Power, Sex, Suicide: Mitochondria and the meaning of life by Nick Lane
Every mitochondrion contains 5 to 10 copies of its genes. Because there are usually hundreds of mitochondria in every cell, there are many thousands of copies of the same genes in each cell, whereas there are only two copies of the genes in the nucleus (the control centre of the cell).
Mitochondrial diseases typically affect metabolically active tissues such as the muscle and brain, producing seizures, some movement disorders, blindness, deafness, and muscular degeneration.
From around the mid 1990s, researchers discovered that apoptosis is not governed by the genes in the nucleus, as had previously been assumed, but by the mitochondria. The implications are important in medical research, for the failure to commit apoptosis when called upon to do so is a root cause of cancer.
They are not composed only of DNA, but are coated in specialized proteins, the most important of which are called histones. This is an important difference with bacteria, for no bacteria coat their DNA with histones: their DNA is naked. The histones not only protect eukaryotic DNA from chemical attack, but also guard access to the genes.
Metabolically active cells, such as those of the liver, kidneys, muscles, and brain, have hundreds or thousands of mitochondria, making up some 40 per cent of the cytoplasm. The egg cell, or oocyte, is exceptional: it passes on around 100 000 mitochondria to the next generation. In contrast, blood cells and skin cells have very few, or none at all; sperm usually have fewer than 100. All in all, there are said to be 10 million billion mitochondria in an adult human, which together constitute about 10 per cent of our body weight.
Mitochondria even have their own ribosomes, the protein-building factories, which are bacterial in appearance. Various antibiotics work by blocking protein assembly in bacteria, and also block protein synthesis in the mitochondria, but not from the nuclear genes in eukaryotes.
The acquisition of mitochondria was the pivotal moment in the history of life.
The Nobel laureate Christian de Duve has long been interested in the origin and history of life. He suggests in a wise final testament, Life Evolving, that the origin of the eukaryotes may have been a bottleneck rather than an improbable event—in other words, their evolution was an almost inevitable consequence of a relatively sudden change in the environmental conditions, such as a rise in the amount of oxygen in the atmosphere and oceans.
Methanogens are also found in the guts of cattle and even people, as the hindgut is exceedingly low in oxygen. The methanogens thrive in vegetarians because grass, and vegetation in general, is low in sulphur compounds. Meat is much richer in sulphur; so sulphate-reducing bacteria usually displace methanogens in carnivores. Change your diet, and you will notice the difference in polite company.
Bacteria generally have far less DNA than even simple single-celled eukaryotes such as yeast. This difference can be measured either in terms of the total number of genes—usually adding up to hundreds or thousands—or the total DNA content. This latter value is known as the C-value, and is measured in ‘letters’ of DNA. It includes not only the genes, but also the stretches of so-called non-codingDNA—DNA that does not code for proteins, and so can’t really be called ‘genes’. The differences in both the number of genes and the C-value are revealing.
Nonetheless, it is a fact, requiring an explanation, that eukaryotes generally have orders of magnitude more DNA than prokaryotes. This is not without a cost. The energy required to copy all this extra DNA, and to ensure it is copied faithfully, affects the rate and circumstances of cell division, with implications that we will explore later.
The third big difference lies in the packing and organization of DNA. As we noted in the Introduction, most bacteria possess a single circular chromosome. This is anchored to the cell wall, but otherwise floats freely around the cell, ready for quick replication. Bacteria also carry genetic ‘loose change’ in the form of tiny rings of DNA called plasmids, which replicate independently and can be passed from one bacterium to another. The daily exchange of loose plasmids in this way is equivalent to shopping with loose change, and explains how the genes for drug resistance spread so quickly in a population of bacteria—just as a coin may find itself in twenty different pockets in a day.
For now, though, the most important take-home point is that there is an energetic cost to all of this complexity. Where bacteria are almost always ruthlessly streamlined and efficient, most eukaryotes are lumbering and labyrinthine.
