MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes) is caused by mtDNA mutations. The metabolic consequence of ETC dysfunction that DIRECTLY causes lactic acidosis is:
- A Excess acetyl-CoA from impaired TCA cycle overflows into ketogenesis
- B Proton leak across the inner mitochondrial membrane acidifies the cytoplasm
- C Blocked NADH oxidation by impaired ETC causes NADH/NAD+ ratio to rise, forcing pyruvate → lactate via LDH to regenerate NAD+ ✓
- D Impaired gluconeogenesis in mitochondria causes glucose deficiency
Explanation
Defective ETC (complex I most commonly in MELAS — m.3243A>G mutation in mt-tRNA-Leu) cannot oxidize NADH to NAD+. Elevated NADH/NAD+ ratio inhibits TCA cycle dehydrogenases (isocitrate, alpha-ketoglutarate, malate dehydrogenase) — effectively blocking the TCA cycle — and forces pyruvate reduction to lactate via lactate dehydrogenase to regenerate the NAD+ needed for continued glycolysis. This is why mitochondrial disease causes type B lactic acidosis (not type A from hypoxia/ischemia) — lactate/pyruvate ratio is elevated (>20), and the acidosis occurs without tissue hypoperfusion.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.