Trouble in the powerhouse 01/08/07. By Jon Turney Mitochondria and human disease.

The famous success of sequencing the human genome has uncovered a host of new links between variations in DNA and disease. But until recently few realised that a small loop of DNA outside the cell nucleus, in the mitochondria that provide power for our cells, is also a crucial factor in some very puzzling medical conditions. At the University of Newcastle upon Tyne, neurologists Doug Turnbull and Patrick Chinnery are in the forefront of the effort to track the causes of these often-elusive illnesses.

"There's something inherently fascinating about the mitochondrial genome", says Professor Turnbull. And it is intriguing that the tiny mitochondria within cells are equipped with their own complement of DNA, with an evolutionary history distinct from the much larger mass of nuclear DNA that carries almost all human genes (see box, below). But why would a neurologist be drawn to investigate them? One reason is that mitochondrial defects often affect the nervous system because it requires a lot of energy. Patients sometimes have unusual symptoms such as paralysis of the eye movements, known as chronic progressive external ophthalmoplegia, or drooping eyelids, known as ptosis. "Sometimes the clinical features are relatively easy to recognise as being 'mitochondrial'," says Professor Chinnery. In many patients however, the clinical features are similar to many other neurological conditions, which adds to the challenge for clinicians.

This is important in the confusing world of mitochondrial disease, in which the same underlying biochemical problem can lead to quite different symptoms – a severe, progressive neurological disease in one patient, but only mild deafness in another member of the same family, for example. And that is only the start of the complexities that cloaked mitochondrial diseases for most of medical history. The same clinical condition can also be caused by different genetic defects. And those defects can be in one of the 37 genes that are actually kept in the mitochondria, or in one of the nuclear genes that make other key components that mitochondria need to function.

It is now apparent that mitochondrial diseases affect between 1 in 10 000 and 1 in 5000 people, although most of the conditions are so rare that most doctors will not see the same one twice. However, by specialising in the area in Newcastle, Professors Turnbull and Chinnery have been able to work with several hundred patients from across the UK – far more than most other centres in the world. "Patrick's and my contribution over the years has been that we've worked really hard to understand the patients, and then to dissect what's going on," says Professor Turnbull. Their research, as well as the diagnosis and management of tricky cases, has also been helped by the UK's national commissioning for mitochondrial disease, set up by the NHS.

Power drain

Unraveling mitochondrial diseases, the first of which was only tied to a particular stretch of DNA in 1988, is complex. But as mitochondria basically exist to manage energy conversion, the vast majority of the conditions arise from defects in the respiratory chain, the set of enzymes that produce energy for the cell. If it didn't work at all, cells would just die, so these defects tend reduce the efficiency of the use of oxygen.

This is one reason why symptoms vary so much. Impaired mitochondrial performance tends to become a problem in tissues with a heavy energy demand – such as brain or muscle – or that are under stress for some other reason. And the conditions are often progressive.

The emerging understanding of faulty mitochondria has not yet given rise to any dramatic cures. But as with other conditions with a genetic underpinning, information – starting with an accurate diagnosis – is a boon for many patients.

Some of the information is straightforward. A man, for example, can be reassured that he cannot pass on his mitochondrial DNA mutation to any children. Only the mother's mitochondria survive in a fertilised egg, so only her mitochondrial genes are present in her sons and daughters. However, the rest of the details of inheritance of mitochondrial diseases are anything but straightforward. For one thing, this simplification does not apply to mitochondrial conditions that are due to changes in nuclear genes. The enzyme that copies mitochondrial DNA, for example, is specific to the mitochondria but is made under the direction of a nuclear gene. If the enzyme, DNA polymerase gamma, makes mistakes, mitochondria can accumulate altered copies of their DNA. Specific mutations in different parts of the polymerase are now known to cause disease. In 2006, the Newcastle group reported a dominant mutation in a piece of the enzyme that helps to bind DNA, and leads to deletions in mitochondrial DNA. "These accumulate in muscle throughout life, reaching a critical threshold level, and then causing a biochemical defect", Professor Chinnery explains.

A further complication is that the maternal transfer of mitochondria has its own subtleties, which are not yet fully understood. Unlike nuclear genes, an egg has many copies of the mitochondrial DNA. And the cell divisions that ultimately give rise to the egg seem to incorporate a quality check that can weed out defective mitochondria. In which case, are there ways of preventing the transmission of mitochondrial diseases from one generation to the next? To investigate, Professor Chinnery is focusing on understanding inheritance patterns, and the cellular mechanisms underlying them, while Professor Turnbull and colleagues are developing techniques using nuclear transfer, which may do the trick. The idea is to swap a nucleus (or pronucleus) from a cell with defective mitochondria into a cell with healthy mitochondria.

Improving the mitochondrial population in later life may also offer a route to better treatment. Muscle samples taken by biopsy often show a mosaic of defective and normal mitochondria, for example. "If there is a mutation, there is usually a mixture of mutated and wild-type mitochondria, in varying proportions," says Professor Chinnery. But muscle 'satellite cells', a specialised type of stem cell, tend to have fewer mitochondrial DNA defects. So activating them in some way, either by killing some mature muscle cells or using antibodies or certain drugs under development, might improve the state of the overall mitochondrial population in the muscle. Less dramatically, it is possible that simple exercise programmes may help some patients.

There are many uncertainties as these ideas are followed up. Exercise increases the number of mitochondria in our muscle cells. Does that mean patients should try to exercise more? Professor Turnbull says "yes", his colleague only "maybe". They agree, though, that work with elderly athletes suggests that exercise can increase the number of normal copies of mitochondrial DNA.

These leads may offer ways to increase the quality of life for those with muscular symptoms, but do not yet indicate how to help those with neurological conditions. But that hope still moves the work on. "I've spent ten years studying molecular mechanisms – now I want to move from diagnosis to treatment," says Professor Chinnery. His lab will continue to specialise in the influences of the DNA in the cell nucleus on mitochondria, while Professor Turnbull's will focus on the mitochondrial DNA itself – though the interaction between the two is increasingly recognised as the key to specific symptoms.

The whole, multifaceted effort is a choice example of work that is driven by encounters with patients in the clinic but that also speaks to a larger goal. "We like to think of ourselves as clinical scientists – every patient presents us with a different question," says Professor Turnbull. Both the team leaders are now keen to get more direct payoffs for their patients, and enthuse about the advantages of working in the NHS when dealing with rare diseases. National referral and commissioning systems make it much easier to accumulate more patients for study, and develop expertise in diagnosis and treatment.

At the same time, they are keen to pursue hints that these specific genetic defects can shed light on more general biological problems, particularly the causes of ageing. Mitochondrial DNA damage detected in tissues from aged individuals does not look much different from DNA damage in genetic diseases. In the end, "Our ambition is to understand the molecular mechanisms by which mitochondrial DNA defects are generated and propagated – and their involvement in the ageing process," says Professor Turnbull. As in many areas of research on human disease, studies of rare phenomena may help in the understanding of processes that affect us all.

Reference

1 Baudouin SV et al. Mitochondrial DNA and survival after sepsis: a prospective study. Lancet 2005;366(9503):2118–21. Abstract

Jon Turney is a science writer based in London.