3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction

The acylcarnitines comprise a wide range of acyl groups linked via an ester bond to the hydroxyl group of L-carnitine. Mass spectrometry methods are capable of measuring the relative abundance of hundreds of acylcarnitines in a single drop of blood. As such, acylcarnitines can serve as sensitive biomarkers of disease. For certain acylcarnitines, however, their biochemical origin, and biomedical significance, remain unclear. One such example is 3-methylglutaryl (3MG) carnitine (C5-3M-DC). Whereas 3MG carnitine levels are normally very low, elevated levels are detected in discrete inborn errors of metabolism (IEM) as well as different forms of heart disease. Moreover, acute injury, including γ radiation exposure, paraquat poisoning, and traumatic brain injury manifest elevated levels of 3MG carnitine in blood and/or urine. Recent evidence indicates that two distinct biosynthetic routes to 3MG carnitine exist. The first, caused by an inherited deficiency in the leucine catabolism pathway enzyme, 3-hydroxy-3-methylglutaryl (HMG) CoA lyase, leads to a buildup of trans-3-methylglutaconyl (3MGC) CoA. Reduction of the double bond in trans-3MGC CoA generates 3MG CoA, which is then converted to 3MG carnitine by carnitine acyltransferase. This route, however, cannot explain why 3MG carnitine levels increase in IEMs that do not affect leucine metabolism or various chronic and acute disease states. In these cases, disease-related defects in aerobic energy metabolism result in diversion of acetyl CoA to trans-3MGC CoA. Once formed, trans-3MGC CoA is reduced to 3MG CoA and esterified to form 3MG carnitine. Thus, 3MG carnitine, represents a potential biomarker of disease processes associated with compromised mitochondrial energy metabolism.