Fatty Acid Oxidation (β-Oxidation)
β-Oxidation is the process by which fatty acids are broken down in the mitochondria to produce Acetyl-CoA, NADH, and FADH₂ for energy production. It is the major energy source for heart, liver (fasting), and skeletal muscle.
Activation of Fatty Acids
Step 1 (cytosol): Fatty acid + CoA + ATP → Fatty acyl-CoA + AMP + PPi [Acyl-CoA Synthetase]. Costs 2 ATP equivalents (ATP → AMP). This "primes" the fatty acid before it enters the mitochondria.
Carnitine Shuttle (Rate-Limiting Step)
Long-chain fatty acids (>12C) cannot cross the inner mitochondrial membrane directly. They are transported by Carnitine:
- Fatty acyl-CoA + Carnitine → Acylcarnitine [Carnitine Palmitoyltransferase I (CPT-I), outer membrane]
- Acylcarnitine transported across membrane (Carnitine-acylcarnitine translocase)
- Acylcarnitine → Fatty acyl-CoA [CPT-II, inner membrane]
CPT-I is inhibited by Malonyl-CoA (the first product of FA synthesis) — ensures simultaneous synthesis and oxidation do not occur (reciprocal regulation).
β-Oxidation Cycle (4 Steps, Repeated)
Each cycle shortens the fatty acyl chain by 2 carbons, releasing 1 Acetyl-CoA:
- Oxidation: Acyl-CoA → trans-Δ²-Enoyl-CoA + FADH₂ [Acyl-CoA Dehydrogenase]
- Hydration: Enoyl-CoA → L-3-Hydroxyacyl-CoA [Enoyl-CoA Hydratase]
- Oxidation: Hydroxyacyl-CoA → 3-Ketoacyl-CoA + NADH [L-3-Hydroxyacyl-CoA Dehydrogenase]
- Thiolysis: 3-Ketoacyl-CoA + CoA → Acetyl-CoA + Acyl-CoA (shortened by 2C) [Thiolase]
Energy Yield — Palmitate (C16:0)
Palmitate requires 7 cycles of β-oxidation (yields 8 Acetyl-CoA):
- 7 FADH₂ × 1.5 ATP = 10.5 ATP
- 7 NADH × 2.5 ATP = 17.5 ATP
- 8 Acetyl-CoA × 10 ATP = 80 ATP
- Total: 108 ATP − 2 ATP (activation) = ~106 ATP net
Compare: Glucose (180g) → 32 ATP; Palm itate (256g) → 106 ATP ⇒ Fats have much higher energy density per gram.
Unsaturated Fatty Acid Oxidation
Requires additional enzymes: Enoyl-CoA isomerase (for cis bonds at odd positions) and 2,4-Dienoyl-CoA reductase (for bonds at even positions). Yield is slightly less than saturated fatty acids.
Odd-Chain Fatty Acids
Last 3C product is Propionyl-CoA (not Acetyl-CoA). Propionyl-CoA → Methylmalonyl-CoA [Propionyl-CoA Carboxylase, requires Biotin] → Succinyl-CoA [Methylmalonyl-CoA Mutase, requires B12] → enters TCA cycle. This is the ONLY way fatty acids contribute to gluconeogenesis.
Clinical
- MCAD deficiency: Medium-chain acyl-CoA dehydrogenase deficiency; most common FA oxidation defect; hypoketotic hypoglycemia; can be fatal in infants; detected on newborn screen
- Carnitine deficiency: Can be primary (SLC22A5 gene) or secondary; impairs FA oxidation → cardiomyopathy, muscle weakness
- Zellweger syndrome: Peroxisome biogenesis disorder; cannot oxidize very long chain FA (VLCFA >C22) — neurodegeneration