Slc25a23, also known as SCaMC-3, is a member of the mitochondrial solute carrier gene family. It is involved in mitochondrial calcium (Ca²⁺) uptake and plays a role in regulating mitochondrial function, including ATP production and oxidative stress-related cell death pathways. It is associated with the mitochondrial Ca²⁺ uniporter (MCU) complex, which is crucial for mitochondrial Ca²⁺ homeostasis [1,2,4].

RNA interference-mediated knockdown of Slc25a23 in cells decreases mitochondrial Ca²⁺ uptake and reduces cytosolic Ca²⁺ clearance after histamine stimulation. Its knockdown also lowers basal mROS accumulation, attenuates oxidant-induced ATP decline, and reduces cell death [2]. In neurons, mice deficient in Slc25a23 (SCaMC-3 KO mice) show a rapid fall in mitochondrial ATP upon NMDA exposure, along with blunted increases in respiration, a delayed decrease in cytosolic ATP levels, and earlier delayed Ca²⁺ deregulation. SCaMC-3 KO neurons have higher vulnerability to in vitro excitotoxicity, and SCaMC-3 KO mice are more susceptible to kainate-induced seizures [3].

In conclusion, Slc25a23 is essential for mitochondrial matrix Ca²⁺ influx, and its function is closely related to maintaining mitochondrial ATP levels and preventing excitotoxicity-related neuronal death. Studies using Slc25a23 KO mouse models have revealed its significance in neurological disease-related processes, such as excitotoxicity and seizure susceptibility.

References:

1. Alevriadou, B Rita, Patel, Akshar, Noble, Megan, Stathopulos, Peter B, Madesh, Muniswamy. 2020. Molecular nature and physiological role of the mitochondrial calcium uniporter channel. In American journal of physiology. Cell physiology, 320, C465-C482. doi:10.1152/ajpcell.00502.2020. https://pubmed.ncbi.nlm.nih.gov/33296287/

2. Hoffman, Nicholas E, Chandramoorthy, Harish C, Shanmughapriya, Santhanam, Cheung, Joseph Y, Madesh, Muniswamy. 2014. SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death. In Molecular biology of the cell, 25, 936-47. doi:10.1091/mbc.E13-08-0502. https://pubmed.ncbi.nlm.nih.gov/24430870/

3. Rueda, Carlos B, Traba, Javier, Amigo, Ignacio, del Arco, Araceli, Satrústegui, Jorgina. . Mitochondrial ATP-Mg/Pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 35, 3566-81. doi:10.1523/JNEUROSCI.2702-14.2015. https://pubmed.ncbi.nlm.nih.gov/25716855/

4. Wang, Jin, Jiang, Jinyong, Hu, Haoliang, Chen, Linxi. 2024. MCU complex: Exploring emerging targets and mechanisms of mitochondrial physiology and pathology. In Journal of advanced research, 68, 271-298. doi:10.1016/j.jare.2024.02.013. https://pubmed.ncbi.nlm.nih.gov/38417574/