Carnitine, mitochondrial function and therapy☆
Section snippets
Roles of the carnitine acyltransferases
The carnitine acyltransferases are a family of proteins that are widely distributed in the cell, and the properties of which are specifically tailored to their complementary roles in the above-mentioned functions of carnitine. Only one of the transferases has direct access to the cytosolic pool of acyl-CoA esters, the long-chain-specific carnitine palmitoyltransferase 1 (CPT 1). As LC-acyl moieties are a major substrate for mitochondrial ATP formation, CPT 1 occupies a central role in energy
Physiological consequences of equilibration between acylcarnitine and acyl-CoA esters
The intracellular distribution of the acyltransferases is integrative and related to the requirements of every cell to regulate carbohydrate and lipid metabolism co-ordinately. Therefore, the effects of changes in their catalytic activity are widespread and varied. The physiological effects that range from the selection of metabolic fuels by tissues, to the regulation of processes are dependent on the localised concentrations of acyl-CoA esters. These include the regulation of insulin secretion
Pathological consequences of deficiencies of carnitine carriers and the carnitine acyltransferases
Genetic and functional characterisation of the enzymes and carriers of the carnitine system (reviewed in [29], [30]) has advanced considerably in the last 10 years. Identification of deficiencies in the carnitine system has been facilitated by reliable and now routine methods for the determination of urinary and plasma levels of individual acylcarnitines [31], [32]. Changes in the metabolomic profile indicate which protein involved in carnitine metabolism is deficient. The particular defect is
Therapy through modulation of carnitine availability
The therapeutic potential of l-carnitine and some of its short-chain acyl-esters, namely, acetyl-l-carnitine and propionyl-l-carnitine, is still a matter of debate [60], [61], [62], [63], [64], [65], [66]. However, it is evident that in certain (rare) genetic disorders (e.g. those involving defects in the high-affinity plasmalemmal l-carnitine transporter) that l-carnitine treatment could represent a life saving therapy [67]. Indeed, these patients experience a severe plasma and tissue l
Acknowledgements
V.A.Z. would like to thank the British Heart Foundation and Diabetes UK for supporting research in his laboratory. A.A. thanks Dr. Claudio Cavazza (Sigma Tau S.p.A.) for helpful discussions, and dedicates his contribution to the memory of the late Dr. Anna Colorizio.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Mitochondrial Medicine and Therapeutics, Part II”.