Question

A man comes into the hospital with a history of exercise intolerance. The patient was given a

bicycle exercise test, which consists of riding a bicycle with the workload increased until the

workload can no longer be maintained (in other words, the patient can no longer physically

ride the bike). The results indicated that the patient’s work capacity was reduced to 20-30%

of that of controls and plasma lactate and pyruvate levels were much higher in the patient.

The physicians measured oxygen consumption using intact mitochondria isolated from a

biopsy of the patient's muscle tissue. They checked each citric acid cycle enzyme and found

that the rate of oxygen consumption was about 25% of the control value using succinate as

substrate, but was normal with fumarate and malate.

A) What appears to be the primary defect in the patient and why did this defect lead to a

decrease in both oxygen consumption and mitochondrial ATP generation?

B) Who would have a greater increase in glycolytic flux during the bicycle exercise, the

patient or the control? Explain your reasoning.

Answer 1

It is given that the patient is exhibiting exercise intolerance. His work capacity is reduced 20-30% of the control and plasma lactate levels are very high. He also exhibited reduced oxygen consumption.

The above information suggests that he may possess a mutation in the aerobic respiratory pathway either in the TCA cycle or ETC component. He exhibited a normal rate with fumarate and malate as the substrate but not with fumarate. So, the defect must be at the level of fumarate.

He might possess a mutation in the succinate dehydrogenase. Succinate is converted to Fumarate by succinate dehydrogenase. This reaction also generates 1 FADH2 per cycle. Succinate dehydrogenase is also a component of the electron transport chain. It acts as complex-II in the electron transport chain. Since succinate dehydrogenase is mutated, oxygen consumption and ATP production by oxidative phosphorylation is compromised.

He would exhibit a greater flux through glycolysis than normal individuals since he does not possess a functional TCA cycle. To compensate for the compromised TCA cycle, the flux through glycolysis is increased to generate more ATP.