Then there are the tiny organs within cells, the so-called organelles, such as the mitochondria and the chloroplasts in plants and algae. The chloroplasts are worth a special mention. They are responsible for photosynthesis, the process by which solar energy is converted into the currency of biological molecules, which possess their own chemical energy. Like the mitochondria, the chloroplasts derive from bacteria, in this case the cyanobacteria, the only group of bacteria capable of true photosynthesis (to generate oxygen). It is notable that both mitochondria and chloroplasts were once free-living bacteria, and still retain a number of partially independent traits, including a contingent of their own genes. Both are involved in energy generation for their host cells. Both these organelles are tangibly different from the other membrane systems of eukaryotic cells, and these differences set them apart.
As we noted in the previous chapter, there are potentially big advantages to getting rid of the unwieldy cell wall, not least being able to change shape and engulf food whole by phagocytosis. According to Cavalier-Smith, phagocytosis is the defining feature that set the eukaryotes apart from bacteria.
Like bacteria, archaea are tiny, typically measuring a few thousandths of a millimetre (microns) across, and they do not have a nucleus. Like bacteria, they have a single circular chromosome. Again, like bacteria, the archaea take on many shapes and forms, and so presumably have some sort of cytoskeleton. One reason why they were discovered so recently is that archaea are mostly ‘extremophiles’, that is, they thrive in the most extreme and arcane of environments, from boiling acid-baths beloved of Thermo-plasma, to putrid marshes (inhabited by marsh-gas producing methanogens) and even buried oilfields. In the latter case, the archaea responsible have attracted commercial interest, or rather annoyance, as they ‘sour’ the wells—they raise the sulphur content of oil, which corrodes the well-casings and metal pipelines. Greenpeace could hardly conceive a more wily sabotage.
These unique genes code for forms of energy metabolism (such as the generation of methane gas) and cell structures (such as membrane lipids) that are not found in any other bacteria. The differences are important enough for most scientists to regard the archaea as a separate ‘domain’ of life. This means that we now classify all living things into three great domains—the bacteria, the archaea, and the eukaryotes (which, as we have seen, includes all multicellular plants, animals, and fungi). The bacteria and the archaea are both prokaryotic (lacking a cell nucleus) while the eukaryotes all do have a nucleus.
For example, toxins like diphtheria toxin block protein assembly on ribosomes in both the archaea and eukaryotes, but not in bacteria. Antibiotics like chloramphenicol, streptomycin, and kanamycin block protein synthesis in the bacteria, but not in the archaea or eukaryotes.
All this means the archaea are about as close to a missing link between the bacteria and the eukaryotes as we are ever likely to find.
So there is more to being ‘eukaryotic’ than just lacking a cell wall; but might it be no more complex than lifestyle? Were the ancestral eukaryotes simply wall-less archaea, which modified their existing cytoskeleton into a more dynamic scaffolding that enabled them to change shape and eat food in lumps, by phagocytosis? Might this alone account for how they came by their mitochondria—they simply ate them? And if so, might there still be a few living fossils from the age before mitochondria lurking in hidden corners, relics of those primitive eukaryotes that shared more traits with the archaea?
More than a thousand species of primitive eukaryotes do not possess mitochondria.
The archaea are prokaryotes (without a nucleus), one of the three domains of life, while the archezoa are eukaryotes (with a nucleus) that never had any mitochondria.
other two groups are less deadly but no less smelly. The best-known metamonad is Giardia lamblia, another intestinal parasite. Giardia does not invade the intestinal walls or enter the bloodstream, but the infection is still thoroughly unpleasant, as any travellers who have incautiously drunk water from infected streams know to their cost. Watery diarrhoea and ‘eggy’ flatulence may persist for weeks or months. Turning to the third group, the parabasalia, the best known is Trichomonas vaginalis, which is among the most prevalent, albeit least menacing, of the microbes that cause sexually transmitted diseases (though the inflammation it produces may increase the risk of contracting other diseases such as AIDS). T. vaginalis is transmitted mainly by vaginal intercourse but can also infect the urethra in men. In women, it causes vaginal inflammation and the discharge of a malodorous yellowish-green fluid. All in all, this portfolio of foul ancestors just goes to prove that we can choose our friends but not our relatives.
