Seeking the hidden danger signals of death: mitochondrial DNA through a lattice of light

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1. Please give a summary of your research.

My creative invention was the discovery and visualisation of a fundamental cellular process that occurs billions of times in our bodies every day, but until now, no one knew existed. Every day, our body eliminates billions of old, functionally exhausted or damaged cells through a cell “suicide” program. This process of cell clearance is essential to our development and the day-to-day health of our tissues and organs. Our bodies do it “silently” so it will not trip any alarms (i.e. our immune system). We showed in 2014 that a family of proteins called caspases were required for this stealthy form of death. Without caspases, dying cells generate danger signals that awaken the immune system, triggering an anti-viral response. The origin of these signals was unknown, but our work suggested they emanate from the cell’s energy-producing organelles, the mitochondria.

 

To understand how and why this was occurring, I adopted a revolutionary new imaging technique called lattice light-sheet microscopy (LLSM) and genetically engineered a cell system that allowed me to video mitochondria inside the cell as the process of suicide occurred. These videos showed, for the first time, DNA from inside the mitochondria (mtDNA) escaping out into the cell’s cytoplasm, in a unique phenomenon we termed “mitochondrial herniation”. mtDNA is recognised by the cell’s own intracellular innate immune sensors which subsequently trigger the anti-viral response.

 

This discovery has broad implications for the study of cell death and mitochondrial biology. Furthermore, mtDNA, a potent pro-inflammatory danger signal, is implicated in the development of a wide range of inflammatory and autoimmune diseases such as lupus and rheumatoid arthritis. My work provides the first documented mechanism by which mtDNA can escape the mitochondria and suggests that mitochondrial herniation and aberrant cell death may contribute to a wide range of human pathologies.

2. Please include any additional details you would like to share

At the time of my work, LLSM was not yet available in Australia, and the idea that mitochondrial DNA was released by Bak and Bax during cell death had been ridiculed by experts in the field. While it was well established that during cell suicide, Bak and Bax damage the outer layer of the mitochondria, my videos showed that this event triggers mitochondrial herniation, whereby the inner compartment of the mitochondria balloons out into the cellular space, allowing mtDNA to escape. Innate immune sensors that normally patrol the cell for invading viral DNA cannot tell the difference between viral and mtDNA. When activated, they generate powerful danger signals called cytokines. Normally, caspases kill the cell faster than the DNA sensors can activate cytokine production, so even though this process is happening inside us all, day in, day out, it happens “silently”, so until now remained entirely unknown.  

 

Now that we know mitochondrial herniation occurs, it is exciting to think we might be able to use this to our advantage. There are many situations where triggering our immune systems during cell death may be beneficial, particularly during infections or cancer, and there are drugs that are currently available that we can now test this theory with. Furthermore, now that we know how useful LLSM can be, it is even more exciting to think what other biological processes have previously gone unnoticed, that we will now be able to uncover. In particular, I am excited to apply these methods to better understand diseases in which mtDNA has been implicated, such as HIV and Dengue infections and inflammatory diseases such as Rheumatoid Arthritis and Lupus – diseases which affect millions of people in both developed and developing countries worldwide.

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