Metabolism
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Muscle weakness, heart failure and profound hypoglycaemia in a young girl
Key points from this exercise:
Carnitine is a small water-soluble molecule that is filtered at the glomerulus; normally about 98% of filtered free carnitine is reabsorbed by active transport in the renal tubules.
Carnitine deficiency can result from a defect in this transport protein, which is found not only in the kidney, but also in tissues such as muscle that take up carnitine from the circulation.
Most acyl carnitine is not reabsorbed in the kidneys, but is excreted. This means that abnormal organic acids that are esterified to carnitine can also cause carnitine deficiency.
Fatty acid oxidation is severely impaired by carnitine deficiency, leading to fasting hypoglycaemia with negligible production of ketone bodies (which are formed as a product of fatty acid oxidation in the liver).
Fatty acids are still mobilised from adipose tissue in the fasting state in carnitine deficiency, and are taken up by liver and muscle. They cannot be metabolised, and are esterified to triacylglycerol, leading to fatty infiltration of liver and muscle. This leads to metabolic impairment, early fatigue and muscle weakness, and cardiomyopathy, which may lead to heart failure.
Fatty acids that enter tissues are rapidly esterified with CoA. Acyl CoA does not cross the mitochondrial membrane.
At the outer face of the outer mitochondrial membrane the fatty acyl group is transferred from CoA onto carnitine by carnitine acyltransferase 1. Acyl carnitine is then transported into the mitochondrial matrix by an acyl carnitine / carnitine transporter that takes in acyl carnitine only in exchange for efflux of free carnitine from the mitochondrial matrix.
At the inner face of the inner mitochondrial membrane carnitine acyltransferase 1 transfers the fatty acyl group from carnitine onto CoA. The resultant fatty acyl CoA is a substrate for mitochondrial oxidation.
Only long-chain fatty acids require carnitine for mitochondrial uptake. Short- and medium-chain fatty acids can enter the mitochondria without the need for carnitine.