Even if the original invading bacterium was a parasite, the unbalanced ‘partnership’ may have survived, as long as its unwelcome guest did not fatally weaken the host cell. Many infections today become less virulent over time, as parasites also benefit from keeping their host alive—they do not have to search for a new home every time their host dies. Diseases like syphilis have become much less virulent over the centuries, and there are hints that a similar attenuation is already underway with AIDS. Interestingly, such attenuation over generations also takes place in amoebae such as proteus. In this case, the infecting bacteria initially often kill the host amoebae, but eventually become necessary for their survival.
Oxygen is toxic to anaerobic (oxygen-hating) organisms—it ‘corrodes’ unprotected cells in the same way that it rusts iron nails. If the guest was an aerobic bacterium, using oxygen to generate its energy, while the host was an anaerobic cell (generating energy by fermentation), then the aerobic bacterium may have protected its host against toxic oxygen—it could have worked as an internally fitted ‘catalytic converter’, guzzling up oxygen from the surroundings and converting it into harmless water. Siv Andersson calls this the ‘Ox-Tox’ hypothesis.
groups. Had they, too, once possessed mitochondria? Similar studies were carried out, and so far all the ‘archezoa’ that have been tested turn out to have once possessed mitochondria, and lost them later on. For example, not only did Giardia apparently once have mitochondria, but it, too, may still preserve relics, in the form of tiny organelles called mitosomes, which continue to carry out some of the functions of mitochondria (if not the best known, aerobic respiration). Perhaps the most surprising results concerned the microsporidia. This supposedly ancient group not only did possess mitochondria in the past, but now turns out not to be an ancient group at all—they are most closely related to the higher fungi,
While it remains possible that the real archezoa are still out there, just waiting to be found, the consensus view today is that the entire group is a mirage—every single eukaryote that has ever been examined either has, or once had, mitochondria. If we believe the evidence, then there never were any primitive archezoa. And if this is true, then the mitochondrial merger took place at the very beginning of the eukaryotic line, and was perhaps inseparable from it: the merger was the unique event that gave rise to the eukaryotes.
This team compared complete genome sequences from representatives of each of the three domains of life, and found that eukaryotes possess two distinct classes of genes, which they referred to as informational and operational genes. The informational genes encoded all the fundamental inheritance machinery of the cell, enabling it to copy and transcribe DNA, to replicate itself, and to build proteins. The operational genes encoded the workaday proteins involved in cellular metabolism—in other words, the proteins responsible for generating energy and manufacturing the basic building blocks of life, such as lipids and amino acids. Interestingly, almost all the operational genes came from the α-proteobacteria, presumably by way of the mitochondria, and the only real surprise was how many more of these genes there were than expected—it seems the genetic contribution of the ancestor of the mitochondria was greater than anticipated. But the biggest surprise was the allegiance of the informational genes. These genes lined up with the archaea, as anticipated, but they bore a strong resemblance to the genes in a completely unexpected group of archaea: they were most similar to methanogens, those swamp lovers that shun oxygen and produce the marsh gas methane.
In the same way, the packaging of DNA with histones is so similar in the methanogens and the eukaryotes that the most likely explanation is that they derived the full package from a common ancestor—both were developed from the same prototype.
it seems we inherited both our informational genes and our histone proteins from the methanogens.
Every promising example has turned out not to be a missing link at all, but rather to have adapted to a simpler lifestyle at a later date. The ancestors of all these apparently primitive groups did possess mitochondria, and their descendents eventually lost them while adapting to new niches, often as parasites. It seems possible to be a eukaryote without having mitochondria—there are a thousand such species among the protozoa—but it does not seem possible to be a eukaryote without once having had mitochondria, deep in the past. If the only way to be a eukaryotic cell is via the possession of mitochondria, then it might be that the eukaryotic cell itself was originally crafted from a symbiosis between the bacterial ancestors of the mitochondria and their host cells.
