Power, Sex, Suicide: Mitochondria and the Meaning of Life (68 page)

Wilson, E. B. 14

Woese, Carl 40, 41, 42–3

Wolbachia
(sex-determining parasite) 230, 238–9

Woodruff, William 164–6, 168

work, energy requirement of 72

World Trade Center, identification of victims 4

Wright, Alan 297–9, 300

Wyllie, Andrew 203–4, 205

Wynne-Edwards, Vero 191

Zamzami, Naoufal 208

¹
In 1998, Johannes Hackstein and his colleagues at the University of Nijmegen in Holland discovered a hydrogenosome that had retained its genome, albeit a small one. The isolation of this genome deserved a medal: the hydrogenosome belonged to a parasite that could not be grown in culture and so had to be ‘micro-manipulated’ from its comfortable home in the hind-gut of cockroaches. Having achieved the unthinkable, Hackstein’s group published the complete gene sequence in
Nature
in 2005, and confirmed that hydrogenosomes and mitochondria do have a common -proteobacterial ancestor.

¹
Respiration can be stopped by exposing cells to carbon monoxide in the dark, and started again by illuminating the cells, which causes carbon monoxide to dissociate. Warburg reasoned that the speed of respiration would depend on the speed at which carbon monoxide (CO) dissociated after illumination. If he shone light at a wavelength readily absorbed by the ferment, CO would dissociate quickly, and he would measure a quick rate of respiration. On the other hand, if the ferment did not absorb light at a particular wavelength, CO would not dissociate and respiration would remain blocked. By illuminating the ferment with 31 different wavelengths of light (generated by flames and vapour lamps), and measuring the rate of respiration in each case, Warburg pieced together the absorption spectrum of the ferment.

²
Sir Hans Krebs received the Nobel Prize in 1953 for elucidating the cycle, although many others contributed to a detailed understanding. Krebs’ seminal paper on the cycle in 1937 was rejected by
Nature
, a personal set-back that has since encouraged generations of disappointed biochemists. In addition to its central role in respiration the Krebs Cycle is also the cell’s starting point for making amino acids, fats, haems, and other important molecules. I regret this is not the place to discuss it.

¹
No microbes are truly independent of the sun’s energy. All life on earth, even the microbes in the deep hot biosphere, gains its energy from redox reactions. These are only made possible because the oceans and air are out of chemical equilibrium with the earth itself—an imbalance that depends on the oxidizing power of the sun. The microbes of the deep hot biosphere make use of redox reactions that would not be possible were it not for the relative oxidation of the oceans, ultimately attributable to the sun. One reason that their metabolism and turnover is so slow—a single cell may take a million years to reproduce—is that they are dependent on the desperately slow trickle-down of oxidized minerals from further up.

¹
In his excellent book
Mendel’s Demon
, Mark Ridley muses about the need for a merger in the evolution of the eukaryotic cell: was it a fluke, along with the retention of a contingent of mitochondrial genes? Could the eukaryotes have evolved without such a merger? Ridley argues that both the merger and the retention of genes were probably flukes. I disagree, but for an alternative view I can strongly recommend his book.

¹
Technically the periplasm refers to the space between the inner and outer cell membranes of Gram-negative bacteria. These are named after the way in which they are coloured by a particular stain known as the Gram stain. Bacteria that are coloured by this stain are called Gram-positive; bacteria that are not stained are called Gram-negative. This odd behaviour actually reflects differences in the cell wall and the cell membrane. Gram-negative bacteria have two outer cell membranes and a thin cell wall, which is contiguous with the outer cell membrane. In contrast, Gram-positive bacteria have a thicker cell wall, but only one cell membrane. Technically, then, only Gram-negative bacteria have a periplasm, because only Gram-negative bacteria have a space between their two cell membranes. However, both types of bacteria have a cell wall, which encloses a space that lies outside the cell but inside the wall. For simplicity I shall refer to this space as the periplasm, because it fulfils many of the same purposes in all bacteria, despite their differing structures.

