A patient with Leigh syndrome (subacute necrotizing encephalomyelopathy) has lactic acidosis, hypotonia, and brainstem dysfunction in infancy. Muscle biopsy enzyme analysis reveals isolated complex I (NADH:ubiquinone oxidoreductase) deficiency. The clinical finding of lactic acidosis in this patient is best explained by:

• A Excessive fatty acid oxidation generating acetyl-CoA that is converted to lactate
• B Overactivity of complex II compensating for complex I deficiency, generating excess FADH2 that is converted to lactate
• C Mitochondrial membrane damage allowing lactate to accumulate in the mitochondrial matrix
• D Inability to regenerate NAD+ from NADH via the ETC, causing pyruvate to accumulate and be reduced to lactate by lactate dehydrogenase ✓

Explanation

Complex I transfers electrons from NADH to ubiquinone (coenzyme Q), regenerating NAD+. When complex I is deficient, the mitochondrial NADH/NAD+ ratio rises dramatically; the high NADH drives the pyruvate dehydrogenase reaction in reverse and reduces oxaloacetate, impairing the TCA cycle. More critically, excess pyruvate is reduced to lactate by lactate dehydrogenase (which requires NADH, abundantly available), causing lactic acidosis. This explains why mitochondrial respiratory chain disorders consistently present with elevated lactate:pyruvate ratios. Dichloroacetate (PDH activator) is sometimes used to reduce lactic acid production.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.