Professor Mike Ryan and Dr Michael Lazarou
Functionalism of mitochondrial Complex I accessory subunits in health and disease
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.