Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Abstract

Mitochondrial fatty acid oxidation is an essential pathway for energy production, especially during prolonged fasting and sub-maximal exercise. Long-chain fatty acids are the most abundant fatty acids in the human diet and in body stores, and more than 15 enzymes are involved in long-chain fatty acid oxidation. Pathogenic mutations in genes encoding these enzymes result in a long-chain fatty acid oxidation disorder in which the energy homeostasis is compromised and long-chain acylcarnitines accumulate. Symptoms arise or exacerbate during catabolic situations, such as fasting, illness and (endurance) exercise. The clinical spectrum is very heterogeneous, ranging from hypoketotic hypoglycemia, liver dysfunction, rhabdomyolysis, cardiomyopathy and early demise. With the introduction of several of the long-chain fatty acid oxidation disorders (lcFAOD) in newborn screening panels, also asymptomatic individuals with a lcFAOD are identified. However, despite early diagnosis and dietary therapy, a significant number of patients still develop symptoms emphasizing the need for individualized treatment strategies. This review aims to function as a comprehensive reference for clinical and laboratory findings for clinicians who are confronted with pediatric and adult patients with a possible diagnosis of a lcFAOD.

Keywords: Carnitine transport; Inborn errors of metabolism; Mitochondrial long-chain fatty acid oxidation; ß-oxidation.

Fig. 1

Schematic representation of mitochondrial fatty acid oxidation in humans. Long-chain fatty acids enter the cell from the bloodstream and enter the mitochondria through the carnitine shuttle, followed by a step-wise degradation involving a series of enzymes of the long-chain fatty acid oxidation machinery resulting in the production of acetyl-CoA. Potential treatments to produce acetyl-CoA independent of the fatty acid oxidation enzymes are indicated. These include medium-chain triglycerides, ketone bodies and triheptanoin. Abbreviations: CI-V, Complex I-V; CACT, Carnitine Acylcarnitine Translocase; CD36, Cluster of Differentiation 36; CoA, Coenzyme A; CPT1, Carnitine Palmitoyl Transferase type 1; CPT2, Carnitine Palmitoyl Transferase type 2; FABPpm, plasma membrane-associated Fatty Acid Binding Protein; FATP, Fatty Acid Transport Protein; LCEH, Long-Chain Enoyl-CoA Hydratase; LCHAD, Long-Chain 3-Hydroxyacyl-CoA-Dehydrogenase; LCKAT, Long-Chain Ketoacyl-CoA Thiolase; MCAD, Medium-Chain Acyl-CoA Dehydrogenase; MCKAT, Medium-Chain 3-Ketoacyl-CoA Thiolase; OCTN2, Organic Cation Transporter 2; SCAD, Short-Chain Acyl-CoA Dehydrogenase; SCHAD, Short-Chain 3-hydroxyacyl-CoA Dehydrogenase; T2, acetoacetyl-CoA thiolase