The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
that membranes need in order not to rupture. There is a trade-off here with regard to
oxidisability, as was explained in Section 3.9.
Mitochondria also have a lot of a diphospholipid called cardiolipin (so named because
it was first discovered in the heart). Cardiolipin is formed by joining two copies of the simplest
phospholipid, phosphatidate, at their phosphates; its molecular structure is shown in Figure
4.1. Cardiolipin is the only anionic lipid present in significant amounts in the inner
mitochondrial membrane, and its concentration decreases with age; 1 this change has been
shown to cause reduced performance of certain membrane proteins. 1,2 A possible mechanism
for this effect is that loss of cardiolipin causes an increase in the pH of the water right next
to the membrane (see Section 11.2.2), which may markedly affect mitochondrial function
(see Section 11.3.7).
All membranes also have a component which is rather more distantly related to fats: it
is classed as a lipid, but unlike phospholipids it is not derived from fats but instead is built
from scratch in the liver, as well as being extracted from food by epithelial cells in the gut. It
is cholesterol. Cholesterol (see Fig. 4.2 for structure) is a steroid, a molecule only about half
the length of the average phospholipid, and its presence in membranes increases their fluidity,
which is necessary to keep them intact. Cells in culture that have been genetically modified
to lack cholesterol are very prone to suffer membrane rupture, 3 which is of course instantly
fatal to the cell; the same effect has been shown in red blood cells. 4
4.2. Synthesis and Transport of Fatty Acids and Cholesterol
Most of our cells, despite needing cholesterol so vitally, do not make it themselves—at
least, not in the quantity they need. 5 They are also rather ineffective at destroying it (or
packaging it away) when they transiently need less of it, though they do package it to some
extent. They can afford this because a few types of cell, particularly ones in the liver and in
the gut, have a very high capacity for cholesterol synthesis and degradation (for liver) or
absorption and release (for gut), and can therefore buffer the less capable cells elsewhere.
But in order to achieve this buffering, the liver and gut cells must somehow exchange
cholesterol with all other cells. They do this via the blood stream. Cholesterol is secreted by
the liver and gut and imported by other cells in a particle called a low-density lipoprotein,
or LDL;* and it is transported the other way in a similar (but easily distinguishable
biochemically) particle called a high-density lipoprotein (HDL). 6 Both of these transport
processes are highly regulated by the cells that are doing the import and export. The particles
themselves are also highly structured, being organised around a protein scaffolding (just
one big polypeptide in the case of LDL; many more for HDL) and being wrapped in a coat
of phospholipid, which is necessary in order to allow the particle to move freely in the
blood, since it makes the particle more water-soluble. 7
A similar situation exists for fatty acids. Most cells are capable of building the
phospholipids (and related molecules) that they need, but not from absolute scratch: they
need the component fatty acids to be supplied in the blood. Fatty acids are present in LDL,
as explained above, but the amount of LDL imported (or HDL exported) is fixed by the
cell’s cholesterol requirements and is thus not (necessarily) adequate for the cell’s fatty acid
requirements. Most fatty acid is acquired by a different mechanism: it circulates in the blood
bound to albumin, which mediates its uptake by cells. 8 In contrast to cholesterol, however,
there is no “reverse transport” system to rid the cell of excess fatty acid: this is not necessary,
* Strictly, what the liver and gut secrete into the blood is not LDL but precursors of it, called chylomicrons
(from the gut) and VLDL, very low density lipoprotein (from the liver). These are converted to LDL by an
enzyme called lipoprotein lipase. 7