A research team has discovered the process – and filmed the actual moment – that can change the body’s response to a dying cell. Importantly – what they call the ‘Great Escape’ moment may one day prove to be the crucial trigger for autoimmune diseases like arthritis.

The research team discovered – and filmed – the exact moment when DNA escapes out of the mitochondria during cell death.

The study, published in Science, was led by Professor Benjamin Kile from Monash University’s Biomedicine Discovery Institute (BDI) and was a collaboration between the Walter and Eliza Hall Institute and Monash BDI, with the Howard Hughes Medical Institute (HHMI) Janelia Research Campus, US.

Mitochondria – the cell machinery that produce energy – are the ultimate double agent; they are essential to keep cells alive but, when damaged, they can trigger the body’s own immune system with potentially devastating consequences. The DNA inside mitochondria (mtDNA) has many similarities with bacterial DNA, and the body reacts to its presence outside the mitochondria, or indeed outside the cell, as if under attack from invading pathogens. A similar failure to distinguish ‘self’ from ‘non-self’ underlies inflammatory and autoimmune diseases.  

New technology captures Great Escape

While the release of mtDNA is thought to contribute to autoimmune diseases such as lupus, how it escapes from the mitochondria has never been explained. Monash BDI researcher Dr Kate McArthur, while completing her PhD at the Walter and Eliza Hall Institute, and Institute co-author Dr Lachlan Whitehead used a revolutionary new microscope to capture the moment when mitochondria form a ‘hernia’ that balloons out of the mitochondria, expelling the DNA into the rest of the cell.

The live-cell lattice light-sheet microscope – developed by Nobel Prize winner Eric Betzig – is a new technique that allows scientists to observe living cells at groundbreaking resolution.

Dr McArthur, who traveled to the HHMI Janelia Research Campus multiple times between 2015 and 2017, remembers the moment when she witnessed, for the first time, the mitochondria actively expelling its DNA.

“As scientists, we are taught to be quite skeptical when we see something unexpected, so I think my initial reaction was “No way…”.

“It was only after I had carefully repeated the experiment many times that I began to realise what we had found,” she said.

A revolution in microscopy

With the lattice light-sheet microscope researchers can watch the inner workings of living cells with unprecedented detail and in ‘real time’; a groundbreaking achievement that has enabled research that – until now – was simply not possible.

Institute researchers Dr Lachlan Whitehead, Dr Niall Geoghegan and Dr Kelly Rogers, who were co-authors on the paper, spent seven months building the Institute’s lattice light-sheet microscope. It is the only custom-built microscope of its kind in Australia and was used in the final stages of the project.

Without the lattice light-sheet microscope technology, this research would not have been possible, Dr Rogers said.

“Imagine looking at a picture from the AFL Grand Final and trying to understand what happened from that one picture that captures one second of the game. It isn’t possible.

“With the lattice light-sheet, we can watch the whole match in real time and in high definition. It is a game changer,” Dr Rogers said.

Collateral damage

Professor Kile said when a cell committed suicide – a normal part of the human body’s balancing act to control blood cell numbers – two proteins called BAK and BAX were triggered.

“What we witnessed – in real time – was these professional killer proteins opening up huge ‘macropores’ in the outer membrane of the mitochondria, leading the inner contents to herniate out, and bringing the mtDNA with it,” Professor Kile said.

“BAK and BAX deliver the ‘kill shot’ designed to permanently disable the cell. But in doing that, mtDNA is lost from the mitochondria. In essence, this is collateral damage, which, if it isn’t controlled properly, triggers the immune system to drive pathological inflammation,” he said.

The discovery was cemented by images captured by Monash University’s Titan Krios cryo-electron microscope, currently the most advanced microscope for biological electron microscopy, and the Walter and Eliza Hall Institute’s new, custom-built lattice light-sheet microscope.

Collaboration answers fundamental questions

Professor Kile said fundamental discoveries such as this were rare, and this one had profound implications for the understanding of a wide range of autoimmune diseases and infections.

“This has been a brilliant collaboration – between Monash’s Biomedicine Discovery Institute, the Walter and Eliza Hall Institute of Medical Research here in Melbourne and the Janelia Research Campus in the US – which has brought together cutting-edge technologies and first-class expertise to address questions that, before now, had never been asked, and would have been impossible to answer,” Professor Kile said.

The research team also included Institute scientists Dr Mark van Delft and Associate Professor Guillaume Lessene, and was initiated by Professor Kile and Dr McArthur while at the Institute. Dr McArthur was enrolled as a PhD student at the Institute through the University of Melbourne’s Department of Medical Biology. The research was supported by the Australian National Health and Medical Research Council, the Australian Cancer Research Foundation and the Victorian Government.

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