Functionalism of mitochondrial Complex I accessory subunits in health and disease

PhD Top-up Scholarships

$12,250 AUD

23/01/2017 → 28/02/2019

Carolyn Sue


Marris Dibley


Monash University


Professor Mike Ryan and Dr Michael Lazarou

Project Name

Functionalism of mitochondrial Complex I accessory subunits in health and disease

Project Details

Marris Dibley is exploring what can go wrong inside the tiny machinery of the mitochondria. Marris is a PhD candidate at the Monash Biomedicine Discovery Institute and a recipient of grant funding from the Mito Foundation. He is studying a critical part of the mitochondria, the electron transport chain, which is a multi-purpose engine that breaks down sugar into usable energy and generates molecular building blocks for our body. Marris is studying the largest part of the electron transport chain, complex I, and determining how the subtle interactions of its subunits may contribute to disease. Using the revolutionary new CRISPR/CAS9 system, Marris will edit the DNA of mitochondria like a writer would edit text on a page. The edited genes will create proteins in a laboratory setting, and Marris will study how faulty proteins interact with their cellular environment.

Defects in complex I are directly responsible for 35 per cent of all mitochondrial disease, making the structure a prime target for research. If the electron transport chain is the body’s engine, complex I is the starting motor, initiating the transfer of energy downstream. Like a motor, complex I is attached to the mitochondrial membrane; instead of brackets and bolts, our bodies use subunits and accessory subunits.  Marris’ lab has already demonstrated that accessory subunits are fundamentally important to the mitochondria’s functioning. They hypothesise that accessory subunits are involved in critical roles: the stability and assembly of complex I, the insertion of subunits into the mitochondrial membrane, the minimisation of damaging free radicals, and the regulation of the enzymatic activity that enables cellular power production. Interruption to any these roles would damage the cell.

Complex I is a molecular machine that is attached to the mitochondrial membrane with subunits and accessory subunits. When the machine doesn’t properly assemble and attach, it cannot generate energy at required rates. This lack of energy can manifest as the various symptoms in mitochondrial disease, particularly in those organs that require the most energy, such as the eyes, heart, brain and skeletal muscle. Marris’ research explores the critical function of accessory subunits within complex I.  By learning more about how complex I correctly assembles – and how it doesn’t – Marris’ research can shed light on factors that lead to mitochondrial disease.

End of Project Update – 2019

After four years of research, Marris Dibley’s work into protein subunits that comprise mitochondrial complex I has yielded promising results.

An interesting subject of the research was a family of small mitochondrial proteins which contain a specific motif of three amino acids: Leucine-Arginine-Tyrosine (LYRM) as well as a distal phenylalanine. Already, these proteins have shown to be essential components of complex I and previous research has revealed their importance in generating and maintaining interactions with the energy generating OXPHOS enzymes and protein translating ribosome.

Marris and his team were able to identify a new protein of this family that, if defective, can result in metabolic dysfunction. As such, mutations in this protein could represent a previously undescribed cause for mitochondrial disease. This discovery has recently been submitted into a scientific journal for publication and will be publicly available soon. Importantly, this gene can be included in future genetic screens for mitochondrial disease patients.

Marris’ work on LYRM-proteins also led to an international collaboration with Professor Robert Taylor and Dr Charlotte Alston from the Wellcome Centre for Mitochondrial Research in the UK. The project focused on four patients with mutations in a complex I subunit called ‘NDUFA6’. The research showed that the mutation leads to the manifestation of varying degrees of mito. They were able to combat the mutation via the introduction of a healthy version of the protein into the cells, therefore, confirming the cause was specifically the mutation in NDUFA6. This important research not only helps understand the function of complex I in mitochondrial disease but also helps provide definitive diagnoses and aetiology to patients and families. You can read about the research here.

Marris acknowledges that “scientific research does not exist in a bubble” and thanks his supervisor Professor Mike Ryan and the members of the Ryan Lab at the Monash Biomedicine Discovery Institute, as well as the many collaborators for their assistance.