title: SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death.
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.
authors.affiliation: Department of Biochemistry, Temple University, Philadelphia, PA 19140 Center for Translational Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.forename: Harish C
authors.initials: HC
authors.lastname: Chandramoorthy
authors.forename: Santhanam
authors.initials: S
authors.lastname: Shanmughapriya
authors.forename: Xueqian Q
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Sandhya
authors.initials: S
authors.lastname: Vallem
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Doonan
authors.forename: Karthik
authors.initials: K
authors.lastname: Malliankaraman
authors.forename: Shuchi
authors.initials: S
authors.lastname: Guo
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017920:Antiporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002999:Clone Cells; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C086357:ATP-Mg-Pi carrier proteins, mitochondria; D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C487500:SLC25A24 protein, human; C487501:SLC25A25 protein, human; C034703:mitochondrial calcium uniporter; D006632:Histamine; D000255:Adenosine Triphosphate; D002118:Calcium