<scp>MICU</scp>
            1 and
            <scp>MICU</scp>
            2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter

Kamer, Kimberli J.; Mootha, Vamsi K.

doi:10.1002/embr.201337946

Cited by 200 publications

(306 citation statements)

References 21 publications

(62 reference statements)

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“…First, the differences between these studies may be partly due to the methodology (acute versus chronic inhibition) or cell types used. In fact, such variability in mitochondrial Ca 2+ uptake when examining the same gene has been seen in studies focused on other components of the uniporter (43)(44)(45)(46)(47) Third, MCUR1 is not the MPT Ca 2+ sensor itself. Instead, a potential mechanism is that MCUR1 bridges the uniporter and MPT complexes, although it is not established whether these interactions involve other scaffolding proteins.…”

Section: +mentioning

confidence: 96%

Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition

Chaudhuri

Artiga

Abiria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During the mitochondrial permeability transition, a large channel in the inner mitochondrial membrane opens, leading to the loss of multiple mitochondrial solutes and cell death. Key triggers include excessive reactive oxygen species and mitochondrial calcium overload, factors implicated in neuronal and cardiac pathophysiology. Examining the differential behavior of mitochondrial Ca 2+ overload in Drosophila versus human cells allowed us to identify a gene, MCUR1, which, when expressed in Drosophila cells, conferred permeability transition sensitive to electrophoretic Ca 2+ uptake. Conversely, inhibiting MCUR1 in mammalian cells increased the Ca 2+ threshold for inducing permeability transition. The effect was specific to the permeability transition induced by Ca 2+, and such resistance to overload translated into improved cell survival. Thus, MCUR1 expression regulates the Ca 2+ threshold required for permeability transition.T he mitochondrial permeability transition (MPT) pore is large, and its opening collapses the mitochondrial membrane potential (ΔΨ), depleting the matrix of solutes <1.5 kDa. The osmotic imbalance swells and disrupts mitochondria, leading to cell death. The molecular structure of the MPT pore is unknown, although cyclophilin D [peptidyl-prolyl isomerase F (PPIF)], the ADP/ATP translocase, the F1-FO-ATP synthase, and spastic paraplegia 7 are key for its function (1-5).Key triggers for the MPT include oxidative damage and Ca 2+

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Section: +mentioning

confidence: 96%

Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition

Chaudhuri

Artiga

Abiria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The major mtCU-forming proteins have been identified, including the pore, MCU (Baughman et al, 2011;Chaudhuri et al, 2013;De Stefani et al, 2011); its dominant-negative form, MCUb (Raffaello et al, 2013); a scaffold, EMRE ; and helix-loop-helix structural domain (EF-hand) containing Ca 2+ -sensitive regulators, MICU1 (Csordá s et al, 2013;Mallilankaraman et al, 2012a;Perocchi et al, 2010;Wang et al, 2014) and MICU2 (Kamer and Mootha, 2014;Patron et al, 2014;Plovanich et al, 2013). To date, a MICU complex (a hetero/homo-dimer of MICU1 and MICU2) appears to determine both the threshold and cooperative activation of the mtCU by Ca 2+ (Csordá s et al, 2013;Hung et al, 2014;Patron et al, 2014;Perocchi et al, 2010;Plovanich et al, 2013).…”

Section: Mitochondrial Camentioning

confidence: 99%

“…Indeed, we demonstrated that MICU1 protein is scarcely present in the heart. MICU2, which seems to contribute to the regulation of mtCU by forming dimers with MICU1 (Kamer and Mootha, 2014;Patron et al, 2014) (Andrienko et al, 2009;Maack et al, 2006;Robert et al, 2001;Trollinger et al, 2000). However, at the even higher beating frequency of mouse heart, suppressing the response to individual (Csordá s et al, 2013).…”

Section: +mentioning

confidence: 99%

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

Paillard

Csordás

Szanda

et al. 2017

Biophysical Journal

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“…We combined this taxonomic profile with comparative genomics (4) to search for mitochondrial proteins (6) that are conserved in vertebrates and kinetoplastids but absent in yeast. This approach led to the identification of mitochondrial calcium uptake 1 and 2 (MICU1/2), the calcium sensing regulatory components of the uniporter (4,(7)(8)(9)(10), which then facilitated identification of the mitochondrial calcium uniporter (MCU), the putative poreforming subunit (11)(12)(13).…”

mentioning

confidence: 99%

Reconstitution of the mitochondrial calcium uniporter in yeast

Kovács-Bogdán

Sancak

Kamer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The mitochondrial calcium uniporter is a highly selective calcium channel distributed broadly across eukaryotes but absent in the yeast Saccharomyces cerevisiae. The molecular components of the human uniporter holocomplex (uniplex) have been identified recently. The uniplex consists of three membrane-spanning subunits -mitochondrial calcium uniporter (MCU), its paralog MCUb, and essential MCU regulator (EMRE)-and two soluble regulatory components-MICU1 and its paralog MICU2. The minimal components sufficient for in vivo uniporter activity are unknown. Here we consider Dictyostelium discoideum (Dd), a member of the Amoebazoa outgroup of Metazoa and Fungi, and show that it has a highly simplified uniporter machinery. We show that D. discoideum mitochondria exhibit membrane potential-dependent calcium uptake compatible with uniporter activity, and also that expression of DdMCU complements the mitochondrial calcium uptake defect in human cells lacking MCU or EMRE. Moreover, expression of DdMCU in yeast alone is sufficient to reconstitute mitochondrial calcium uniporter activity. Having established yeast as an in vivo reconstitution system, we then reconstituted the human uniporter. We show that coexpression of MCU and EMRE is sufficient for uniporter activity, whereas expression of MCU alone is insufficient. Our work establishes yeast as a powerful in vivo reconstitution system for the uniporter. Using this system, we confirm that MCU is the pore-forming subunit, define the minimal genetic elements sufficient for metazoan and nonmetazoan uniporter activity, and provide valuable insight into the evolution of the uniporter machinery.

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MICU 1 and MICU 2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter

Cited by 200 publications

References 21 publications

Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition

Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition

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

Reconstitution of the mitochondrial calcium uniporter in yeast

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