SLC25A23 augments mitochondrial Ca ²⁺ uptake, interacts with MCU, and induces oxidative stress–mediated cell death

Abstract

Knockdown of SLC25A23 decreases mitochondrial Ca ²⁺ uptake, and SLC25A23 interacts with MCU and MICU1, components of mitochondrial Ca ²⁺ uniporter. Expression of SLC25A23 EF-hand-domain mutants has a dominant-negative phenotype of reduced mitochondrial Ca ²⁺ uptake. It also attenuates basal ROS and oxidant-induced ATP decline and 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 I _MCU. 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.