Many chemicals that are poisons exert their toxic effects by interfering with some aspect of aerobic respiration, usually involving the electron transport chain of the mitochondria. Three such poisons are cyanide, 2,4-dinitrophenol, and the antibiotic oligomycin.
Cyanide is a potent and deadly human poison. It causes its effects by binding to one of the electron carriers and inhibiting the passage of electrons to oxygen, so that electron transport, proton-pumping, and ATP synthesis stop virtually instantaneously.
2,4-dinitrophenol is also a deadly poison to humans. It is an example of the general class of poisons known as “uncouplers”, which allow protons to pass back from the intermembrane space to the matrix without passing through the ATP synthase enzyme. Electron transport and proton pumping continue, but ATP is not made. Such uncouplers are also called ionophores.
Oligomycin, an antibiotic, is not deadly to humans, but does interfere with respiration, which is how it kills bacteria, and accounts for its side effects in humans. It is representative of a group of poisons that directly inhibit ATP synthase by blocking the passageway for protons. As with the uncouplers, electron transport and proton pumping continue, but ATP is not made (although for a different reason).
Use the information above, the following observations, and your knowledge of respiration when answering the questions.
When a person breathes a particular deadly poison (compound A), the following effects are observed. Clinically, body temperature quickly increases, causing profuse sweating, and ultimate death. At the biochemical level it is noted that normal to greater than normal amounts of oxygen are used, and normal to greater amounts of carbon dioxide are produced. The pH of the mitochondrial intermembrane space does not change appreciably; if it does, it may increase slightly.
When a person ingests a particular toxin (compound B), the following effects are observed. At the biochemical level, it is noted that the Krebs cycle continues to function, producing NADH, and that the NADH is oxidized back to NAD+ as it donates electrons to the electron transport chain. Strikingly, the pH of the mitochondrial intermembrane space is noted to drop significantly.
In the 1950s, certain weak uncoupling agents were used to promote weight loss. They worked very well; in fact, they worked so well at “burning calories” that many people died from using them and they were pulled from the market. Which of the following statements explains how uncouplers could cause weight loss?
|A||Uncouplers allow ATP to be made but prevent its transport out of the mitochondria, thus uncoupling its manufacture from its use.|
|B||Uncouplers increase the metabolic rate, and allow caloric energy temporarily stored in reduced coenzymes to remain “unharvested” as ATP; it is simply released as heat.|
|C||Uncouplers prevent oxygen from accepting electrons, so that ATP is not made, and energy is not available to digest and absorb food.|
|D|| Uncouplers, due to their toxic effects, cause appetite suppression, and lower the overall metabolic rate.|
As we have seen from the solution to question 6, uncouplers function by allowing the inner mitochondrial membrane to become permeable to protons, and we know from question six that energy is released but not used (harvested as ATP); it is simply dissipated as heat. Choice A is incorrect because uncouplers decrease the formation of ATP; choice C is incorrect because it describes a cyanide-like poison that shuts down electron transport. Choice D makes little sense; if anything, an uncoupler would cause the metabolic rate to rise.