Slc25a51, also known as MCART1, is the primary mammalian mitochondrial NAD+ transporter [3,4,5,6,7,8,9]. Mitochondria require NAD+ to carry out respiration and energy transduction processes. Slc25a51 imports oxidized NAD+ into the mitochondrial matrix, thus connecting substrate oxidation in the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain and oxidative phosphorylation [3,4]. This function is crucial for maintaining normal mitochondrial functions and overall cellular metabolism.

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 cancer cells 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) cells, knockdown of Slc25a51 attenuated their growth and metastasis, while overexpression enhanced these processes through activation of SIRT5 and reprogramming of glucose metabolism from oxidative phosphorylation to glycolysis [10]. Absence of Slc25a51 in breast cancer cells led to increased nuclear NAD+ levels, enhanced PARP1-mediated nuclear ADP-ribosylation, and faster DNA repair, reducing sensitivity to PARP1 inhibition [7]. In hepatocytes of mice with reduced Slc25a51 expression, mitochondrial NAD+ levels and SIRT3 activity decreased, accompanied by reduced oxygen consumption rate, hepatic steatosis, and hypertriglyceridemia [8].

In conclusion, Slc25a51 is essential for mitochondrial NAD+ import, which is crucial for mitochondrial respiration, energy production, and maintaining normal cellular metabolism. Gene-knockout and other loss-of-function models have revealed its significant roles in diseases such as AML, various cancers, and metabolic disorders. These findings suggest that Slc25a51 could be a potential therapeutic target in these disease areas.