What is mitochondrial disease?

Deep inside almost all of our cells are microscopic powerhouses: the mitochondria. They’re responsible for turning food into a usable form of energy. But when these engines fail, the consequences can be devastating. Here’s Liz Curtis, founder of the Lily Foundation, speaking to Sky News…

Liz - We lost our third daughter Lily to a mitochondrial disease. She was eight months old when she passed away but was diagnosed at seven weeks following a number of seizures where she'd stopped breathing and which ended her in intensive care on life support. So we were told then when she was about seven weeks that she had this disease with no cure and no treatment and that she was going to die.

That was Liz Curtis. As she was just explaining, her daughter Lily was diagnosed with mitochondrial disease - which is an umbrella term for a group of disorders caused by defective mitochondria that can affect the brain, heart, muscles, and other energy-demanding organs. Currently, there’s no cure for these severely life-limiting conditions, but now, an amazing scientific breakthrough is allowing children who would have been at risk of disease to be born without inheriting the genetic defect in their mitochondrial DNA.
But what exactly do we mean by this? Sir Doug Turnbull is a clinical neurologist and a leading expert on these conditions…

Doug - Well, mitochondria are, in simplified terms, the powerhouse of the cell. They convert the food that we eat into a usable form of energy. So when mitochondria are defective, as they are in mitochondrial diseases, one of the things that happens is the cell runs out of energy. Mitochondria are inherited exclusively through the mother. They carry a small piece of DNA called mitochondrial DNA, and mitochondrial DNA diseases are transmitted purely maternally.

James - Usually we think of genetic material as residing in a cell's nucleus. That's where the DNA is. But you've just referred there to mitochondrial DNA, and we know that mitochondria sit in the main body of the cell outside the nucleus.

Doug - Yes, that's correct, James. It's an entirely separate piece of DNA. It's a tiny piece of DNA. It's only 13,500 bases compared to the 3 billion bases present in the nuclear DNA. It only encodes for 37 genes, all of which are essential for allowing the mitochondria to work properly.

James - And so when they don't work properly, mitochondria are involved with metabolising, turning food into energy. So one would assume it's going to affect a wide variety of organs in the body when they go wrong.

Doug - Yes, it tends to particularly involve those organs which require a lot of energy. Good examples of this are that the heart is frequently involved in mitochondrial disease, as are the muscles and the brain. So it does tend to be those organs which have a high energy use. And how might it present in those energy-hungry organs? For example, you can get cardiac disease, heart disease, where your heart doesn't pump properly. It can lead to muscle weakness. In the brain, it can have much more varied effects. If you get mitochondrial disease as a young child, it can cause neurodegeneration of the lower part of the brain called the brainstem. Later in life, it can induce epilepsy, incoordination, poor cognitive function, and a variety of different clinical phenotypes associated with mitochondrial disease.

James - What are the determinants of those phenotypes then? Are all mitochondria affected in a person with mutated mitochondrial DNA?

Doug - Mitochondrial DNA is present in multiple copies within an individual mitochondrion and therefore in literally thousands of copies within an individual cell. Mitochondrial genetics is a bit complicated in the sense that you can actually have all your mitochondrial DNA being normal, all of it having a mutation, or, in quite a large number of patients, a mixture of normal and abnormal mitochondrial DNA. This is termed heteroplasmy. That mixture between what we call normal and abnormal mitochondria is critical. The higher the level of abnormal mitochondrial DNA you have, the more likely you are to get disease. Some patients are completely asymptomatic, some are very severely affected by the mitochondrial DNA mutation, so it does vary. There are other factors which will influence this. We're not entirely sure what those factors are; some will be genetic, some will be environmental. Understanding what causes that difference in phenotype is an area of intense research at the moment, because if you understood the difference that was causing that phenotype, then potentially you might have a treatment that would actually help patients.

James - Where are we with treatments for mitochondrial diseases related to mutations in mitochondrial DNA?

Doug - I think it's very important to say that as a clinician who's looked after patients for many, many years, for certain aspects of mitochondrial DNA diseases, we do have treatments. For example, at one stage, a lot of our patients were dying from cardiac disease, but some of the advances in cardiac drugs have meant that we can manage the cardiac disease, at least in some patients. For example, some patients might develop a heart block and you can have a pacemaker put in. Some patients, as I've mentioned before, with central nervous system involvement will develop epilepsy, and we can try to treat the epilepsy with drugs. It's successful in most patients to a degree, so those are treatments for current symptoms. However, trying to cure mitochondrial DNA disease is a much more difficult problem, and as yet, there are no curative therapies for patients with mitochondrial DNA diseases. This is why we must look for curative therapies, but it also highlights why prevention is so critical for families who have mitochondrial DNA disease running through many generations.