²
Thermoplasma
are variable in size, but usually quite large, spherical cells with a small genome. If they live in strong acid, and need to restrict the entry of protons into the cell, they could do this by lowering their surface-area to volume ratio—i.e., by being large and spherical in shape. Large size, of course, undermines the efficiency of respiration, which might explain the small genome size. It would be interesting to know whether cell volume in
Thermoplasma
correlates with the acidity of their surroundings.

³
Fermentation presents some interesting dilemmas, for although it is far less efficient than respiration, in terms of the quantity of ATP generated from one molecule of glucose, it is also faster—it produces more ATP in a short space of time. This means that cells growing by fermentation can out-compete those growing by respiration for the same resources. Exactly how this works out in reality, however, is less certain, as fermentation can’t complete the oxidation of molecules like glucose, but rather releases waste products like alcohol into the surroundings, to our own benefit. Of course, this is also to the benefit of any cells that can burn alcohol, which is to say, are capable of respiration. So, like the hare and the tortoise, it may be that respiration, though slower, pays dividends in the end. In terms of phagocytosis, running out of energy in ‘mid-bite’ may be more detrimental than biting slowly. A second interesting possibility is that respiration actually
encouraged
the evolution of multicellular organisms, as they were large enough to hoard any raw materials, to prevent the fermenting cells from frittering them away first.

¹
One question is how the cell interprets a signal to ‘know’ that more cytochrome oxidase is needed. A free-radical signal is also produced if there is a low demand for ATP: electrons then back up in the respiratory chains, which leak radicals, but the situation is not improved by adding new complexes: there is still a low demand for ATP, and electron flow remains sluggish. But the cell can detect ATP levels, and so in principle could combine two signals: ‘high ATP’ with ‘high free radicals’. An appropriate response would now be to dissipate the proton gradient, to maintain electron flow (see
Part 2
,
page 92
). There is evidence that this happens. In contrast, if there were not enough respiratory complexes, then ATP levels would decline and electrons again would back-up in the respiratory chains. Now the signal would combine ‘low ATP’ with ‘high free radicals’. Such a system could in theory discriminate the need for more respiratory complexes from low demand.

¹
How do we reconcile Max Rubner’s exponent of 2/3 with Max Kleiber’s 3/4? The usual answer is that within species the metabolic rate does indeed vary with 2/3, and the 3/4 exponent only becomes apparent when we compare different species.

²
In fact they make a specific prediction based on this. The presence of a network obliges individual mitochondria to operate more slowly than they would if they were relieved from the constraints of the network. When grown in culture, cells have a lavish supply of nutrients delivered to them directly from the surrounding medium: there is no network, so cells can’t be constrained by it. If unconstrained, the metabolic rate should rise. On this basis, West, Woodruff, and Brown calculate that cultured mammalian cells should become more metabolically active in culture, and they predict that cells should contain approximately 5000 mitochondria after several generations in culture, each with about 3000 respiratory complexes. These numbers seem wrong. Mammalian cells tend to adapt to culture by
losing
mitochondria, becoming instead dependent on fermentation to provide energy, giving off the waste product lactate. Accumulation of lactate is known to impede the growth of mammalian cell cultures. As to the number of respiratory complexes in a single mitochondrion, most estimates are in the order of 30 000, not 3000. Far from ‘agreeing with observation’, West, Woodruff, and Brown’s estimate appears to be an order of magnitude out.

³
Another re-analysis, published in 2003 by Craig White and Roger Seymour, at the University of Adelaide, came to a similar conclusion.

¹
Lizards are sluggish when cold (as are torpid mammals or birds), and so vulnerable to predators. The earless lizard finds a way around this problem by using a blood sinus on top of its head. In the mornings, it pokes its head out of its burrow, and remains there, keeping a wary eye out for predators, ready to duck back inside if necessary. It can warm its whole body via the blood sinus on its head, and only when warm and up to speed does it venture out. Natural selection never misses a trick: some lizards have a connection from this sinus to the eyelids, through which they can squirt blood at predators, especially dogs, who find the taste repugnant.

