| Mitochondrial and extramitochondrial effects of long-chain acylcarnitines.
Liepins E (2018)
Acylcarnitines have been known for decades as long-chain fatty acid intermediates, but many aspects of their molecular action are still unclear. In our studies we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of energy metabolism. Carnitine palmitoyltransferase 1 (CPT 1)-mediated long-chain acylcarnitine synthesis is a step in mitochondrial FA oxidation, and various mitochondrial disorders that are characterized by incomplete FA oxidation cause the accumulation of long-chain acylcarnitines. In mitochondrial genetic disorders, ischemia and the late stages of heart failure, acylcarnitines accumulate in mitochondria because of a transient or permanent inhibition of FA-dependent oxidative phosphorylation in the mitochondria. Recently we showed that long-chain acylcarnitines, but not acyl-CoAs, accumulate at concentrations that are harmful to mitochondria. Acylcarnitine accumulation in the mitochondrial intermembrane space is a result of increased carnitine palmitoyltransferase 1 (CPT1) and CPT2 activity in ischemic myocardium and it leads to inhibition of oxidative phosphorylation, which in turn induces mitochondrial membrane hyperpolarization and stimulates the production of reactive oxygen species (ROS) in cardiac mitochondria. In the isolated rat heart set-up, the supplementation of perfusion buffer with palmitoylcarnitine before occlusion resulted in a 2-fold increase in the long-chain acylcarnitine content of the heart mitochondria and increased the infarct size (IS) by 33%. A pharmacologically induced decrease in the mitochondrial acylcarnitine content reduced the infarct size by 44%. Similar effect was observed in trimethyllysine dioxygenase (the first enzyme in the biosynthesis pathway of carnitine and acylcarnitne) knock-out mice if compared to wild-type BL6 mice.
In healthy subjects in the fed state, to facilitate glucose metabolism, the increased concentration of insulin inhibits long-chain acylcarnitine production and subsequent FA metabolism. Disturbances in insulin signalling lead to the inability of insulin to inhibit long-chain acylcarnitine production in the postprandial state. Increase in the content of long-chain acylcarnitine accelerates insulin resistance by impairing Akt phosphorylation at Ser473.
In conclusion, long-chain acylcarnitine accumulation in ischemic heart is harmful to mitochondria and decreasing the acylcarnitine content via cardioprotective drugs may represent a novel treatment strategy. Moreover, the reduction of acylcarnitine content is an effective strategy to improve cardiac insulin sensitivity.
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Labels: MiParea: Genetic knockout;overexpression, mt-Medicine, Pharmacology;toxicology
- Latvian Inst Organic Synthesis