Miklós Müller, from the Rockefeller University in New York. They called their theory the ‘hydrogen hypothesis’, and as the name implies it has little to do with oxygen and much to do with hydrogen. The key, said Martin and Müller, is that hydrogen gas can be generated as a waste product by some strange mitochondria-like organelles called hydrogenosomes. These are found mostly among primitive single-celled eukaryotes, including parasites such as Trichomonas vaginalis, one of the discredited ‘archezoa’. Like mitochondria, hydrogenosomes are responsible for energy generation, but they do this in bizarre fashion by releasing hydrogen gas into their surroundings.
For now, lets simply note that the ‘hydrogen hypothesis’ of Martin and Müller argues that it was the hydrogen metabolism of this common ancestor, not its oxygen metabolism, which gave the first eukaryote its evolutionary edge.
hydrogen is hard to come by in any environment containing oxygen, as hydrogen and oxygen react together to form water.
4 Hydrogen hypothesis. Simplified schematic showing the relationship between a versatile bacterium and a methanogen. (a) The bacterium is capable of different forms of aerobic and anaerobic respiration, as well as fermentation to generate hydrogen; under anaerobic conditions the methanogen makes use of the hydrogen and carbon dioxide given off by the bacterium. (b) The symbiosis becomes closer as the methanogen is now dependent on hydrogen produced by the bacterium, which is gradually engulfed, (c) The bacterium is now completely engulfed. Gene transfer from the bacterium to the host enables the host to import and ferment organics in the same way as the bacterium, freeing it from its commitment to methanogenesis. The dashed line indicates that the cell is chimeric.
So the answer to the question of life, the universe, and everything, or the origin of the eukaryotic cell, was simply gene transfer. Through a series of small and realistic steps, the hydrogen hypothesis explains how a chemical dependency between two cells evolved to become a single chimeric cell containing organelles that function as mitochondria.
As atmospheric oxygen levels rose, so too did the sulphate concentration of the oceans (because the formation of sulphate, SO42-, requires oxygen).
As I discussed in an earlier book, Oxygen: The Molecule that Made the World, what actually happens is this. The foul sulphurous fumes emanating from volcanoes contain sulphur in forms such as elemental sulphur and hydrogen sulphide. When this sulphur reacts with oxygen, it is oxidized to produce sulphates. This is the same problem we face today with acid rain—the sulphur compounds released into the atmosphere from factories become oxidized by oxygen to form sulphuric acid, H2S04. The ‘S04’ is the sulphate group, and it is this group that the sulphate-reducing bacteria need to oxidize hydrogen—which in chemical terms is exactly the same thing as reducing the sulphate, hence the name of the bacteria. Here is the rub. When oxygen levels rise, sulphur is oxidized to form sulphates, which accumulate in the oceans—the more oxygen, the more sulphate. This is the raw material needed by the sulphate-reducing bacteria, which convert sulphate into hydrogen sulphide. Although a gas, hydrogen sulphide is actually heavier than water, and so it sinks down towards the bottom of the oceans. What happens next depends on the dynamic balance in the concentrations of sulphate, oxygen, and so on. However, if hydrogen sulphide is formed more rapidly than oxygen in the deep oceans (where photosynthesis is less active because sunlight does not permeate down) then the outcome is a ‘stratified’ ocean. The best example today is the Black Sea. In general, in stratified oceans the depths become stagnant, reeking of hydrogen sulphide (or technically, ‘euxinic’),
Gram per gram, even when sitting comfortably, you are converting 10000 times more energy than the sun every second.
hero of bioenergetics, Peter Mitchell, who won the Nobel Prize for chemistry in 1978, is hardly a household name, even though he ought to be as well known as Watson and Crick.