²
The scaling equation is given as metabolic rate = aM
^b
in which
a
is a species-specific constant,
M
is the mass, and
b
is the scaling exponent. The constant
a
is fivefold greater in mammals than in reptiles, but both groups still scale with size (the lines are parallel). The fractal model can’t explain why different species should have different
a
constants, in other words why the resting metabolic rate and capillary density in various organs is different in mammals and reptiles; nor can it explain the rise of endothermy. The explanation again lies in the tissue demand for more oxygen to power greater aerobic performance: this is the driving force that leads to the remodelling of muscle and organ architecture, and with it the fractal supply network.

³
In respiration, ATP is formed from ADP and phosphate, and during cellular work it is converted back to them. If all the cell’s ADP and phosphate has already been converted to ATP, then there is a shortage of raw materials, which means that respiration must come to a halt. Once the cell has consumed some ATP, more ADP and phosphate are formed, and respiration starts again. Thus the speed of respiration is tied to the demand for ATP.

⁴
Some marsupials, such as kangaroos, are capable of moving at great speeds despite a low resting metabolic rate. They can do this because hopping differs from running, in that oxygen consumption tapers off with speed—they can hop faster and faster without consuming more and more oxygen. Hopping is more efficient because it makes use of the elastic rebound, which can be dissociated from aerobic muscle contraction to some extent.

¹
These ideas attract passionate devotees, some of whom will doubtless feel that because Lynn Margulis is a visionary who has proved an entire field wrong before, then she is necessarily right. Another of my heroes, Peter Mitchell, revolutionized biochemistry, but towards the end of his life was proved completely wrong about several aspects of his own theory. Likewise, I fear Margulis is plain wrong to condemn neo-Darwinism as irrelevant.

¹
The caspase cascade amplifies a signal through the action of enzymes. An enzyme is a catalyst, which acts on a substrate but is unchanged itself, enabling it to act on many substrates. If these substrates are themselves enzymes, activated by the first enzyme, then each step amplifies the response. If the first enzyme activates 100 secondary enzymes, and each of these activates 100 executioners, then we would have an army of executioners 10 000 strong—each of which is also an enzyme that strikes repeatedly. Add in another intermediary step and we have a caspase army a million strong.

²
Some forms of the extrinsic pathway of apoptosis, mediated by the death receptors, do bypass the mitochondria altogether, but these are likely to be refinements to the original pathway, which probably did involve mitochondria; otherwise it is hard to explain why most forms of the extrinsic pathways do involve mitochondria.

¹
As we noted in
Part 4
, there is a way out of high free-radical production when the chain is blocked, and that is to uncouple electron flow from ATP production (see also
Part 2
,
page 92
). The proton gradient is dissipated as heat, which reduces free-radical production and may have contributed to the evolution of endothermy.

¹
Here is Bryan Sykes in
The Seven Daughters of Eve
: ‘The control region mutations are not eliminated precisely because the control region has no specific function. They are neutral. It appears that this stretch of DNA has to be there in order for mitochondria to divide properly, but that its own precise sequence does not matter very much.’

²
In fact modern humans do carry a similar sequence in their nuclear DNA—a
numt
that had been transferred from the mitochondria to the nucleus (see
page 132
) long ago. The sequence amounts to a DNA fossil, as the mutation rate in the nucleus is some 20 times slower than in the mitochondria; it has therefore remained relatively unchanged.

³
This includes the supposedly neutral control region: if recombination does not take place then the entire mitochondrial genome is a single unit, and the control-region sequences can be eliminated in a non-random manner because they are linked to regions that
do
undergo selection. And in fact it would be surprising if the control region was not subject to direct selection, as it binds factors responsible for transcribing mitochondrial proteins—a task as important as their very existence, for they may as well not exist if they are not transcribed when needed. In 2004, Wallace and colleagues showed that some control-region mutations might indeed have detrimental consequences—some are linked with Alzheimer’s disease.