TCA Cycle and ETC (Bioenergetics, Oxidative Phosphorylation) MCQs

Biochemistry · 43 free questions with answers & explanations.

1. A patient with Leigh syndrome (subacute necrotizing encephalomyelopathy) has markedly elevated blood lactate and pyruvate with a normal lactate-to-pyruvate ratio. This pattern most likely indicates deficiency of:
2. Cyanide poisoning causes cellular asphyxia despite normal blood oxygen levels. Cyanide inhibits which complex of the mitochondrial electron transport chain?
3. 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:
4. Succinate dehydrogenase (SDH, Complex II) is unique among the TCA cycle enzymes because it is also an integral component of the electron transport chain. Mutations in SDHB, SDHC, or SDHD subunit genes predispose to paragangliomas and pheochromocytomas. The carcinogenic mechanism involves accumulation of which metabolite?
5. A toxicologist suspects cyanide poisoning in a patient found unresponsive. Labs show arterial-venous O2 difference is nearly zero despite high arterial pO2, and there is severe lactic acidosis. Which specific step in the ETC is inhibited by cyanide?
6. Succinate dehydrogenase (SDH/Complex II) is the only enzyme shared between the TCA cycle and the ETC. Mutations in SDH subunits (SDHA, SDHB, SDHC, SDHD) cause hereditary paragangliomas and phaeochromocytomas via a specific molecular mechanism. What is this mechanism?
7. Leigh syndrome (subacute necrotizing encephalomyelopathy) is a mitochondrial disease often caused by mutations in Complex I subunits or SURF1 (cytochrome c oxidase assembly factor). Why does brain necrosis occur in areas of high energy demand (basal ganglia, brainstem) rather than uniformly?
8. 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?
9. Fumarase deficiency (fumarate hydratase deficiency) is a rare TCA cycle disorder causing severe encephalopathy and lactic acidosis in neonates. Heterozygous mutations in fumarase also predispose to uterine leiomyomas, renal cell carcinoma, and cutaneous leiomyomas (Hereditary Leiomyomatosis and Renal Cell Cancer — HLRCC). Accumulated fumarate acts as an oncometabolite by inhibiting which epigenetic enzyme?
10. In the electron transport chain, ubiquinol (CoQH2) donates electrons to Complex III (cytochrome bc1). The Q cycle mechanism results in 4 protons being translocated per 2 electrons passed through Complex III. If the P/O ratio for NADH oxidation is approximately 2.5 ATP per FADH2 pair, what is the correct sequence of electron carriers within Complex III from ubiquinol to cytochrome c?
11. Leber's hereditary optic neuropathy (LHON) is caused by point mutations in mitochondrial DNA (mtDNA) encoding subunits of Complex I (NADH dehydrogenase). The most common pathogenic mutations are at mtDNA positions 11778, 3460, and 14484. Why does retinal ganglion cell degeneration occur selectively in LHON despite the ubiquitous expression of Complex I?
12. Oligomycin completely inhibits ATP synthase (Complex V) in isolated mitochondria. What will be the immediate effect on the proton motive force (PMF) and on the rates of ETC complexes I-IV?
13. Fumarate hydratase (fumarase) is a TCA cycle enzyme that also functions as a tumor suppressor. Germline mutations in the fumarate hydratase (FH) gene predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The oncogenic mechanism involves accumulation of fumarate, which competitively inhibits:
14. A 25-year-old woman with sensorineural hearing loss, ptosis, and proximal muscle weakness has ragged-red fibers on muscle biopsy. Genetic testing reveals a large mitochondrial DNA deletion. The ETC complex most sensitive to mitochondrial DNA deletions encoding core subunits would be:
15. Uncoupling protein 1 (UCP1, thermogenin) in brown adipose tissue dissipates the proton gradient across the inner mitochondrial membrane as heat rather than ATP synthesis. Which metabolite directly activates UCP1 during cold exposure, and which molecule inhibits it?
16. Succinate dehydrogenase (SDH, Complex II) differs from all other TCA cycle enzymes in that it is embedded in the inner mitochondrial membrane and directly feeds electrons to the ubiquinone pool. Which of the following is a unique clinical relevance of SDH subunit mutations?
17. A 2-year-old boy presents with progressive lactic acidosis, failure to thrive, and hypotonia. Plasma lactate-to-pyruvate (L:P) ratio is markedly elevated (>30). MRI shows symmetric bilateral lesions in the basal ganglia and brainstem. Muscle biopsy shows cytochrome c oxidase (complex IV) deficiency. This clinical syndrome is known as:
18. Succinate dehydrogenase (complex II / SDH) is unique among TCA cycle enzymes because it is embedded in the inner mitochondrial membrane and also functions as complex II of the electron transport chain. Mutations in SDHB, SDHC, or SDHD subunits are associated with which cancer predisposition syndrome?
