Mitochondrial complex I (NADH:ubiquinone oxidoreductase) deficiency is the most common cause of mitochondrial disease in childhood. Mutations in complex I subunit genes cause impaired electron transfer from NADH to ubiquinone. The primary metabolic consequence at the cellular level is:
- A Increased NAD+/NADH ratio causing TCA cycle to run faster
- B NADH accumulation causing TCA cycle inhibition, reversal of malate-aspartate shuttle, lactate accumulation, and reduced ATP synthesis ✓
- C Superoxide production only without affecting NADH/NAD+ ratio
- D Preferential oxidation of FADH2-linked substrates via complex II to compensate
Explanation
Complex I catalyses the transfer of two electrons from NADH to ubiquinone (CoQ10), regenerating NAD+. Deficiency causes NADH accumulation (increased NADH/NAD+ ratio). Consequences are multifactorial: (1) The TCA cycle (which uses NAD+ as cofactor in isocitrate dehydrogenase, alpha-KG dehydrogenase, and malate dehydrogenase) is inhibited by high NADH through product inhibition; (2) The malate-aspartate shuttle, which transfers cytosolic NADH into mitochondria, is reversed, impeding aerobic glucose utilisation; (3) Pyruvate dehydrogenase is inhibited by high NADH, causing pyruvate to be reduced to lactate (lactic acidaemia is the hallmark of mitochondrial disease); (4) ATP synthesis falls due to reduced electron flow through the ETC. While ROS production does occur at complex I, NADH/NAD+ disruption is the primary metabolic consequence.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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Written and medically reviewed by the StethoPrep medical team.