Biochemistry · Metabolic pathway
Fatty acid β-oxidation !
When fasting, mitochondria cut fatty acids two carbons at a time: they give acetyl-CoA, NADH and FADH₂ and far more energy than glucose.
Updated 2026-11-01
Interactive map
Balance: FADH₂ +7NADH +7
Key facts
- Takes place in the mitochondrial matrix; long-chain fatty acids enter through the carnitine shuttle (CPT-I is the regulated step).
- Each turn: oxidation (FAD) → hydration → oxidation (NAD⁺) → thiolysis; 1 acetyl-CoA leaves.
- Palmitate (16 C): 7 turns → 8 acetyl-CoA, 7 FADH₂ and 7 NADH; about 106 net ATP (108 minus 2 for activation).
- Malonyl-CoA inhibits CPT-I: fat synthesis and oxidation do not run together.
- Medium-chain fatty acids (MCT) enter without carnitine; very-long-chain ones start in the peroxisome.
In detail
- Activation: on the outer membrane acyl-CoA synthetase forms acyl-CoA (ATP → AMP + PPi).
- CPT-I (outer membrane) swaps CoA for carnitine: acylcarnitine. This is the step malonyl-CoA blocks.
- Carnitine-acylcarnitine translocase (CACT) exchanges acylcarnitine inwards for free carnitine outwards.
- CPT-II (inner face of the inner membrane) puts CoA back: acyl-CoA in the matrix and free carnitine.
- In the matrix the four reactions repeat until the whole chain is split into acetyl-CoA.
- Unsaturated: need an isomerase (and a 2,4-dienoyl-CoA reductase using NADPH). Odd-chain: the last turn leaves propionyl-CoA.
- Also called
- Mitochondrial beta-oxidation, Lynen spiral
Regulation
- Glucagon and adrenaline activate hormone-sensitive lipase and raise the free fatty acids reaching liver and muscle.
- Insulin slows lipolysis and, through ACC and malonyl-CoA, closes entry at CPT-I.
- Fasting and PPARα raise β-oxidation enzymes; high NADH or acetyl-CoA slows it.
The steps, one by one
- Entry · Long-chain acyl-CoA synthetase (ACSL) irreversible Palmitate + coenzyme A + ATP → Acyl-CoA + AMP + pyrophosphateActivates the fatty acid in the cytosol by linking it to CoA; spends two high-energy bonds (ATP → AMP). It then enters through the carnitine shuttle.If it fails: Entry into the mitochondrion (CPT-I, translocase, CPT-II) is where carnitine and CPT-II deficiencies fail.
- Step 1 · Acyl-CoA dehydrogenase (VLCAD, MCAD, SCAD by chain length) irreversible Acyl-CoA + FAD → trans-Δ²-Enoyl-CoA + fadh2First oxidation: makes a trans double bond between C2 and C3; the electrons go to FAD and then, through ETF, to ubiquinone.If it fails: MCAD deficiency is the most common β-oxidation defect: hypoketotic hypoglycaemia on fasting. Hypoglycin blocks this same enzyme. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency →
- Step 2 · Enoyl-CoA hydratase trans-Δ²-Enoyl-CoA + H₂O ⇌ L-3-Hydroxyacyl-CoAAdds water across the double bond and forms L-3-hydroxyacyl-CoA.If it fails: For long chains this activity and the next two are carried out by the mitochondrial trifunctional protein (HADHA/HADHB).
- Step 3 · 3-Hydroxyacyl-CoA dehydrogenase (HADH; LCHAD for long chains) L-3-Hydroxyacyl-CoA + NAD⁺ ⇌ 3-Ketoacyl-CoA + NADHSecond oxidation: the alcohol becomes a keto group and NADH is formed.If it fails: LCHAD deficiency: hypoglycaemia, cardiomyopathy and retinopathy; the mother of an affected fetus can develop acute fatty liver of pregnancy or HELLP syndrome.
- Step 4 · β-Ketothiolase (3-ketoacyl-CoA thiolase) 3-Ketoacyl-CoA + coenzyme A ⇌ Acyl-CoA + Acetyl-CoAA new CoA cuts off the last two carbons: one acetyl-CoA leaves and an acyl-CoA 2 C shorter starts again.If it fails: The acetyl-CoA goes to the Krebs cycle or, in the fasting liver, to ketone bodies.
Clinical notes
- β-Oxidation defects (MCAD, VLCAD, LCHAD, CPT-II, carnitine) cause hypoketotic hypoglycaemia during fasting or fever.
- The tandem mass spectrometry acylcarnitine profile in newborn screening detects many of them.
- Ackee hypoglycin inhibits acyl-CoA dehydrogenases: severe hypoglycaemia (Jamaican vomiting sickness).
- At rest the heart gets most of its ATP from β-oxidation.
Pathways
- Krebs cycle (citric acid cycle)
- Ketogenesis (ketone body synthesis)
- Fatty acid synthesis (lipogenesis)
Related conditions
- Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
- Primary carnitine deficiency
- Carnitine palmitoyltransferase II (CPT-II) deficiency
- Jamaican vomiting sickness (ackee poisoning)
- Diabetic ketoacidosis
Related
- Carnitine palmitoyltransferase I (CPT-I)
- Medium-chain acyl-CoA dehydrogenase (MCAD)
- Carnitine (L-carnitine)
- Palmitate (palmitic acid)
- Acetyl-CoA
- Carnitine shuttle
- Malonyl-CoA
- Hormone-sensitive lipase (HSL)
- NAD⁺ (nicotinamide adenine dinucleotide)
- ATP (adenosine triphosphate)
- Krebs cycle (citric acid cycle)
- Ketogenesis (ketone body synthesis)
- Odd-chain fatty acids and propionate metabolism
- Peroxisomal oxidation (β- and α-oxidation)
Test yourself
Think of the answer, then tap the question to see it.
What does each turn of β-oxidation yield?
1 FADH₂, 1 NADH and 1 acetyl-CoA, and the acyl-CoA becomes 2 carbons shorter.
How many turns does palmitate need and how many acetyl-CoA does it give?
7 turns and 8 acetyl-CoA, because the last turn splits a 4-C piece in two.
Which molecule blocks fatty acid entry into the mitochondrion?
Malonyl-CoA, which inhibits carnitine palmitoyltransferase I (CPT-I).
Why do β-oxidation defects cause hypoglycaemia with low ketones?
Without acetyl-CoA from fat the liver makes no ketones and lacks energy for gluconeogenesis, while tissues burn more glucose.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Mitochondrial Fatty Acid Beta-Oxidation (Reactome, 2026); mitochondrial fatty acid beta-oxidation of saturated fatty acids (Reactome, 2026); Carnitine shuttle (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.