Elsevier

Advanced Drug Delivery Reviews

Volume 61, Issue 14, 30 November 2009, Pages 1353-1362
Advanced Drug Delivery Reviews

Carnitine, mitochondrial function and therapy

https://doi.org/10.1016/j.addr.2009.04.024Get rights and content

Abstract

Carnitine is important for cell function and survival primarily because of its involvement in the multiple equilibria between acylcarnitine and acyl-CoA esters established through the enzymatic activities of the family of carnitine acyltransferases. These have different acyl chain-length specificities and intracellular compartment distributions, and act in synchrony to regulate multiple aspects of metabolism, ranging from fuel-selection and -sensing, to the modulation of the signal transduction mechanisms involved in many homeostatic systems. This review aims to rationalise the extensive range of experimental and clinical data that have been obtained through the pharmacological use of L-carnitine and its short-chain acylesters, over the past two decades, in terms of the basic biochemical mechanisms involved in the effects of carnitine on the various cellular acyl-CoA pools in health and disease.

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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