Contents · 13 sections
- 1. General scheme
- 2. Carnitine shuttle
- 3. Four reactions of Lynen's spiral
- 4. Energy yield for palmitate (C16)
- 5. Oxidation of unsaturated fatty acids
- 6. Oxidation of odd-chain fatty acids
- 7. Alternative pathways
- 8. Ketogenesis
- 9. Regulation
- 10. Tissue-specific features
- 11. Inherited disorders of β-oxidation
- 12. Clinical significance
- 13. FAQ
In a nutshell. β-Oxidation is the mitochondrial pathway of fatty acid (FA) catabolism. Stages: cytosolic activation (acyl-CoA), carnitine shuttle across the mitochondrial membranes, Lynen's 4-reaction spiral (FAD-dependent dehydrogenation → hydration → NAD⁺-dependent dehydrogenation → thiolysis), release of acetyl-CoA → Krebs cycle. Palmitate (C16) → 8 acetyl-CoA + 7 FADH₂ + 7 NADH = 106 ATP. In starvation, the liver converts excess acetyl-CoA into ketone bodies. Disorders: MCAD deficiency (common congenital), VLCAD, CPT I/II — hypoglycemia + ↑ muscle enzymes during fasting/exercise.
1. General scheme
- Main pathway of FA catabolism — in mitochondria.
- FA activation in the cytosol: FA + ATP + CoA → acyl-CoA + AMP + PPi (acyl-CoA synthetase).
- Transport of long-chain FAs (> C14) across the inner mitochondrial membrane — carnitine shuttle.
- Medium-chain (C6–C12) and short-chain (< C6) FAs cross directly.
- In the matrix: "Lynen's spiral" — 4 reactions, releasing acetyl-CoA each cycle.
- Acetyl-CoA → Krebs cycle → CO₂ + H₂O + ATP.
2. Carnitine shuttle
- CPT I (carnitine palmitoyltransferase I) on the outer surface of the inner membrane: acyl-CoA + carnitine → acylcarnitine + CoA.
- Carnitine/acylcarnitine translocase — transmembrane transport.
- CPT II on the matrix side: acylcarnitine + CoA → acyl-CoA + carnitine.
- Regulation: malonyl-CoA inhibits CPT I — the "switch" between FA synthesis and β-oxidation.
- Under low insulin / glucagon dominance: ↓ malonyl-CoA → ↑ β-oxidation.
3. Four reactions of Lynen's spiral
- Dehydrogenation: acyl-CoA + FAD → trans-Δ²-enoyl-CoA + FADH₂ (acyl-CoA dehydrogenase: SCAD/MCAD/LCAD/VLCAD according to chain length).
- Hydration: enoyl-CoA + H₂O → 3-hydroxyacyl-CoA (enoyl-CoA hydratase).
- NAD⁺-dependent dehydrogenation: 3-hydroxyacyl-CoA + NAD⁺ → 3-ketoacyl-CoA + NADH (3-hydroxyacyl-CoA dehydrogenase).
- Thiolysis: 3-ketoacyl-CoA + CoA → acyl-CoA (−2 C) + acetyl-CoA (β-ketothiolase).
Result of one turn: −2 carbons, +1 FADH₂, +1 NADH, +1 acetyl-CoA.
4. Energy yield for palmitate (C16)
- 7 turns of the spiral → 7 FADH₂ + 7 NADH + 8 acetyl-CoA.
- 7 FADH₂ × 1,5 ATP = 10,5 ATP.
- 7 NADH × 2,5 ATP = 17,5 ATP.
- 8 acetyl-CoA × 10 ATP (Krebs cycle + ETC) = 80 ATP.
- Minus 2 ATP for activation (ATP → AMP).
- Total: 108 − 2 = 106 ATP (classic figure); with modern P/O ratios — ~106–108.
5. Oxidation of unsaturated fatty acids
- Additional enzymes required: enoyl-CoA isomerase (shifts double bond to trans-Δ²) and 2,4-dienoyl-CoA reductase (for double bonds at even positions).
6. Oxidation of odd-chain fatty acids
- At the end of the spiral, propionyl-CoA (3C) is formed.
- Propionyl-CoA → methylmalonyl-CoA (propionyl-CoA carboxylase, biotin) → succinyl-CoA (methylmalonyl-CoA mutase, B12) — gluconeogenic pathway.
- B12 or biotin deficiency → accumulation of methylmalonic acid.
7. Alternative pathways
- Peroxisomal β-oxidation — very long-chain FAs (VLCFA > C22), branched-chain FAs (phytanic acid — ω-oxidation + α-oxidation).
- ω-Oxidation — in the smooth ER (CYP4A); used when β-oxidation is impaired.
- α-Oxidation — for phytanic acid (Refsum disease due to phytanoyl-CoA hydroxylase deficiency).
