L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine

Abstract

Biomarker discovery and implementation are at the forefront of the precision medicine movement. Modern advances in the field of metabolomics afford the opportunity to readily identify new metabolite biomarkers across a wide array of disciplines. Many of the metabolites are derived from or directly reflective of mitochondrial metabolism. L-carnitine and acylcarnitines are established mitochondrial biomarkers used to screen neonates for a series of genetic disorders affecting fatty acid oxidation, known as the inborn errors of metabolism. However, L-carnitine and acylcarnitines are not routinely measured beyond this screening, despite the growing evidence that shows their clinical utility outside of these disorders. Measurements of the carnitine pool have been used to identify the disease and prognosticate mortality among disorders such as diabetes, sepsis, cancer, and heart failure, as well as identify subjects experiencing adverse drug reactions from various medications like valproic acid, clofazimine, zidovudine, cisplatin, propofol, and cyclosporine. The aim of this review is to collect and interpret the literature evidence supporting the clinical biomarker application of L-carnitine and acylcarnitines. Further study of these metabolites could ultimately provide mechanistic insights that guide therapeutic decisions and elucidate new pharmacologic targets.

Keywords: acyl-carnitine; metabolic flexibility; metabolism; metabolomics; mitochondria; pharmacometabolomics.

Figure 1

The Carnitine Shuttle. The figure highlights the major components of the carnitine shuttle system used to import long-chain fatty acids (LCFA) into the mitochondria for oxidation. LCFA are converted to acyl-CoA via acyl-CoA synthase. Then, the enzyme, carnitine palmitoyltransferase (CPT) 1, produces acylcarnitines from acyl-CoA and free carnitine. Carnitine-acylcarnitine translocase (CACT) moves acylcarnitine across the inner mitochondrial membrane (IMM) as carnitine is exported out. CPT2 converts the acylcarnitine back into acyl-CoA and free carnitine. Acyl-CoA is then available for β-oxidation that produces 1 molecule of acetyl-CoA per cycle of oxidation, which enters the TCA cycle. The cycle provides the necessary electron donors to feed into the electron transport chain (ETC), thus powering oxidative phosphorylation.FAT = fatty acid transferase, CoA = coenzyme A, OCTN2 = organic cation/carnitine transporter 2, TCA cycle = tricarboxylic acid cycle, FADH2 and NADH = electron donors, OMM/IMM = outer/inner mitochondrial membrane.

Figure 2

Mechanism of valproic acid (VPA)-induced hyperammonemia. (1) VPA is attached to coenzyme A (CoA) and transferred to LC creating VPA-carnitine, which is then renally excreted. (2) VPA-carnitine inhibits an ATP-dependent carnitine transporter, effectively blocking LC entry into the cell. (3) Other VPA metabolites, 2-en-VPA and 3-Keto-VPA, trap mitochondrial free CoA so that it cannot participate in ATP production, further inhibiting the ATP-dependent carnitine transporter. (4) The decrease in free CoA and LC results in decreased formation of N-acetylglutamate, which is a necessary co-factor for carbamoylphosphate synthetase I (CPS I), the primary enzyme of the first steps of the urea cycle. This leads to the accumulation of ammonia as it can no longer be incorporated into urea and excreted, resulting in hyperammonemia.