SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death

Nicholas E. Hoffman, Harish C. Chandramoorthy, Santhanam Shanmughapriya, Xueqian Q. Zhang, Sandhya Vallem, Patrick J. Doonan, Karthik Malliankaraman, Shuchi Guo, Sudarsan Rajan, John W. Elrod, Walter J. Koch, Joseph Y. Cheung, Muniswamy Madesh

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)936-947
Number of pages12
JournalMolecular biology of the cell
Volume25
Issue number6
DOIs
StatePublished - Mar 15 2014

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EF Hand Motifs
Oxidative Stress
Cell Death
Adenosine Triphosphate
Mitochondrial Membrane Potential
Mitochondrial Proteins
Ion Transport
Mitochondrial Membranes
Protein Transport
RNA Interference
Oxidants
Superoxides
Histamine
Small Interfering RNA
Signal Transduction
Complementary DNA
Phenotype
Membranes
Ectopic Gene Expression

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Hoffman, Nicholas E. ; Chandramoorthy, Harish C. ; Shanmughapriya, Santhanam ; Zhang, Xueqian Q. ; Vallem, Sandhya ; Doonan, Patrick J. ; Malliankaraman, Karthik ; Guo, Shuchi ; Rajan, Sudarsan ; Elrod, John W. ; Koch, Walter J. ; Cheung, Joseph Y. ; Madesh, Muniswamy. / SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death. In: Molecular biology of the cell. 2014 ; Vol. 25, No. 6. pp. 936-947.
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abstract = "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.",
author = "Hoffman, {Nicholas E.} and Chandramoorthy, {Harish C.} and Santhanam Shanmughapriya and Zhang, {Xueqian Q.} and Sandhya Vallem and Doonan, {Patrick J.} and Karthik Malliankaraman and Shuchi Guo and Sudarsan Rajan and Elrod, {John W.} and Koch, {Walter J.} and Cheung, {Joseph Y.} and Muniswamy Madesh",
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Hoffman, NE, Chandramoorthy, HC, Shanmughapriya, S, Zhang, XQ, Vallem, S, Doonan, PJ, Malliankaraman, K, Guo, S, Rajan, S, Elrod, JW, Koch, WJ, Cheung, JY & Madesh, M 2014, 'SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death', Molecular biology of the cell, vol. 25, no. 6, pp. 936-947. https://doi.org/10.1091/mbc.E13-08-0502

SLC25A23 augments mitochondrial Ca2+ uptake, interacts with MCU, and induces oxidative stress-mediated cell death. / Hoffman, Nicholas E.; Chandramoorthy, Harish C.; Shanmughapriya, Santhanam; Zhang, Xueqian Q.; Vallem, Sandhya; Doonan, Patrick J.; Malliankaraman, Karthik; Guo, Shuchi; Rajan, Sudarsan; Elrod, John W.; Koch, Walter J.; Cheung, Joseph Y.; Madesh, Muniswamy.

In: Molecular biology of the cell, Vol. 25, No. 6, 15.03.2014, p. 936-947.

Research output: Contribution to journalArticle

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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