Carnitine shuttle and long-chain fatty acid entry into mitochondria
The carnitine shuttle uses carnitine, a small carrier molecule, to carry long-chain fatty acids into the matrix (the inner compartment) of the mitochondrion for energy production.
Remember
Long-chain fatty acids cannot cross the mitochondrial membranes on their own, so they need carnitine to carry them across, which is why the shuttle limits fat oxidation.
A long-chain fatty acid cannot get across the two membranes around the mitochondrion unaided, so it needs the carnitine shuttle. First, the fatty acid is attached to coenzyme A (CoA, a carrier molecule) to give fatty acyl CoA (the fatty acid attached to CoA). In that form it still cannot get through the inner membrane by itself.
Carnitine palmitoyltransferase I (CPT I), an enzyme on the outer membrane, swaps the CoA for carnitine to make fatty acyl carnitine (the fatty acid carried on carnitine). A translocase, an enzyme of the shuttle, carries it across the inner membrane into the matrix. Inside the matrix, carnitine palmitoyltransferase II swaps the carnitine back for CoA.
With the fatty acid back on CoA, beta oxidation (the repeated chopping of a fatty acid into two-carbon units) can begin. Each unit becomes acetyl-CoA, which goes on to the Krebs cycle to make ATP.
The shuttle is also a control point. In the fed state, when the liver is storing fat, malonyl-CoA, which acts as a brake on the shuttle, is high and inhibits CPT I, so fatty acids are kept out of the mitochondria. When malonyl-CoA falls in fasting, the brake comes off and fatty acids enter the mitochondria to be oxidised.
If carnitine is lacking or a shuttle enzyme is faulty, the body stops burning long-chain fat. Defects of the shuttle cause a spectrum of disease, from muscle breakdown with exercise to hypoketotic hypoglycaemia in fasting. This means low blood glucose without the ketones expected in fasting.
Key facts
- Barrier
- long-chain fatty acyl CoA cannot cross the inner mitochondrial membrane by itself.
- Carrier
- carnitine takes the place of CoA, and the resulting fatty acyl carnitine can be carried across the inner membrane.
- Enzymes
- the shuttle uses the enzymes carnitine palmitoyltransferase I, a translocase and carnitine palmitoyltransferase II.
- Control in the liver
- in the fed state, malonyl-CoA inhibits CPT I, which is how the cell stops long-chain fatty acids being burned.
- Site of beta oxidation
- for long-chain fatty acids it takes place in the mitochondrial matrix, the inner compartment.
- Deficiency
- a lack of carnitine or a faulty shuttle enzyme stops long-chain fat being burned, and such defects cause a spectrum of disease, from muscle breakdown with exercise to low blood sugar with low ketone levels when fasting.
Exam traps
- Porin channels (pores that let small molecules through) in the outer membrane do not take a long-chain fatty acid into the matrix, because the inner membrane would still block it.
- Hormone-sensitive lipase releases fatty acids from stored triglyceride in fat cells, so it acts before the mitochondria are involved and does not control their entry.
- The inner membrane has no ATP-dependent pump that actively transports fatty acyl CoA into the matrix, because the carnitine shuttle is the specific transport mechanism.
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