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Rogue Molecules Trigger Autoimmunity

A research team has filmed the actual moment that can change the body’s response to a dying cell. Importantly, they say, this “Great Escape” moment may one day prove to be the crucial trigger for autoimmune diseases like arthritis.

The research team, led by Prof Benjamin Kile from Monash University’s Biomedicine Discovery Institute (BDI), filmed the exact moment when DNA escapes out of mitochondria during cell death ( Mitochondria are organelles inside cells that produce energy. They are essential to keep cells alive, but when damaged they can trigger the body’s own immune system with potentially devastating consequences.

Because the DNA inside mitochondria (mtDNA) has many similarities with bacterial DNA (they share a common ancestry), the body reacts to its presence outside the mitochondria or the cell as if it is under attack from invading pathogens. It is a similar failure to distinguish self from non-self that underlies inflammatory and autoimmune diseases.

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 researcher Dr Kate McArthur, while completing her PhD at the Walter and Eliza Hall Institute, used a revolutionary new microscope at the Janelia Research Campus in the USA to capture the moment when mitochondria form a “hernia” that balloons out of the mitochondria, expelling the DNA into the rest of the cell.

Kile explains that two proteins called BAK and BAX are triggered when a cell commits suicide. “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, bringing the mtDNA with it,” 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 study was published in Science (