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Damaged mitochondria activate autoimmunity suggests genome study

17 May 2021
Appeared in BioNews 1095

Accumulation of defective mitochondria in cells may contribute to autoimmune conditions, such as Sjögren's syndrome, according to a recent study.

Researchers showed that mice lacking the IRGM1 gene showed similar autoimmune symptoms to patients with Sjögren's syndrome because they were not able to properly recycle their mitochondria. This left damaged parts of mitochondria in the cells, triggering an immune response against them.

Many autoimmune diseases exhibit increased type 1 interferon, said Dr Michael Fessler, senior author and head of the immunity, inflammation, and disease laboratory at the US National Institute of Environmental Health Sciences (NIEHS) in North Carolina. 'Our studies show how mitochondrial DNA that is not removed activates the immune system in mice and how it may happen in humans.'

Mitochondria are considered powerhouses of the cell, generating energy for cells. If part of a cell becomes damaged, it is usually actively recycled by the cell in a process called autophagy, or in the case of mitochondria, mitophagy. One of the genes known to be involved in autophagy and mitophagy is IRGM1.

The scientists knew already that mice lacking the IRGM1 gene showed symptoms similar to those of people with Sjögren's syndrome, such as inflammation in the tear and salivary glands. Since IRGM1 is known to be important for mitophagy, they explored whether autoimmunity and mitophagy were connected.

'We speculated that if autophagy is deficient, then maybe autophagic clearance of mitochondria, called mitophagy, is also deficient,' added Dr Fessler. 'If so, this might provide new hints into what happens in Sjögren's syndrome.'

The researchers explored this link and the mechanisms underlying it. They found that mitochondrial debris, including DNA and RNA usually found only in mitochondria, triggered an immune response driven by interferons, molecules well known to play a role in autoimmunity and Sjögren's syndrome.

To confirm that interferons underlie the autoimmune symptoms seen in mice without IRGM1, the scientists blocked their function. 'When we genetically blocked interferon in the IRGM1 knockout mouse, we cured the Sjögren's-like autoimmune disease,' said first author on the paper Dr Prashant Rai, a visiting fellow at NIEHS.

Interestingly, they found that this response was different depending on the specific type of cell where the mitophagy was disrupted. They looked at macrophages, specialised cells of the immune system, and fibroblasts, which make up connective tissue. 'Both fibroblasts and macrophages made type 1 interferon, but the mechanism was different, suggesting that autoimmune diseases can affect different tissues in a selective manner,' said Dr Rai.

This research was published in Nature Immunology.

SOURCES & REFERENCES
Autoimmunity origins may lie in defective mitochondria
National Institute of Environmental Health Sciences |  1 March 2021
Damaged mitochondria may drive autoimmunity
Sjogren's Syndrome News |  11 May 2021
IRGM1 links mitochondrial quality control to autoimmunity
Nature Immunology |  28 January 2021
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