaraman et al, 2012b). Previous studies have shown that Mg 2+ controls the allosteric activation of the uniporter (Bragadin et al, 1979; Favaron and Bernardi, 1985; Kroner, 1986) and we demonstrate here that Mg 2+ is needed to support the effect of MICU1 on mtCU cooperativity (SFig3). …”

Section: Discussionsupporting

confidence: 57%

“…MICU1-KD in both hepatocytes and HeLa cells showed significantly lesser slope than their respective controls (Fig3A; Hepatocytes; KD: 1.6±0.1 vs. Ctrl: 2.9±0.3, p<0.05 and HeLa cells; KD: 2.1±0.05 vs. Ctrl: 3.4±0.19, p<0.025). Previous literature has proposed that the cooperativity of mtCU’s activation is affected by the presence of Mg 2+ (Favaron and Bernardi, 1985; Kroner, 1986). Without Mg 2+ , the difference in slope between Ctrl and MICU1-KD was no longer detectable and both became similar to MICU1-KD in the presence of Mg 2+ (Fig3A right, KD: 2.2±0.1 vs. Ctrl: 2.3±0.1).…”

Section: Resultsmentioning

confidence: 99%

“…However, the spatial coupling alone cannot explain the highly cooperative nature of mitochondrial Ca 2+ uptake. Indeed, Ca 2+ -and time-dependent activation of mitochondrial Ca 2+ uptake has been observed (Csordas and Hajnoczky, 2003; Kroner, 1986), but the missing molecular identity of the mitochondrial Ca 2+ uniporter (mtCU) prevented a better understanding of the non-linear behavior.…”

Section: Introductionmentioning

confidence: 99%

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MICU1 Controls Both the Threshold and Cooperative Activation of the Mitochondrial Ca2+ Uniporter

et al. 2013

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Summary Mitochondrial Ca2+ uptake via the uniporter is central to cell metabolism, signaling and survival. Recent studies identified MCU as the uniporter’s likely pore and MICU1, an EF-hand protein, as its critical regulator. How this complex decodes dynamic cytoplasmic [Ca2+] ([Ca2+]c) signals, to tune out small [Ca2+]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca2+ accumulation during small [Ca2+]c elevations, yet an attenuated response to agonist-induced [Ca2+]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca2+]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca2+ binding, yet cells show impaired oxidative metabolism and sensitization to Ca2+ overload. Collectively, the data indicate that MICU1 senses the [Ca2+]c to establish the uniporter’s threshold and gain, thereby allowing mitochondria to properly decode different inputs.

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Section: Discussionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MICU1 Controls Both the Threshold and Cooperative Activation of the Mitochondrial Ca2+ Uniporter

et al. 2013

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“…Notably, the Ca 2+ uniport exhibits allosteric positive control by Ca 2+ (Csordas and Hajnoczky, 2003; Kroner, 1986a, b), which is inhibited by a variety of calmodulin inhibitors (Csordas and Hajnoczky, 2003). Among the recently identified molecules of mitochondrial Ca 2+ uptake, the MCU has been shown to be sensitive to ruthenium red, Ru360 and gadolinium (Baughman et al, 2011; De Stefani et al, 2011).…”

Section: Drugs Affecting the Imm Ca2+ Transportmentioning

confidence: 99%

Calcium transport across the inner mitochondrial membrane: Molecular mechanisms and pharmacology

Csordás

Várnai

Golenár

et al. 2012

Molecular and Cellular Endocrinology

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Growing evidence supports that mitochondrial calcium uptake is important for cell metabolism, signaling and survival. However, both the molecular nature of the mitochondrial Ca2+ transport sites and the calcium signals they respond to remained elusive. Recent RNA interference studies have identified new candidate proteins for Ca2+ uptake across the inner mitochondrial membrane, including LETM1, MCU, MICU1 and NCLX. The sensitivity of these factors to several drugs has been tested and in parallel, some new inhibitors of mitochondrial Ca2+ uptake have been described. This paper provides an update on the pharmacological aspects of the molecular mechanisms of the inner mitochondrial membrane Ca2+ transport.

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“…Recently (see also below), it has been suggested that the uniporter rate (or better, its affinity for Ca 2 þ ) can be modulated (increased or decreased) by protein kinases, in particular by p38 MAP kinases (inactivation), 4 or protein kinase C (the z isoform activates, whereas the b/d isoforms inactivate it 5 ), although this modulation still requires further clarification. A highly interesting, yet largely neglected phenomenon, is the Ca 2 þ -induced activation of Ca 2 þ uptake, a phenomenon initially described 20 years ago by Kroner 6 and recently re-visited by Moreau et al 7 It consists in a substantial acceleration of the Ca 2 þ uptake rate if non-energized mitochondria are first exposed for different periods of time to micromolar Ca 2 þ concentrations. A simple experiment demonstrating this phenomenon in isolated mitochondria is shown in Figure 1.…”

Section: Giacomellomentioning

confidence: 99%