Acute kidney injury (AKI) represents an important global health issue, affecting around 13.3 million people worldwide and accounting for nearly 1.7 million deaths each year. Due to the limited availability of early diagnostic tools and the lack of effective therapeutic strategies, AKI remains a major clinical need and a key priority for biomedical research.

Slc25a24 encodes the SCaMC-1 protein, a mitochondrial carrier involved in ATP-magnesium/inorganic phosphate transport and in buffering calcium levels in the mitochondrial matrix, protecting cells against oxidative stress-induced cell death. However, the expression and function of Slc25a24 in the kidney have not been characterized. We explored the role of Slc25a24 in AKI.

In a transcriptomics array of murine nephrotoxic AKI, Slc25a24 was identified as one of the most upregulated genes encoding mitochondrial proteins. The functional implications of Slc25a24 upregulation were explored in mice and in cultured murine tubular cells.

Results: Slc25a24 expression was increased during murine nephrotoxic AKI induced by cisplatin or a folic acid overdose, as well as in human AKI. Slc25a24 overexpression in AKI was validated at the mRNA and protein levels and was localized mainly to proximal tubular cells. In cultured mouse tubule cells, the pro-inflammatory cytokine TWEAK increased Slc25a24 expression.

Slc25a24-deficient mice developed more severe AKI (folic acid or cisplatin), characterized by lower kidney function, more severe kidney inflammation and cell death and the nephroprotective gene Klotho downregulation. In cultured proximal tubular cells, Slc25a24 downregulation induced by specific small interfering RNA resulted in an increased proinflammatory response and cell death, and downregulated Klotho and in the sensitization to inflammation induced by TWEAK or TWEAK/TNFα/interferon-γ.

In conclusion, our findings identify Slc25a24 as a potential nephroprotective factor in AKI, highlighting it as a promising candidate for future therapeutic strategies.