Evolutionary diversity of the mitochondrial calcium uniporter

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Science (Impact Factor: 31.48). 05/2012; 336(6083):886. DOI: 10.1126/science.1214977
Source: PubMed

ABSTRACT Calcium uptake into mitochondria occurs via a recently identified ion channel called the uniporter. Here, we characterize the phylogenomic distribution of the uniporter's membrane-spanning pore subunit (MCU) and regulatory partner (MICU1). Homologs of both components tend to co-occur in all major branches of eukaryotic life, but both have been lost along certain protozoan and fungal lineages. Several bacterial genomes also contain putative MCU homologs that may represent prokaryotic calcium channels. The analyses indicate that the uniporter may have been an early feature of mitochondria.

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    • "It was found that the extent of DCD was proportional to the time for which the mitochondria were polarized and therefor able to accumulate Ca 2+ (Castilho et al. 1998). The identification of the mitochondrial Ca 2+ uniporter (Patron et al. 2013; Bick et al. 2012), and the resultant ability to manipulate uniporter expression in primary neuronal culture, has allowed more elegant and less invasive experiments to be performed. Studies by Hardingham et al. (Qiu et al. 2013) in which expression levels of the mitochondrial Ca 2+ uniporter were manipulated in primary neuronal cultures, found that the extent of NMDA-induced cell death increased with overexpression of the uniporter, in parallel with increased matrix calcium accumulation, while knockdown had a neuroprotective effect. "
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    ABSTRACT: Mitochondria play multiple roles in the maintenance of neuronal function under physiological and pathological conditions. In addition to ATP generation, they can act as major short-term calcium sinks and can both generate, and be damaged by, reactive oxygen species. Two complementary preparations have been extensively employed to investigate in situ neuronal mitochondrial bioenergetics, primary neuronal cultures and acutely isolated nerve terminals, synaptosomes. A major focus of the cell culture preparation has been the investigation of glutamate excitotoxicity. Oxidative phosphorylation, calcium transport and reactive oxygen species play complex interlocking roles in the life and death of the glutamate exposed neuron. Synaptosomes may be isolated from specific brain regions at any developmental stage and therefore provide a valuable ex vivo approach in studying mouse models. Recent advances have allowed synaptosomal bioenergetics to be studied on a microgram scale, and, in combination with approaches to correct for functional and transmitter heterogeneity, have allowed hypotheses concerning presynaptic mitochondrial dysfunction to be tested on a variety of genetic models of neurodegenerative disorders.
    Journal of Bioenergetics 08/2014; 47(1-2). DOI:10.1007/s10863-014-9573-9 · 2.71 Impact Factor
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    • "Functional studies are required to determine whether bacterial homologs are also able to form channels. In that case they would be among the first identified prokaryotic calcium channels [37]. "
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    ABSTRACT: The molecular components of the mitochondrial Ca2+ uptake machinery have been only recently identified. In the last months, in addition to the pore forming subunit and of one regulatory protein (named MCU and MICU1 respectively) other four components of this complex have been described. In addition, a MCU KO mouse model has been generated and a genetic human disease due to missense mutation of MICU1 has been discovered. In this contribution, we will first summarize the recent findings, discussing the roles of the different subunits of the mitochondrial Ca2+ uptake complex, pointing to the current contradictions in the published data, as well as possible explanations. Finally we will speculate on the recent, totally unexpected, results obtained in the MCU knock-out (KO) mice.
    Cell calcium 03/2014; 55(3). DOI:10.1016/j.ceca.2014.02.008 · 4.21 Impact Factor
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    • "The Mootha group used MICU1 as a molecular (and computational) bait to identify the core component of the uniporter MCU. Not only do MCU and MICU1 display the same evolutionary pattern of expression and similar RNA expression in a variety of mouse tissues (Bick et al. 2012), but they also physically interact (Baughman et al. 2011). MICU1 (previously known as CBARA1 and EFHA3) is a 54-kDa single-pass membrane protein that contains two highly conserved EF-hand Ca 2+ -binding domains. "
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