Evolutionary Diversity of the Mitochondrial Calcium Uniporter

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Science (Impact Factor: 33.61). 05/2012; 336(6083):886. DOI: 10.1126/science.1214977
Source: PubMed


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 · 3.21 Impact Factor
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    • "Protein sequences from 138 eukaryotic organisms corresponding to the published phylogenetic tree (Bick et al., 2012) were downloaded as follows: 132 species from the KEGG Organisms Database, release 58 (Kanehisa et al., 2006) and six species (Thecamonas trahens, Capsaspora owczarzaki, Sphaeroforma arctica, Salpingoeca rosetta, Allomyces macrogynus, and Spizellomyces punctatus) from the Origins of Multicellularity Sequencing Project at the Broad Institute (7/9/2012; Ruiz-Trillo et al., 2007). For each of the ten reference genomes, a species-centric binary phylogenetic matrix X g,i was constructed to contain 1 if reference gene g shared sequence similarity with any protein in species i (BLASTP; expect < 1 3 10 À3 ) and 0 otherwise. "
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    ABSTRACT: The availability of diverse genomes makes it possible to predict gene function based on shared evolutionary history. This approach can be challenging, however, for pathways whose components do not exhibit a shared history but rather consist of distinct "evolutionary modules." We introduce a computational algorithm, clustering by inferred models of evolution (CLIME), which inputs a eukaryotic species tree, homology matrix, and pathway (gene set) of interest. CLIME partitions the gene set into disjoint evolutionary modules, simultaneously learning the number of modules and a tree-based evolutionary history that defines each module. CLIME then expands each module by scanning the genome for new components that likely arose under the inferred evolutionary model. Application of CLIME to ∼1,000 annotated human pathways and to the proteomes of yeast, red algae, and malaria reveals unanticipated evolutionary modularity and coevolving components. CLIME is freely available and should become increasingly powerful with the growing wealth of eukaryotic genomes.
    Cell 07/2014; 158(1):213-25. DOI:10.1016/j.cell.2014.05.034 · 32.24 Impact Factor
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    • "EMRE appeared to mediate the interaction between MCU and the MICU proteins. Furthermore, evolutionary analysis revealed that the MICU proteins co-evolved most closely with MCU [14], while within the particular context of mammalian systems, only elimination of EMRE abrogates Ca 2+ currents to an extent comparable to MCU deletion [9] "
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    ABSTRACT: The recent discovery of genes encoding the mitochondrial calcium (Ca2+) uniporter has revealed new opportunities for studying how abnormal Ca2+ signals cause disease. Ca2+ transport across the mitochondrial inner membrane is highly regulated, and the uniporter is the channel that acts as a major portal for Ca2+ influx. Low amounts of mitochondrial Ca2+ can boost ATP synthesis, but excess amounts, such as following cytoplasmic Ca2+ overload in heart failure, triggers mitochondrial failure and cell death. In fact, precisely because mitochondrial Ca2+ transport is so tightly regulated, a fundamental understanding of how the uniporter functions is necessary. Two key uniporter features allow Ca2+ influx without mitochondrial damage during normal physiology. First, the channel is significantly more selective than other known Ca2+ channels. This prevents the permeation of other ions and uncoupling of the electrochemical gradient. Second, the uniporter becomes active at only high Ca2+ concentrations, preventing a resting leak of cytoplasmic Ca2+ itself. Now possessing the identities of the various proteins forming the uniporter, we can proceed with efforts to define the molecular determinants of permeation, selectivity and Ca2+-regulation.
    Biochemical and Biophysical Research Communications 07/2014; 449(4). DOI:10.1016/j.bbrc.2014.04.141 · 2.30 Impact Factor
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