Abstract
Emerging findings suggest that two lineages of mitochondrial Ca(2+) uptake participate during active and resting states: 1) the major eukaryotic membrane potential-dependent mitochondrial Ca(2+) uniporter and 2) the evolutionarily conserved exchangers and solute carriers, which are also involved in ion transport. Although the influx of Ca(2+) across the inner mitochondrial membrane maintains metabolic functions and cell death signal transduction, the mechanisms that regulate mitochondrial Ca(2+) accumulation are unclear. Solute carriers--solute carrier 25A23 (SLC25A23), SLC25A24, and SLC25A25--represent a family of EF-hand-containing mitochondrial proteins that transport Mg-ATP/Pi across the inner membrane. RNA interference-mediated knockdown of SLC25A23 but not SLC25A24 and SLC25A25 decreases mitochondrial Ca(2+) uptake and reduces cytosolic Ca(2+) clearance after histamine stimulation. Ectopic expression of SLC25A23 EF-hand-domain mutants exhibits a dominant-negative phenotype of reduced mitochondrial Ca(2+) uptake. In addition, SLC25A23 interacts with mitochondrial Ca(2+) uniporter (MCU; CCDC109A) and MICU1 (CBARA1) while also increasing IMCU. In addition, SLC25A23 knockdown lowers basal mROS accumulation, attenuates oxidant-induced ATP decline, and reduces cell death. Further, reconstitution with short hairpin RNA-insensitive SLC25A23 cDNA restores mitochondrial Ca(2+) uptake and superoxide production. These findings indicate that SLC25A23 plays an important role in mitochondrial matrix Ca(2+) influx.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Transport Systems, Acidic / antagonists & inhibitors
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Amino Acid Transport Systems, Acidic / genetics
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Amino Acid Transport Systems, Acidic / metabolism
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Antiporters / antagonists & inhibitors
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Antiporters / genetics*
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Antiporters / metabolism
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Calcium / metabolism*
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Calcium Channels / genetics*
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Calcium Channels / metabolism
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Calcium Signaling
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Calcium-Binding Proteins / antagonists & inhibitors
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cation Transport Proteins / genetics
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Cation Transport Proteins / metabolism
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Cell Death
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Clone Cells
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Gene Expression Regulation
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HeLa Cells
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Histamine / pharmacology
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Humans
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Ion Transport / drug effects
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitochondrial Membrane Transport Proteins / genetics
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Mitochondrial Membrane Transport Proteins / metabolism
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Mitochondrial Proteins / antagonists & inhibitors
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Mitochondrial Proteins / genetics*
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Mitochondrial Proteins / metabolism
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Oxidative Stress
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Oxygen Consumption / drug effects
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Protein Structure, Tertiary
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / metabolism
Substances
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ATP-Mg-Pi carrier proteins, mitochondria
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Amino Acid Transport Systems, Acidic
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Antiporters
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Calcium Channels
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Calcium-Binding Proteins
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Cation Transport Proteins
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MICU1 protein, human
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
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RNA, Small Interfering
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Reactive Oxygen Species
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SLC25A24 protein, human
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SLC25A25 protein, human
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mitochondrial calcium uniporter
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Histamine
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Adenosine Triphosphate
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Calcium