The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
dissipated. So, if the respiratory chain were generating such a disparity, then the ATP synthase
could be drawing on it for energy to make ATP, and there would be absolutely no need for
the chemical link that had so long been sought. In Mitchell’s own words: “The elusive
character of the ‘energy-rich’ intermediates of the orthodox chemical coupling hypothesis
would be explained by the fact that these intermediates do not exist.” 21
Most specialists found Mitchell’s hypothesis unattractive at first, but experimental data
in support of it eventually emerged from other labs 22 and it is now universally accepted.*
The ion in question is simply the proton: Complexes I, III and IV (but not the FAD-linked
enzymes) all extract energy (by “normal,” chemical bond-making and -breaking processes)
from the electrons they are shuttling, and use this energy to translocate protons from inside
the inner membrane to outside to create the required disparity. (The movement of water
across the membrane, noted in Section 2.3.2.4, does not affect this.) These protons return
into the mitochondrion through Complex V, and the potential energy that they release in
doing so is converted into the creation of the bond between ADP and phosphate that makes
ATP (see Fig. 2.8). This situation can equally be described in terms of force rather than
energy; Mitchell named the force generated by the respiratory chain, which drives the ATP
synthase, the proton-motive force.
Exactly how the respiratory chain proteins move the protons, and how the ATP synthase
constructs ATP, are still matters of intense research. For example, Mitchell proposed in
1975 a mechanism of action for the simplest proton-pumping respiratory chain enzyme,
Complex III, 23 and his hypothesis—the Q cycle—is still broadly accepted, but there are
some details of it that may need to be revised, 24 and new hypotheses are still emerging to fill
in its details at the level of enzymatic binding of substrates. 25-27 Recent progress has been
most dramatic with regard to ATP synthase, which is now known 28,29 to work as a turbine,
with the centre of the complex rotating within the rest of it.
2.3.5. A Note About Other Energy-Transducing Biological Systems
The release of energy from sugars, by combining them with oxygen, is—to a first
approximation—the reverse of photosynthesis, the process by which plants (using organelles
also derived by endosymbiosis, chloroplasts) construct sugars and oxygen from carbon
dioxide and water, using sunlight as their energy source. It is thus no surprise, given the
ubiquitous reversibility of enzymes, that the machinery of chloroplast photosynthesis is
very similar to that of respiration. Likewise, bacteria have energy-transducing systems which
exhibit strong similarities to those of mitochondria. Comparisons between mitochondria
and these other systems (chloroplasts, in the case of plants) might in principle be useful, as
are, for example, comparisons between mitochondria of different animal species (which
will be the topic of Section 6.5.3). But not in practice. I have found that the differences
between mitochondria and their non-animal counterparts are in fact more confounding
than helpful, so I will not introduce them.
2.4. Mitochondrial DNA, or mtDNA
2.4.1. The Discovery of Mitochondrial DNA
In about 1961, as Mitchell was elucidating the fundamentals of mitochondrial function,
a surprising discovery was made regarding mitochondrial structure. I say “about,” because
this discovery was one of the messy ones which it is not really fair to attribute to a particular
* This universal acceptance applies to the “core” chemiosmotic hypothesis set out in 1961, but there is still
deep disagreement regarding refinements of it which were first made explicit in 1966. We will explore this
topic in Section 11.3.