Unravelling the genetic mystery behind mitochondrial disease

Mitochondrial disease is an illness that robs its sufferers of energy, and damages muscles and major organs like the brain and heart. About 1 in 5000 babies – or one Australian baby born each week – are born with a severe form of the disease, which can often lead to an early death.

Research lead by Dr David Stroud and Professor Mike Ryan from the Monash Biomedicine Discovery Institute in Melbourne has identified two new genes linked to a major cause of mitochondrial disease, with a paper published in Nature on Thursday 15th September.

This research opens the way for better genetic diagnosis of the disease – which goes undiagnosed in up to 40% of cases – and could also help to identify potential therapeutic targets for treatment.

The Nature paper continues a long collaboration between MCRI’s Mitochondrial Research group and Professor Mike Ryan’s group, which has previously identified 6 of the 11 known complex I assembly defects, and now identifies two new assembly factors.

The study combined two cutting edge technologies to provide the first detailed analysis of the structure of human complex I, which as David Thorburn explains, “is a molecular monster comprising 44 subunits, compared to the equivalent bacterial complex, which has just 14 subunits.”

The team identified not only two new genes linked to one of the causes of mitochondrial disease, but also uncovered the importance of 30 “accessory” protein components in the engine that drives the mitochondria.

“The fact that so many different genes contribute to the function of our mitochondria explains why so many patients remain undiagnosed – it’s a complex disease,” Professor Ryan said.

Mitochondria are the powerhouses of our cells, taking sugars and proteins from the food we eat and turning them into energy in a form our body can use. This process gives us more than 90% of the energy we need for our bodies to function properly.

In people with mitochondrial disease, the mitochondria are unable to produce this energy, which can lead to organ failure, and potentially, death.

To unravel the genetic mystery behind a major cause of mitochondrial disease, researchers, including MCRI’s Ann Frazier and Tegan Strait, studied Complex I, one of the engines that helps drive the mitochondria. Professor Ryan said human Complex I was made up of 30 extra protein components than the Complex I of bacteria.

“This has always been a mystery because both bacterial and human Complex I have the same overall function,” Professor Ryan said.

“Our research shows almost all the additional protein components are critical to human health.”

Using cutting-edge gene editing technology, TALENs and also CRISPR/Cas9 , the researchers generated 30 cell lines, each one lacking one of the 30 accessory subunits.  The method they developed could be used to study more of the genes responsible for mitochondrial disease in laboratories around the world.

Professor Ryan said the extra protein components humans have might keep Complex I more stable than the Complex I found in bacteria.

“This might be necessary because our cells live so much longer than bacteria, which divide every 20 minutes,” Professor Ryan said.

The two new genes the researchers found are involved in building Complex I. Dr Stroud said they used gene editing to show that mutating either of the two new genes they identified disrupted Complex I and mitochondrial function.

“These genes can now be added to genetic screening panels globally, leading to earlier diagnosis of more people with the disease,” Dr Stroud said. The new knowledge about the impact of losing each subunit will also assist in interpreting and validating results of genomic studies that identify mutations in these genes.

Australian Mitochondrial Disease Foundation CEO Sean Murray welcomed the research findings as an important step towards improving diagnosis and developing therapeutic techniques and medications to fight mitochondrial disease. “Earlier diagnosis means earlier intervention that may help patients manage their debilitating symptoms and perhaps slow the insidious progression of their disease,” Mr Murray said. “Advances in diagnosis of mitochondrial disease benefit families by ending their often prolonged and painful odyssey of tests, misdiagnosis and wrong turns.”

(Source: Murdoch Children’s Research Institute, Nature)