Research into mitochondrial disease (mito) is a core pillar of Mito Foundation's work. Only through research will we one day find cures for mito and advancements to improve the quality of life for people impacted by mito.

Many hardworking researchers are committed to this goal, such as Dr Sylvie Callegari, who conducts research into mito.

We sat down with Dr Callegari to find out more about her work and its benefit to the mito community.

Dr Callegari, when did you first begin your work in mito research, and what attracted you to this particular field?

My fascination with mitochondria began during my PhD in the School of Pharmacy and Medical Sciences, University of South Australia, where I worked on understanding why some people who are treated with the class of cholesterol-lowering drugs, statins, experience muscle soreness and weakness. It turns out that mitochondrial dysfunction could be an underlying cause of these side effects to statins. This opened my eyes to the multifaceted world of mitochondria. As well as being the cell’s powerhouse, mitochondria are central to a number of vital processes in the cell and their dysfunction has been implicated in many diseases, from mito, to neurodegenerative diseases and even cancer.

Wanting to learn more, I moved to Gottingen, Germany to take up a postdoc position in the lab of Prof. Peter Rehling, a world leader in the field of mitochondrial biochemistry. There I worked on several aspects of mitochondria, including how cells deal with damaged mitochondria (via the clean-up process of PINK1/Parkin mitophagy) and how proteins are imported into mitochondria, a process that is essential for building the mitochondrial powerhouse.

During that time, I came to appreciate how tuned in and responsive mitochondria are to the needs of the cell (for example, to stress or environmental/nutrient changes). This is because the cell has an excellent communication system that can control processes like increasing mitochondrial activity, or cleaning up damaged mitochondria. One of these systems is a tagging system that involves the attachment of ubiquitin molecules onto proteins (like sticky notes) to signal their fate. This is known as the ubiquitin signalling system.

Work by Prof. David Komander, at that time in Cambridge, UK, had provided major breakthroughs about how this signalling system functions, including how it controls PINK1/Parkin mitophagy, whereby defects lead to Parkinson’s disease. Upon learning that Prof. Komander would be moving to Melbourne to start a new division at WEHI, I was excited at the opportunity to better understand how the ubiquitin system controls mitochondrial health and so I joined the lab in late 2019.

In the time that you’ve researched mito, what are some of your findings that will help the mito community? How will they impact the lives of people with mito?

To date, the majority of my mito research has very much been about understanding how mitochondria work and what happens when they are damaged. This basic knowledge is essential for developing therapeutic strategies. However, one of the highlights of my research career was working on a collaborative project with the Wellcome Centre for Mitochondrial Research, UK, where we analysed mitochondrial function in cells from a young patient with a very rare form of mito. Although there was no cure, this work provided the diagnosis for the disease that the family had desperately sought for so long. Seeing, for the first time, the impact our work could have on mito patients and their families was immensely inspiring and has encouraged me to think more about how we can turn research into therapies.

What else have you seen in the field of mito research that may excite the community?

There are several promising treatment avenues for mito on the horizon, particularly with research into gene therapy continuing to make progress. Another treatment strategy currently being explored to treat mito is to use pharmaceutical agents that promote the removal of damaged mitochondria. I am particularly excited by a new class of drugs that inhibit the deubiquitinase USP30 (a protein that removes the ubiquitin signalling molecules that tag damaged mitochondria for removal). By inhibiting USP30, mitochondrial turnover is accelerated, thereby clearing the cell of damaged mitochondria. This drug is currently in preclinical trials at Mission Therapeutics Ltd. for use in Parkinson’s disease and mitochondrial disease and represents an exciting new potential treatment.

How has Mito Foundation helped in your research journey?

In our Ubiquitin Signalling division at WEHI we have a broad disease focus and I would love to be able to incorporate mito into some of the therapeutic approaches we are investigating. In 2020, I was lucky enough to be awarded an Incubator Grant from the Mito Foundation. This has allowed me to explore some ideas around how ubiquitin signalling proteins regulate mitochondrial health. If we can understand how mitochondrial health is regulated, we can also develop therapeutic strategies to manipulate the cell to dispose of bad mitochondria and generate new mitochondria.

What's next for you? Are there any potential breakthroughs on the horizon, and what needs to happen to bring those within reach?

Currently my main research focus is understanding how the cell removes damaged mitochondria. Work by a PhD student in the lab recently made a major breakthrough in deciphering how a protein, called PINK1, which is critical for initiating the cleanup of damaged mitochondria, is activated. This study opened up some interesting leads into how PINK1 senses mitochondrial damage, which I am now following up on.

Mutations in PINK1 can cause early onset Parkinson’s disease and there are a number of projects in our division trying to understand the link between Parkinson’s disease and mitochondria. Although my current disease focus is Parkinson’s disease, my research is centred on mitochondria and given my background in mito I try to appreciate where there might be crossover between Parkinson’s and mito and whether treatments for Parkinson’s can also be applied to mito (as in the case of USP30 inhibitors mentioned above).

Overall, I am really excited by how much we are learning about how our mitochondria work and, with ongoing funding, I believe this has the potential to translate to treatments for mito.