TY - JOUR
T1 - SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death
AU - Hoffman, Nicholas E.
AU - Chandramoorthy, Harish C.
AU - Shanmughapriya, Santhanam
AU - Zhang, Xueqian Q.
AU - Vallem, Sandhya
AU - Doonan, Patrick J.
AU - Malliankaraman, Karthik
AU - Guo, Shuchi
AU - Rajan, Sudarsan
AU - Elrod, John W.
AU - Koch, Walter J.
AU - Cheung, Joseph Y.
AU - Madesh, Muniswamy
PY - 2014/3/15
Y1 - 2014/3/15
N2 - Emerging findings suggest that two lineages of mitochondrial Ca 2+ uptake par ticipate during active and resting states: 1) the major eukaryotic membrane potential-dependent mitochondrial Ca2+ uniporter and 2) the evolutionarily conserved exchangers and solute carriers, which are also involved in ion transport. Although the influx of Ca2+ across the inner mitochondrial membrane maintains metabolic functions and cell death signal transduction, the mechanisms that regulate mitochondrial Ca2+ 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 Ca2+ 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 Ca2+ uptake. In addition, SLC25A23 interacts with mito chondrial Ca2+ 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 Ca2+ uptake and superoxide production. These findings indicate that SLC25A23 plays an important role in mitochondrial matrix Ca2+ influx.
AB - Emerging findings suggest that two lineages of mitochondrial Ca 2+ uptake par ticipate during active and resting states: 1) the major eukaryotic membrane potential-dependent mitochondrial Ca2+ uniporter and 2) the evolutionarily conserved exchangers and solute carriers, which are also involved in ion transport. Although the influx of Ca2+ across the inner mitochondrial membrane maintains metabolic functions and cell death signal transduction, the mechanisms that regulate mitochondrial Ca2+ 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 Ca2+ 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 Ca2+ uptake. In addition, SLC25A23 interacts with mito chondrial Ca2+ 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 Ca2+ uptake and superoxide production. These findings indicate that SLC25A23 plays an important role in mitochondrial matrix Ca2+ influx.
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U2 - 10.1091/mbc.E13-08-0502
DO - 10.1091/mbc.E13-08-0502
M3 - Article
C2 - 24430870
AN - SCOPUS:84896262743
SN - 1059-1524
VL - 25
SP - 936
EP - 947
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 6
ER -