Describe the carnitine shuttle and its regulation.

Definition

• Necessary because the inner mitochondrial membrane is impermeable to acyl-CoA
• Carnitine (β-hydroxy-γ-trimethylammonium butyrate) is synthesised in liver and kidney from lysine and methionine, requiring vitamin C, niacin, B6 and iron
• Richest dietary source — red meat

The Steps

Fatty acyl-CoA in cytosol → CPT-I on the outer mitochondrial membrane — rate-limiting → Acyl-carnitine → Carnitine–acylcarnitine translocase carries it in, carnitine out → CPT-II on the inner membrane → Fatty acyl-CoA in the matrix → β-oxidation

Regulation

• CPT-I is inhibited by malonyl-CoA, the first committed intermediate of fatty acid synthesis
• Fed state — insulin → ↑ malonyl-CoA → CPT-I blocked → oxidation off
• Fasting — glucagon → ↓ malonyl-CoA → oxidation ON
• This prevents a futile cycle of simultaneous synthesis and breakdown

Fatty Acids That Bypass It

• Short (< 6 C) and medium chain (6–12 C) fatty acids diffuse directly into the mitochondrion and are activated there
• Hence MCT oil is valuable in carnitine deficiency, CPT deficiency, and in fat malabsorption from any cause

Functions of Carnitine Beyond Transport

• Removes accumulated acyl groups from the mitochondrion as acylcarnitines, freeing coenzyme A
• Maintains the free CoA : acyl-CoA ratio, which many mitochondrial enzymes depend on
• Acylcarnitine profiling of a dried blood spot is the basis of newborn screening for fatty acid oxidation disorders — each defect gives a characteristic pattern

Applied Aspects

• Primary carnitine deficiency — defective OCTN2 transporter; cardiomyopathy, muscle weakness, hypoketotic hypoglycaemia; responds to oral carnitine
• Secondary carnitine deficiency — haemodialysis, valproate therapy, prematurity, severe malnutrition
• CPT-II deficiency — the commonest inherited disorder of lipid metabolism in muscle; exercise-induced rhabdomyolysis and myoglobinuria
• Carnitine supplements are widely sold to athletes on the claim that they increase fat burning; controlled trials have not supported this in people with normal carnitine stores
• Vegetarians have lower carnitine intake but synthesise enough; deficiency from diet alone is not seen in health