Power, Sex, Suicide: Mitochondria and the Meaning of Life (58 page)

There are ways of modulating electron flow down the respiratory chains, so these dire penalties don’t happen whenever electron flow temporarily comes to a halt. The most important is to
uncouple
the chains (so the passage of electrons is not tied to the formation of ATP). Uncoupling is usually achieved by making the membrane more permeable to protons, so their passage back across the membrane is not strictly through an ATPase (the enzyme ‘motor’ that is responsible for generating ATP). The effect is akin to the overflow channels in a hydroelectric dam, which prevent flooding at times of low demand. The continuous circulation of protons allows a continuous passage of electrons down the respiratory chains, without regard for ‘need’, and this prevents the accumulation of electrons in the respiratory chains and so restricts free-radical leakage. But the dissipation of the proton gradient necessarily generates heat, and this too has been put to good use over evolution. In most mitochondria, about a quarter of the proton-motive force is dissipated as heat. When enough mitochondria are assembled, as in the tissues of mammals and birds, the heat generated is sufficient to maintain a high internal temperature, regardless of the external temperature. The origin of endothermy, or true warm-bloodedness, in birds and mammals can be ascribed to such dissipation of the proton gradient, which later made possible the colonization of the temperate and frigid regions, as well as an active nightlife. It released our ancestors from the tyranny of circumstance.

The balance between heat generation and ATP production still affects our health in surprising ways. Uncoupling of the respiratory chain is restricted in the tropics, because too much internal heat production would be detrimental in a hot climate: we could very easily overheat and die. However, this means that the ‘overflow channels’ are partially sealed off, so more free radicals are generated at rest, especially on a high-fat diet. This makes Africans eating a fatty western diet more vulnerable to conditions such as heart disease and diabetes, which are linked with free-radical damage. Conversely, the Inuit, who
have a low incidence of such diseases, dissipate the proton gradient to generate extra internal heat in the frozen north. Accordingly, they have a relatively low free-radical leakage at rest and are less vulnerable to degenerative diseases. On the other hand, dissipating energy as heat is counterproductive in sperm, which depend on the energetic efficiency of a small number of mitochondria to power their swimming. This gives the Arctic peoples a potentially higher risk of male infertility.

In all of these circumstances, free radicals are the signal for change. The respiratory chains act like a thermostat: if free-radical leakage rises, one of several mechanisms cuts in to lower their level again, then switches itself off, just as the fluctuations in temperature switch the boiler on and off in a thermostat. In the case of the respiratory chains, free radicals are almost certainly detected in concert with other indicators of the overall ‘health status’ of the cell, such as ATP levels. So a rise in free-radical leakage set against falling ATP levels within one mitochondrion is the signal to build new subunits for the respiratory chains; if ATP levels are high, free radicals are the signal for greater uncoupling, or perhaps for sex in unicellular eukaryotes; and a sustained, uncorrectable rise in free-radical leakage set against falling cellular ATP levels is the signal for cell death in multicellular individuals. In each case, fluctuations in free-radical leakage are as indispensable to the feed-back loop as are the temperature fluctuations to a thermostat: free radicals are vital to life, and attempting to get rid of them, for example using antioxidants, is folly. This simple fact has forced two other major innovations on life: the origin of two sexes, and the decline and fall of organisms into ageing and death.

Free radicals are reactive and cause damage and mutations, especially to the adjacent mitochondrial DNA. In lower eukaryotes, like yeast, mitochondrial DNA acquires mutations approximately 100 000 times faster than nuclear genes. Yeasts can sustain such a high rate because they don’t depend on mitochondria to generate energy. The mutation rate is far lower in the higher eukaryotes, such as humans, because we do depend on our mitochondria. Mutations in mitochondrial DNA cause serious diseases, and tend to be eliminated by natural selection. Even so, the long-term evolution rate of mitochondrial genes, over thousands or millions of years, is between 10 and 20 times faster than nuclear genes. What’s more, the nuclear genes are reshuffled every generation to give a new hand of genes. These disparate patterns set up a serious strain. The subunits of the respiratory chain are encoded by both nuclear and mitochondrial genes, and to function properly must interact with nanoscopic precision: any changes in gene sequence might change the structure or function of the subunits, and could potentially block electron flow. The only way to guarantee efficient energy generation is to match a single set of mitochondrial genes with a single set of nuclear genes in a cell, and test-drive
the combination. If it crashes, the combination is eliminated; if it drives well, the cell is selected as a feasible progenitor for the next generation. But how does a cell select a single set of mitochondrial genes to test against one set of nuclear genes? Simple: it inherits its mitochondria from just one of the two parents. As a result, one parent specializes to pass on the mitochondria, in the large egg cell, whereas the other parent specializes to pass on no mitochondria—which is why sperm are so small, and why their handful of mitochondria are usually destroyed. Thus, the origin and deepest biological distinction between the two sexes, indeed the main reason for having two sexes at all, rather than none or an infinite number, relates to the passage of mitochondria from one generation to the next.

A similar problem occurs during adult life. This is the basis of ageing and the related degenerative diseases that all too often eclipse our twilight years. Mitochondria accumulate mutations through use, especially in active tissues, and these gradually undermine the metabolic capacity of the tissue. Ultimately, cells can only boost their failing energy supply by producing more mitochondria. As the supply of mint mitochondria dries up, cells are obliged to clone genetically damaged mitochondria. Cells that amplify seriously damaged mitochondria face an energy crisis and take the honourable exit—they commit apoptosis. Because damaged cells are eliminated, mitochondrial mutations don’t build up in ageing tissues, but the tissue itself gradually loses mass and function, and the remaining healthy cells are under a greater pressure to meet their demands. Any additional stresses, such as nuclear gene mutations, smoking, infections, and so on, are more likely to push cells over the threshold into apoptosis.

