Complex I assembly - it's complicated...

In our latest review, Luke Formosa, Marris Dibley, David Stroud and Mike Ryan outline the current understanding of mitochondrial complex I assembly, focussing on the role and importance of complex I assembly factors during this process.

Abstract: 

Mitochondrial complex I is the primary entry point for electrons into the electron transport chain, required for the bulk of cellular ATP production via oxidative phosphorylation. Complex I consists of 45 subunits, which are encoded by both nuclear and mitochondrial DNA. Currently, at least 15 assembly factors are known to be required for the complete maturation of complex I. Mutations in the genes encoding subunits and assembly factors leads to complex I deficiency, which can manifest as mitochondrial disease. The current model of complex I assembly suggests that the enzyme is built by the association of a set of smaller intermediate modules containing specific conserved core subunits and additional accessory subunits. Each module must converge in a spatially and temporally orchestrated fashion to allow assembly of the mature holoenzyme to occur. This review outlines the current understanding of complex I biogenesis, with an emphasis on the assembly factors that facilitate the building of this architectural giant.

Please click here to see the publication.

New research paper published - novel genetic analysis approach for Leigh Syndrome

Dr David Stroud, a NHMRC Doherty Fellow from our lab, co-lead a study with collaborators from the Murdoch Children’s Research Institute, investigating the genetic underpinnings and proteomic changes of patients with Leigh Syndrome.  

Their research revealed that mutations in the MRPS34 gene, a component of the mitoribosome, leading to severe effects on the protein synthesis of mitochondrial encoded proteins required for mitochondrial respiration and energy production. 

A link to the news post on the BDI homepage can be found here.

The publication in the American Journal of Human Genetics can be found here.

Lab Hike 2017: Razorback Trail, Cathedral Ranges National Park

With some delay (due to the navigation capabilities of one senior PhD student), the Ryan lab members started their annual walk in the late morning from the Cooks Mill Ground up to the Razorback Tail.

After a steep and demanding walk up to the sattle of the mountain ranges, we could enjoy a lunch break with a fantastic view over the Cathedral Ranges.

After lunch, we continued climbing on the back of the Razorback, heading towards the Sugarloaf Peak. Reaching the peak, we turned around and could enjoy a fantastic sunset illuminating the mountain ranges in warm light.

A brief Schnitzel and Parma stop was the adequate pit stop for all of us before we got back into the cars and headed home.

 

A novel isoform of NDUFV3 revealed

A recent publication from the Ryan Lab has revealed that the complex I subunit exists in two isoforms. Published in FEBS Letters in December of 2016, the paper identifies a second long isoform of the peripheral N-module subunit NDUFV3 which exhibits tissue specific expression patterns.

A novel isoform of the human mitochondrial complex I subunit NDUFV3. Marris G. Dibley, Michael T. Ryan, David A. Stroud, FEBS Lett. 2016 Dec 17. doi: 10.1002/1873-3468.12527 Pubmed

Mitofusins in mitochondrial fusion - new review by Luke Formosa and Mike Ryan

Luke Formosa and Mike Ryan preview new research into the structural mechanism of Mitofusin 1 and implications for mitochondrial outer membrane fusion published in The Journal of Cell Biology.

Mitochondrial fusion: Reaching the end of mitofusin's tether. Luke E. Formosa, Michael T. Ryan. J.  Cell Biol. 2016 Nov 23. pii: jcb.201611048. PubMed

MonashMitoLab completed the Bloody Long Walk Melbourne 2016

This Sunday, the Ryan Lab (aka "MonashMitoLab") participated in the 2016 edition of the Bloody Long Walk in Melbourne to raise awareness for mitochondrial diseases.

Taking place with typical Melbourne weather, our long journey started at Yarra Bend Park and took us along the Yarra River through the beautiful Melbourne suburbs and ending at St Kilda Beach.

Despite heavy rain, mud and flooded footpaths, the lab team was excited to go through some pain for the good cause.

After some grueling 35k, which pushed everyone to their limits, we finished in less than 6h and under a blue sky and sunshine in St Kilda.

We want to say thank you to the amdf for organising the Bloody Long Walk and for their work to cure mitochondrial diseases.

Unravelling the genetic mystery behind mitochondrial disease

Researchers from the Monash Biomedicine Discovery Institute in Melbourne have identified two new genes linked to a major cause of mitochondrial disease. Their research opens the way for better genetic diagnosis of the disease and could also help to identify potential therapeutic targets for treatment.

Mitochondrial disease is an illness that robs its sufferers of energy, and damages muscles and major organs like the brain and heart. About one 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.

Dr David Stroud and Professor Mike Ryan from the Biomedicine Discovery Institute headed the research team, with their research published today in Nature.

Professor Ryan said the team identified not only two new genes linked to one of the causes of mitochondrial disease, but also uncovered the importance of 30 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 per cent 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, the researchers 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 a cutting-edge gene editing technology, called CRISPR/Cas9, the researchers modified a series of cells to have a different genetic make-up – each cell type lacked a unique gene relating to a Complex I protein only found in humans. 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.”

The two new genes the researchers found are involved in building Complex I. Dr Stroud said they used the CRISPR/Cas9 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.

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.”

 

Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.