Slc25a51-flox Mouse

Slc25a51, also known as MCART1, is a mammalian mitochondrial NAD+ transporter [3,4,7]. It is essential for mitochondrial functions as it imports oxidized NAD+ into the mitochondrial matrix, connecting substrate oxidation by the tricarboxylic acid (TCA) cycle to adenosine triphosphate generation by the electron transport chain and oxidative phosphorylation, thus playing a crucial role in cell respiration and energy transduction [3,4].

Lowering Slc25a51 levels in orthotopic xenograft models led to increased apoptosis and prolonged survival in acute myeloid leukemia (AML) cells. Metabolic flux analyses indicated that its depletion shunted flux away from mitochondrial oxidative pathways without increasing glycolytic flux, and combined with 5-azacytidine treatment, it 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 (key in proline biogenesis), and reduced proline contents [2].

In hepatocellular carcinoma, knockdown of Slc25a51 attenuated cell growth and metastasis, while overexpression enhanced these processes through activating SIRT5 to reprogram glucose metabolism from oxidative phosphorylation to glycolysis [8]. Absence of Slc25a51 in breast cancer cells increased nuclear NAD+ levels, enhanced PARP1-mediated nuclear ADP-ribosylation and DNA repair, and reduced sensitivity to PARP1 inhibition [5]. In hepatocytes and mouse liver, reduced Slc25a51 expression decreased mitochondrial NAD+ levels, SIRT3 activity, and oxygen consumption rate, and caused hepatic steatosis and hypertriglyceridemia [6].

In conclusion, Slc25a51 is crucial for maintaining mitochondrial NAD+ levels and related functions. Gene knockout or knockdown models have revealed its significant roles in cancer (such as AML, multiple cancers, and hepatocellular carcinoma), DNA repair in breast cancer, and metabolic regulation in the liver. These findings suggest that Slc25a51 could be a potential therapeutic target in refractory AML and other related diseases [1,2,5,6,8].