Slc25a25, also known as the mitochondrial ATP-Mg/Pi solute carrier, is a Ca²⁺-regulated transporter located in the inner mitochondrial membrane. It is involved in controlling ATP-Mg²⁺ and Pi shuttle across the membrane, thus regulating mitochondrial ATP production and playing a crucial role in cellular metabolism [1,2,3,4,6]. It is also part of a cilia-dependent metabolic signaling pathway, linking ciliary TRPP2 signaling to mitochondrial metabolism [1].

In gene-knockout mouse models, inactivation of the Slc25a25 gene led to reduced metabolic efficiency, as seen by enhanced resistance to diet-induced obesity and impaired exercise performance on a treadmill. Mouse embryo fibroblasts from Slc25a25⁻/⁻ mice had reduced Ca²⁺ flux across the endoplasmic reticulum, basal mitochondrial respiration, and ATP content [3]. In C. elegans, loss of SLC-25A25 (homolog of Slc25a25) suppressed abnormal mitochondrial Zn²⁺ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9, revealing its role in regulating mitochondrial Zn²⁺ import [5].

In conclusion, Slc25a25 is essential for maintaining normal mitochondrial function, metabolic efficiency, and cellular homeostasis. The Slc25a25 gene-knockout models have revealed its significance in muscle function-related metabolic efficiency and mitochondrial Zn²⁺ regulation, providing insights into potential mechanisms underlying related diseases such as obesity and kidney stone formation [3,4,5].