The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Search for How So Few Anaerobic Cells Cause So Much Oxidative Stress
Fig. 9.1. How pyruvate sustains anaerobic cells.
increased levels in these fibers, 20a even after allowing for the often-seen increase in the number
of mitochondria per fiber, 20b which strongly indicates that it is active.
The activity of SDH in anaerobic fiber segments is of enormous relevance here. Recall
that succinate dehydrogenase is not only a component of the respiratory chain: it is also a
component of the TCA cycle. Like three of the other components, it extracts electrons from
a three- or four-carbon molecule and delivers them (via a small carrier molecule) to the
respiratory chain. Unlike those other three, though, the carrier molecule is not NAD but
FAD, which resides inside the succinate dehydrogenase enzyme itself and hands the electrons
on directly to ubiquinone. But the crucial point is that the TCA cycle is a cycle, so that if the
SDH step is happening then all the other steps must also be happening.* One of those steps
phosphorylates a molecule of GDP to GTP, which is then used to make a molecule of ATP
(see Section 2.3.3.2). Thus, by maintaining the TCA cycle, the cell is doubling the amount of
ATP per glucose molecule that it would get from simple glycolysis; moreover, it is able to
metabolise fatty acids productively too. All in all it is far better off than if it were just turning
glucose into lactate.
Another observation is worth mentioning with regard to ρ 0 cells. The stoichiometry of
glycolysis and OXPHOS is well understood, so it is a straightforward matter to calculate
how many times more glucose a ρ 0 cell would have to metabolise in order to grow at the
* In fact this does not strictly follow, since enzymes can function in either direction. Thus it is logically possible
that the activity of SDH in the matrix is compensated by the opposite reaction (succinate synthesis from
fumarate) elsewhere in the cell, in the same way that, for example, the malate/aspartate shuttle involves
malate dehydrogenation in the matrix and malate synthesis in the cytosol. But examination of SDH’s
location in the TCA cycle shows that, in this case, such a shuttle is not an option, since it would require the
import of succinate, for which there is no available mechanism. A more elaborate shuttle, involving some but
not all of the other parts of the TCA cycle, is also prohibited because it would entail the reversal of the step
that makes GTP: that is, no net ATP synthesis would be occurring.
105