Slc25a51, also known as MCART1, is a mammalian mitochondrial NAD+ transporter [3,4,5]. Mitochondria require NAD+ to carry out fundamental processes fueling respiration and mediating cellular energy transduction. Slc25a51 is essential for these functions as it selectively imports oxidized NAD+ into the mitochondrial matrix [1,3,4]. This process is involved in multiple pathways such as mitochondrial respiration, the tricarboxylic acid (TCA) cycle, and maintaining the mitochondrial NAD+/NADH ratio, which is crucial for cellular energy production and overall cell function [1,4].

Lowering Slc25a51 levels in orthotopic xenograft models led to increased apoptosis and prolonged survival in acute myeloid leukemia (AML) cells [1]. Loss of Slc25a51 in AML cells shunted metabolic flux away from mitochondrial oxidative pathways without increasing glycolytic flux, and its depletion combined with 5-azacytidine treatment limited AML cell expansion in vivo [1]. In cancer cells, loss of Slc25a51 elevated mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, impaired P5CS enzymatic activity in proline biogenesis, and reduced proline contents [2]. In hepatocellular carcinoma (HCC), knockdown of Slc25a51 attenuated the growth and metastasis of HCC cells both in vitro and in vivo [6].

In conclusion, Slc25a51 is a critical regulator for maintaining mitochondrial functions through NAD+ transport. Gene knockout or knockdown models in relevant disease conditions like AML and HCC have revealed its significance in promoting cancer cell proliferation and metastasis. These findings suggest that Slc25a51 may be a potential therapeutic target for refractory AML and HCC [1,2,6].