The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
2.3.2. Preliminaries to Mitochondrial Function
Mitochondria are really quite simple machines, by biological standards. They are only
able to make ATP starting from a few very simple molecules. Therefore, in order that we can
extract energy from the vast range of available foodstuffs, a great deal of preprocessing has
to occur in order to reduce them to these few common denominators.
2.3.2.1. Precursors of ATP Synthesis: Digestion
The most obvious molecular difference between our various foodstuffs is molecular
size. Some of the molecules we digest, such as starch, are enormous; others, like glucose, are
relatively tiny. The first step in reducing the variety of molecules is to break down the bigger
ones into three basic types of smaller molecule: amino acids, fatty acids and monosaccharides.
This happens in the gut and involves neither the construction nor destruction of ATP.
2.3.2.2. ATP Synthesis, But Not Much: Glycolysis
One of the three types of product of digestion, monosaccharides, provides a
source—albeit only a modest one—of ATP without the help of mitochondria, and without
the help of oxygen. A sequence of ten (give or take one—see Fig. 2.3) enzyme-catalysed
reactions can split the simplest monosaccharide, glucose, into two molecules of pyruvate
or lactate (i.e., pyruvic or lactic acid—see Section 2.3.1.1.), and one of those reactions also
makes ATP.
Glycolysis is enough to keep human cells happy for a short while, when there is a transient
shortage of oxygen, but it is not adequate in the long term, not least because lactate is
somewhat toxic. Some single-celled organisms can get along indefinitely with glycolysis,
though; they simply excrete the final product (lactate or ethanol).
2.3.2.3. Breakdown of Amino Acids and Fatty Acids
Amino acids are not amenable to glycolysis-like reactions: without mitochondria they
cannot be used as energy sources at all. Their breakdown need not, in fact, be discussed
further. This is partly because they are only used for ATP production in emergency, when
no other energy source is available, and partly because the way that the cell makes them
available to mitochondria as an energy source is by turning them into pyruvate (exactly
the same molecule that is created by glycolysis), or else into one of the molecules that
mitochondria make from pyruvate in the process of breaking it down further. Therefore,
all the ATP-synthesising reactions involved in amino acid breakdown will be covered in
the discussion of pyruvate breakdown (below).
Fatty acids, similarly, are first broken down (by a sequence of reactions involving the
incorporation of water) into several molecules of acetaldehyde, one of the products of
pyruvate breakdown, so their contribution to ATP will also implicitly be covered below. In
fact this happens inside mitochondria (see Section 2.3.3.1), but again it is not linked to any
ATP synthesis.
2.3.2.4. Transport of Metabolites Across the Mitochondrial Inner Membrane
The subsequent processes involved in ATP synthesis, whose description will occupy the
rest of Section 2.3, all happen in mitochondria. It is therefore necessary to transport pyruvate
(the product of glycolysis that mitochondria use), fatty acids, protons and NADH across the
mitochondrial inner membrane. Pyruvate and fatty acids are each transported by a specialised
carrier protein, the fatty acid one involving the cofactor carnitine. Protons move across
without any active carrier, since the membrane is somewhat permeable to water (their
reservoir). 12 The two NADH molecules created by glycolysis are actually not transported
through the membrane; instead, they pass their electrons to other NAD + molecules that are