The Role Of Mitochondrial Transporters In Cancer Metabolism

Abstract

Mitochondrial transporters play crucial roles in cellular metabolism; however, the specific substrates and functions of many remain unknown. This study aimed to identify the physiological substrate and function of SLC25A47, a liverspecific mitochondrial transporter associated with hepatocellular carcinoma. Using mitochondrial immunoprecipitation and metabolomics approaches in cell lines and mouse models, we demonstrated that SLC25A47 functions as an exporter of Nacetylglutamate (NAG) from the mitochondrial matrix. Overexpression of SLC25A47 led to the depletion of mitochondrial NAG levels, whereas knockout mice showed accumulation of NAG in liver mitochondria. NAG is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS1), which is the rate-limiting enzyme of the urea cycle. By modulating mitochondrial NAG levels, SLC25A47 may serve as a novel regulator of urea cycle activity in hepatocytes. Additionally, we identified the mitochondrial protease YME1L1 as a regulator of SLC25A47 protein levels. This study identifies SLC25A47 as a previously uncharacterized component of hepatic nitrogen metabolism and provides new insights into the regulation of ammonia detoxification in the liver.