A patient presents with lactic acidosis, muscle weakness, ptosis, and progressive ophthalmoplegia. Muscle biopsy shows ragged red fibers (Gomori trichrome). Electron microscopy reveals abnormal paracrystalline inclusions in mitochondria. Gene sequencing shows a large-scale deletion in mitochondrial DNA affecting Complex I and IV subunit genes. Which feature of ATP synthase (Complex V) allows it to continue generating ATP despite partial ETC deficiency?

• A The proton gradient generated by remaining functional complexes (II, III) is sufficient to drive ATP synthase, albeit at reduced rate ✓
• B ATP synthase can use NADH directly as an energy substrate independent of proton gradient
• C ATP synthase can reverse its rotation to pump protons using ATP hydrolysis, maintaining some membrane potential
• D ATP synthase downregulates its inhibitory IF1 protein in response to low delta-psi, increasing coupling efficiency

Explanation

In mitochondrial myopathy with partial mtDNA deletions, some ETC complexes remain functional. Complex II (succinate dehydrogenase) is entirely nuclear-encoded and therefore unaffected by mtDNA deletions. Complex III and IV may be partially functional. The proton gradient (delta-psi, proton motive force) established by functional complexes is utilized by ATP synthase (Complex V) to generate ATP, though at reduced efficiency. This is why residual mitochondrial function can partially sustain the patient clinically. The IF1 (inhibitory factor 1) protein actually inhibits reverse ATPase activity under normal conditions; it upregulates during depolarization to prevent futile ATP hydrolysis. ATP synthase cannot use NADH directly — it is driven exclusively by the proton electrochemical gradient.

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

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Written and medically reviewed by the StethoPrep medical team.