CPS1: a multipurpose mitochondrial enzyme, bile protein, acute liver injury biomarker, and cytokine

Carbamoyl phosphate synthetase 1 (CPS1) is primarily expressed in hepatocytes as a highly abundant mitochondrial matrix enzyme that catalyses the first step of the urea cycle that leads to renal nitrogen disposal. CPS1 is a member of the CPS family that manifests broad evolutionary expression from bacteria to humans. CPS1 expression and enzyme activity are highly regulated transcriptionally and post-translationally. Its autosomal recessive mutation leads to CPS1 deficiency, which causes encephalopathy and coma, typically neonatally, due to severe hyperammonaemia. CPS1 is physiologically secreted, apically, into bile likely via mitochondria-derived vesicles. Normally absent from serum, it is released by basolateral mistargeting and cellular injury and becomes readily detectable in serum during acute liver failure (ALF). Injury-triggered CPS1 release into blood, or media in cultured hepatocytes, is selective as compared with other mitochondrial proteins. This, coupled with its abundance and short (1–2 hours) serum half-life, renders it a prognostic serum biomarker, particularly in human acetaminophen-related ALF. Its rapid turnover is explained by its non-enzymatic role as an immune modulator via its uptake by circulating monocytes leading to differentiation of anti-inflammatory cells that home to, and protect, the injured liver. CPS1 also plays a growing role in several cancers, by CPS1 upregulation or downregulation, particularly via metabolic reprogramming which alters the tumour microenvironment and impacts cancer growth and progression. Therefore, CPS1 has multiple enzymatic and non-enzymatic touch points spanning a wide range of cellular and extracellular functions and roles, with important physiological, homoeostatic, genetic disease, diagnostic and potential therapeutic clinical implications.