19. Oligomycin is an antibiotic that tightly binds the Fo subunit of ATP synthase (complex V), blocking the proton channel through which H+ flows back into the matrix. What is the expected effect on electron transport chain activity and membrane potential in isolated mitochondria treated with oligomycin?
20. Leigh syndrome (subacute necrotising encephalomyelopathy) in infants is most commonly due to mutations in mitochondrial ATP synthase subunit 6 or Complex I subunits. Which metabolic parameter is MOST elevated in a patient with Leigh syndrome during metabolic crisis?
21. Rotenone (a pesticide) is a classic inhibitor of which complex in the electron transport chain, and which substrate pair's re-oxidation is blocked?
22. Succinate dehydrogenase (Complex II / SDH) is unique among TCA cycle enzymes because it is also an integral component of the ETC. SDH is encoded entirely by nuclear DNA. Germline mutations in SDHB, SDHC, or SDHD subunits predispose to which specific tumours?
23. A patient with progressive external ophthalmoplegia, ptosis, and mitochondrial myopathy is found to have a deletion in mitochondrial DNA (mtDNA) affecting Complex I subunits. This patient's cells show markedly reduced Complex I (NADH: ubiquinone oxidoreductase) activity. The clinical feature that distinguishes Complex I deficiency from Complex IV deficiency in children is:
24. Oligomycin, an antibiotic, inhibits the F0 subunit of ATP synthase. Administration of oligomycin to isolated mitochondria would be expected to cause which combination of effects?
25. Leber hereditary optic neuropathy (LHON) is caused by maternally inherited mitochondrial DNA mutations predominantly affecting complex I of the ETC. Why are retinal ganglion cells particularly susceptible to complex I defects?
26. 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:
27. The P/O ratio for NADH oxidation via the mitochondrial ETC is approximately 2.5 ATP per NADH. This is lower than the theoretical maximum because:
28. Rotenone (used as a pesticide) specifically inhibits complex I of the electron transport chain. A patient with rotenone poisoning would show which metabolic consequence?
29. ATP synthase (Complex V) utilises the proton motive force. The F0 component contains a rotating c-ring. For ATP synthesis in human mitochondria, how many protons must pass through the F0 channel to synthesise one molecule of ATP?
30. Rotenone, a pesticide, specifically inhibits Complex I of the ETC. Which metabolic consequence is MOST direct?
31. 2,4-Dinitrophenol (DNP) acts as a chemical uncoupler of oxidative phosphorylation. The mechanism involves:
32. Rotenone is a complex I inhibitor of the ETC. Which substrate can bypass the rotenone block and maintain mitochondrial NADH-independent electron flow into the ETC?
33. A mitochondrial Complex I inhibitor (e.g., rotenone) blocks electron transfer from NADH to CoQ (ubiquinone). In the presence of rotenone, which substrates can STILL generate ATP via oxidative phosphorylation?
34. The P/O ratio describes ATP molecules synthesized per oxygen atom reduced. For NADH-linked substrates (feeding Complex I), the theoretical P/O ratio is approximately 2.5, while FADH2-linked substrates (entering at Complex II) have a P/O ratio of approximately 1.5. This difference reflects:
35. Metformin exerts part of its glucose-lowering effect by inhibiting Complex I of the mitochondrial ETC in hepatocytes. The downstream effect on hepatic gluconeogenesis is mediated through:
36. Succinate dehydrogenase (SDH/Complex II) is unique among the ETC complexes because it does NOT pump protons across the inner mitochondrial membrane. The reason is:
37. 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:
38. Uncoupling protein 1 (UCP1) in brown adipose tissue dissipates the proton gradient without ATP synthesis. A synthetic chemical uncoupler like 2,4-dinitrophenol (DNP) was used as a weight-loss drug but caused fatal hyperthermia. The mechanism by which DNP causes hyperthermia is:
39. Succinate dehydrogenase (Complex II) is unique among TCA cycle enzymes because it is embedded in the inner mitochondrial membrane. Loss-of-function mutations in SDHB (succinate dehydrogenase B subunit) are associated with:
40. Complex II (succinate dehydrogenase, SDH) of the electron transport chain is unique among ETC complexes because it does not pump protons across the inner mitochondrial membrane. Which subunits of SDH are tumour suppressors whose loss-of-function mutations predispose to paragangliomas and phaeochromocytomas?
41. Mitochondrial DNA is transmitted exclusively maternally in humans. A woman has MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) from an MT-TL1 mutation. What is the probability that her son will transmit this disease to his children?
42. Cyanide poisoning causes cytotoxic hypoxia. The mechanism is inhibition of:
43. Succinate dehydrogenase (SDH) is unique among TCA cycle enzymes because it: