A 26 years old patient initially presented with a history of fatigability dating back to early childhood. Even very mild exercise resulted in a rapid exhaustion. After 4 minutes on a bicycle ergometer, the patient's blood lactate concentration rose from 0.8mM to 10mM;it dropped slowly after the end of the exercise but was still elevated 90 minutes later.
A muscle biopsy was obtained and mitochondria isolated from it. The rates of oxygen utilization by these mitochondria with various substrate in the presence of ADP, together with compatible values for mitochondria from a normal volunteer, are shown below.
Oxygen consumption (nanoatoms/min/mg protein)
Substrate Patient Control
Pyruvate 17 92
Glutamate 17 68
Succinate 50 55
(a) Describe the observed differences between the patient's and control mitochondria.
(b) From the data presented, suggested a possible site for the defect in the patient's muscles. Suggest two other substrates which might be tested to substantiate your conclusion, and the expected results with these substrates.
(c) Describe the mechanism which would lead to excessive lactate production when the patient exercised.
(d) Why did the patient become fatigued so rapidly?
a) Describe the observed differences between the patient's and control mitochondria.
Response: The assay measures the amount of each substrate metabolized by the mitochondria by measuring the amount of oxygen consumed by the mitochondria. In other words, the assay is measuring the amount of oxidative phosphorylation that takes place in the mitochondria when they are exposed to the varying substrates. Control mitochondria can readily metabolize pyruvate and convert it to CO2 with the concomitant production of oxygen in the electron transport chain. Remember, the oxidation of substrates in the Krebs cycle is linked to the utilization of oxygen as the final electron acceptor. This coupled process is called oxidative phosphorylation. Pyruvate is a regular substrate in controls but is a poor substrate in this patient. Again, we have a fairly decent ability of the control mitochondria to utilized glutamate, but a poor ability for the patient's mitochondria to utilize glutamate. Finally, both the control's and the patient's mitochondria are able to utilize succinate very similarly.
I will explain in the next question, what this data seems to indicate.
(b) From the data presented, suggested a possible site for the defect in the patient's muscles.
Suggest two other substrates which ...
The solutions discusses mitochondria within patients.