Mitochondria calibrate the overall risk of apoptosis, which rises with age. A genetic defect that causes little stress to a young cell causes far more stress to an old cell, simply because the old cell is by now closer to its apoptotic threshold. Age, however, is not measured in years, but in free-radical leakage. Species that leak free radicals quickly, such as rats, live for a few years and succumb to age-related diseases within this brief timeframe. Species that leak free radicals slowly, like birds, may live ten times as long and succumb to degenerative diseases over this long timeframe, although they often die of other causes (such as crash landings) before these diseases set in. Critically, birds (and bats) live longer without sacrificing their ‘pace of life’—their metabolic rate is similar to mammals that live but a tenth as long. The same mutations in nuclear genes cause the same age-related diseases in different species, but the rate at which they progress varies by orders of magnitude—and tallies with the underlying rate of free-radical leakage. It follows that the best way to cure, or at least postpone, the diseases of old age is to restrict free-radical leakage from the respiratory chains. This approach has the potential to cure
all
diseases of old
age at once, rather than trying to tackle each independently, a tack that has so far failed to deliver a really meaningful clinical breakthrough, and is perhaps destined never to do so.

In sum, mitochondria have shaped our lives, and the world we inhabit, in ways that defy belief. All these evolutionary innovations stem from a handful of rules guiding the passage of electrons down the respiratory chains. Remarkably, we can elucidate all this after two billion years of intimate adaptations. We can do so because, despite their changes, mitochondria have retained distinctive imprints of their heritage. These clues have enabled us to trace the outlines of the story that we have followed in this book. The story is grander, more monumental, than any researcher could ever have guessed until recently. It is not the story of an unusual symbiosis, nor the tale of biological power, the industrial revolution of life. No, it is the story of life itself, not merely on Earth, but anywhere in the universe, for the morals of this story relate to the operating system that governs the evolution of all forms of complex life.

Mankind has always looked to the stars, and wondered why we are here, whether we are alone in this universe. We ask why our world is alive with plants and animals, and what were the chances against it; where we came from, who our ancestors were, what our destiny holds in store. The answer to the question of life, the universe and everything is not 42, as Douglas Adams once had it, but an almost equally cryptic shorthand: it is
mitochondria
. For mitochondria teach us how molecules sprang to life on our planet, and why bacteria dominated for so long. They show us why bacterial sludge is likely to be the climax of evolution across this lonely universe. They teach us how the first genuinely complex cells came into being, and why, since then, life on Earth has ascended a ramp of complexity to the glories we see around us, the great chain of being. They show us why energy-burning, warm-blooded creatures arose, thrusting off the shackles of the environment; why we have sex, two sexes, children, why we must fall in love. And they show us why our days in this firmament are numbered, why we must finally grow old and die. They show us, too, how we might better our twilight years, to stave off the misery of old age that curses humanity. If they don’t show us the meaning of life, they do at least make some sense of its shape. And what is meaning in this world, if it doesn’t make sense?

Antioxidant
any compound that protects against biological oxidation, either directly by becoming sacrificially oxidised itself in place of other molecules, or indirectly by catalysing the decomposition of biological oxidants.

Apoptosis
programmed cell death, or cell suicide; a finely orchestrated and carefully controlled mechanism for removing damaged or unnecessary cells from a multicellular organism.

Archaea
one of the three great domains of life, the other two being the eukaryotes and the bacteria; the archaea are similar to bacteria in their appearance down the microscope, but share a number of molecular similarities with the more complex eukaryotic cells.

Archezoa
a disparate group of single-celled eukaryotic organisms that lack mitochondria; at least some were originally thought never to have had any mitochondria at all, but now all are believed to have possessed mitochondria in their past, and later lost them.

Asexual reproduction
replication of a cell or organism, in which an exact clone of the parent cell or organism is produced.

ADP
adenosine diphosphate, the precursor of ATP.

ATP
adenosine triphosphate; the universal energy currency of life, which is formed from ADP (adenosine diphosphate) and phosphate; splitting ATP releases energy used to power many different types of biochemical work, from muscular contraction to protein synthesis.

ATPase
the enzyme motor within mitochondria that harnesses the flow of protons to form ATP from ADP and phosphate. ATPase is also known as
ATP synthase.

Cell
the smallest biological unit capable of independent life, by means of self-replication and metabolism.

Cell wall
the tough but permeable outer ‘shell’ of bacterial, archaeal and some eukaryotic cells; maintains cell shape and integrity despite changes in physical conditions.

Chemiosmosis
the generation of a proton gradient across an impermeable membrane; the backflow of protons through special channels (the ATPase complexes) is used to power ATP formation.

Chemiosmotic coupling
the coupling of respiration to ATP synthesis by means of a proton gradient across a membrane; the energy released by oxidation is used to pump protons across a membrane, and the passage of protons back through the drive-shaft of the ATPase is used to power ATP synthesis.

Chloroplast
plant cell organelle responsible for photosynthesis; originally derived from endosymbiotic cyanobacteria.

Chromosome
long molecule of DNA, often wrapped in proteins such as histones; may be circular, as in bacteria and mitochondria, or straight, as in the nucleus of eukaryotic cells.

Clonal replication
alternative name for asexual reproduction.

Control region
stretch of non-coding DNA in the mitochondrial genome that binds factors responsible for controlling the expression of mitochondrial genes.

Cytochrome c
mitochondrial protein that shuttles electrons from complex III to complex IV of the respiratory chain; when released from the mitochondria, cytochrome c is a key initiator of apoptosis, or programmed cell death.