A 32-year-old man from rural Maharashtra presents with progressive fatigue, muscle weakness, and recurrent episodes of lactic acidosis (serum lactate 8 mmol/L, normal <2). His mother had similar symptoms and died at age 45. Physical examination reveals proximal muscle weakness and mild hepatomegaly. Muscle biopsy shows ragged-red fibres on Gomori trichrome stain. Genetic testing confirms a mutation in the gene encoding succinate dehydrogenase (Complex II). Which of the following best explains the pathophysiology of his lactic acidosis?

Explanation

## Pathophysiology of Lactic Acidosis in Complex II Deficiency ### Role of Succinate Dehydrogenase in the TCA Cycle Succinate dehydrogenase (SDH, Complex II) catalyzes the oxidation of succinate to fumarate—the only TCA cycle enzyme embedded in the inner mitochondrial membrane and directly coupled to the electron transport chain (ETC). It is unique because it: - Accepts electrons directly to ubiquinone (CoQ), bypassing Complexes I and III - Regenerates FAD~2~ to FAD, maintaining the NAD~/NADH ratio - Links carbohydrate oxidation to oxidative phosphorylation ### Why NAD+ Regeneration Fails When SDH is defective: 1. Electrons cannot be transferred to the ETC 2. NADH accumulates; NAD+ becomes depleted 3. Glycolysis stalls at the glyceraldehyde-3-phosphate dehydrogenase step (which requires NAD+) 4. Pyruvate accumulates and is shunted to lactate via lactate dehydrogenase (LDH) 5. Lactic acidosis results ```mermaid flowchart TD A[Glucose]:::outcome --> B[Glycolysis]:::action B --> C[Pyruvate]:::outcome C --> D{NAD+ available?}:::decision D -->|Yes| E[Acetyl-CoA]:::outcome E --> F[TCA Cycle]:::action F --> G[Succinate → Fumarate<br/>SDH/Complex II]:::action G --> H[ETC: NADH → NAD+]:::action H --> I[Cycle continues]:::outcome D -->|No| J[Pyruvate → Lactate<br/>via LDH]:::urgent J --> K[Lactic Acidosis]:::urgent G -->|SDH defective| L[Electrons blocked]:::urgent L --> M[NADH accumulates<br/>NAD+ depleted]:::urgent M --> J ``` ### Clinical Correlates **Key Point:** Complex II deficiency causes a dual metabolic crisis: - Loss of TCA cycle flux (no fumarate → malate → oxaloacetate regeneration) - Impaired NAD+ regeneration (blocking glycolysis and pyruvate oxidation) **Clinical Pearl:** Ragged-red fibres on muscle biopsy indicate mitochondrial dysfunction; SDH mutations are a known cause of mitochondrial myopathy and can also predispose to paragangliomas and renal cell carcinoma (SDH is a tumour suppressor). **High-Yield:** The lactic acidosis in SDH deficiency is primarily due to NAD+ depletion forcing pyruvate toward lactate, NOT simple TCA cycle stalling. This is why lactate levels are markedly elevated even though the TCA cycle is partially functional. ### Why the Other Options Are Wrong - **Option 0 (Fumarate → Malate block):** While SDH deficiency does block this step, the immediate cause of lactate accumulation is NAD+ depletion, not fumarate accumulation per se. - **Option 2 (Citrate synthase defect):** Citrate synthase is not affected in SDH mutations; this would cause a different metabolic pattern. - **Option 3 (Aconitase defect):** Aconitase deficiency causes a different presentation (iron-responsive leukoencephalopathy); it does not directly cause lactic acidosis. ## Summary SDH deficiency → blocked ETC → NADH accumulation → NAD+ depletion → pyruvate cannot enter TCA cycle → shunted to lactate → lactic acidosis.