8. Ketogenesis
- During starvation, ketogenic diet, DKA — excess hepatic acetyl-CoA exceeds Krebs cycle capacity.
- 2 acetyl-CoA → acetoacetyl-CoA → HMG-CoA → acetoacetate → β-hydroxybutyrate; spontaneously → acetone.
- Ketone bodies are delivered to extrahepatic tissues (brain, muscles, heart) — converted back to acetyl-CoA.
- The liver cannot oxidize ketone bodies (lacks succinyl-CoA:3-ketoacid CoA transferase).
9. Regulation
- Hormones: insulin inhibits β-oxidation (via ↑ malonyl-CoA), glucagon and catecholamines activate lipolysis and β-oxidation.
- Metabolic control: high NADH/NAD⁺ and acetyl-CoA/CoA slows down β-oxidation.
- PPARα — nuclear receptor, activated by FAs/fibrates → ↑ expression of β-oxidation enzymes.
- AMPK — activated during energy depletion, inhibits ACC → ↓ malonyl-CoA → ↑ β-oxidation.
10. Tissue-specific features
- The liver is the main organ of ketogenesis and β-oxidation during fasting.
- Skeletal muscle is active during prolonged aerobic exercise.
- The heart prefers fatty acids (60–90% of energy); switches to glucose during ischemia.
- The brain does not use fatty acids (due to the blood-brain barrier); during fasting > 3 days, 2/3 of its energy comes from ketone bodies.
- Erythrocytes lack mitochondria and rely solely on glycolysis.
11. Inherited disorders of β-oxidation
| Defect | Clinical Practice | Diagnostics |
|---|---|---|
| MCAD deficiency (most common) | Hypoglycemia + hypoketonemia during fasting/infection; Reye-like syndrome | Acylcarnitine profile (C6–C10), ACADM gene mutations |
| VLCAD deficiency | Cardiomyopathy, exercise-induced rhabdomyolysis, hypoglycemia | C14:1 acylcarnitines, genetics |
| LCHAD, trifunctional protein | Hypoglycemia, cardiomyopathy, retinopathy, peripheral neuropathy, maternal HELLP | Acylcarnitine profile (C16-OH, C18-OH) |
| CPT I | Hypoglycemia, hepatomegaly, normal CK | Low serum carnitine, high urinary carnitine |
| CPT II | Myopathic form: rhabdomyolysis triggered by exertion, cold, or fasting; neonatal/lethal form | ↑ CK, acylcarnitines (C16, C18) |
| Systemic primary carnitine deficiency | Cardiomyopathy, muscle weakness, hypoglycemia | Low blood carnitine; L-carnitine supplementation |
| Refsum disease | Retinitis pigmentosa, polyneuropathy, cerebellar ataxia | ↑ Phytanic acid; dairy/ruminant-free diet |
12. Clinical significance
- DKA: insulin deficiency → lipolysis + β-oxidation → ketogenesis → metabolic acidosis.
- Alcoholic ketoacidosis: fasting + ethanol → ↑ NADH/NAD⁺ → shift toward β-hydroxybutyrate (acetoacetate test is negative!).
- Neonatal hypoglycemia in MCAD — screened in all newborns in developed countries.
- Valproic acid inhibits β-oxidation; risk of hepatotoxicity in children < 2 years with an unrecognized β-oxidation defect.
- Fibrates activate PPARα → ↑ β-oxidation → ↓ triglycerides.
13. FAQ
Why does malonyl-CoA "switch" between fatty acid synthesis and oxidation?
Malonyl-CoA is a precursor for fatty acid synthesis (ACC); simultaneously, it inhibits CPT I, blocking the transport of fatty acids into mitochondria. This prevents the cell from oxidizing newly synthesized fatty acids.
Why does the liver lack the reverse pathway for ketone body utilization?
It lacks succinyl-CoA:3-ketoacid-CoA transferase (thiophorase). The liver generates ketones for extrahepatic tissues while directly utilizing acetyl-CoA itself.
Why is MCAD deficiency dangerous during a febrile illness in a child?
Glucose stores are depleted, fatty acids are mobilized, but oxidation is blocked → severe hypoketotic hypoglycemia, encephalopathy, Reye-like syndrome, and risk of sudden death.
What is "hypoketotic hypoglycemia"?
Classic of β-oxidation defects: fasting → low glucose, but almost no ketones in the urine (FAs are not oxidized). Differs from normal fasting (ketosis) and insulinoma (also no ketones, but insulin is ↑).
Why is the acylcarnitine profile determined?
Tandem mass spectrometry detects specific acylcarnitines that accumulate in various β-oxidation defects. The basis of neonatal screening.
See also: Krebs cycle · Glycolysis · Lipids · DKA · Biochemistry Catalog