The combustion of glucose in respiration is an electrochemical reaction—an oxidation to be precise. By today’s definition, a substance is oxidized if it loses electrons. Oxygen (02) is a strong oxidizing agent because it has a strong chemical ‘hunger’ for electrons, and tends to extract them from substances such as glucose or iron. Conversely, a substance is reduced if it gains electrons. Because oxygen gains the electrons extracted from glucose or iron, it is said to be reduced to water (H20). Notice that in forming water each atom of the oxygen molecule also picks up two protons (H+) to balance the charges. Overall, then, the formation of water equates to the transfer of two electrons and two protons—which together make up two whole hydrogen atoms—from glucose to oxygen.
One compound that was known to contain iron, and to bind to oxygen reversibly, was haemoglobin, the pigment that imparts the colour to red blood cells; and it was the colour of blood that gave the first clue to how respiration actually works in living cells. Pigments such as haemoglobin are coloured because they absorb light of particular colours (bands of light, as in a rainbow) but allows through (transmits) light of other colours. The pattern of light absorbed by a compound is known as its absorption spectrum. When binding oxygen, haemoglobin absorbs light in the blue-green and yellow parts of the spectrum, but transmits red light, and this is the reason why we perceive arterial blood as a vivid red colour. The absorption spectrum changes when oxygen dissociates ftom haemoglobin in venous blood. Deoxyhaemoglobin absorbs light across the green part of the spectrum, and transmits red and blue light. This gives venous blood its purple colour.
Keilin named the pigments cytochromes (for cellular pigments) and labelled them a, b, and c, according to the position of the bands on their absorption spectra. These labels are still in use today.
independent. 5 Simplified representation of the respiratory chain, showing complexes I, III, and IV, and the ATPase. Complex II is not shown here, as electrons (e-) enter the chain at either complex I or complex II, and are passed on from either of these complexes to complex III by the carrier ubiquinone (also known as Coenzyme Q, sold in supermarkets as a health food supplement, though with questionable efficacy). The passage of electrons down the chain is illustrated by the curvy line. Cytochrome c carries electrons from complex III to complex IV (cytochrome oxidase) where they react with protons and oxygen to form water. Notice that all of the complexes are embedded separately in the membrane. Whereas ubiquinone and cytochrome c shuttle electrons between the complexes, the nature of the intermediate that connected electron flow down the respiratory chain with ATP synthesis in the ATPase was a mystery that confounded the field for an entire generation.
Indeed Pasteur famously described fermentation as ‘life without oxygen’.
Buchner proposed that fermentation was carried out by biological catalysts that he named enzymes (from the Greek en zyme, meaning in yeast).
So the three great energy highways of life, respiration, fermentation, and photosynthesis, all generate ATP, another profound example of the fundamental unity of life.
This curious phenomenon is not simply a matter of mechanical damage to the membrane: it can also be induced by a number of apparently unrelated chemicals, known as uncouplers, which do not mechanically disrupt the membrane. All these chemicals (including, interestingly, aspirin and, indeed, ecstasy) uncouple the oxidation of glucose from the production of ATP in a similar fashion, but did not seem to share any kind of chemical common denominator.
The ATPase is freely reversible. Under some circumstances it can go into reverse, whereupon it splits ATP, and uses the energy released to pump protons up the drive shaft, back across the membrane against the pressure of the reservoir. In fact the very name ATPase (rather than ATP synthase) signifies this action, which was discovered first.
However, if respiration fails, then bacteria generate ATP by fermentation. Now everything goes into reverse. The ATPase immediately breaks down the freshly made ATP and uses the energy released to pump protons across the membrane, maintaining the charge—which amounts to an emergency repair of the force field. All other ATP-dependent tasks, even those as essential as DNA replication and reproduction, must wait. In these circumstances, it might be said that the main purpose of fermentation is to maintain the proton-motive force. It is more important for a cell to maintain its proton charge than it is to have an ATP pool available for other critical tasks such as reproduction.