Scientists uncover how a mitochondrial mutation rewires immune function

(Press-News.org) Scientists have discovered how a mitochondrial mutation rewires immune function in a model of inherited primary mitochondrial disorders, which often lead to severe disability and death. They have discovered that this single inherited mutation causes whole-body issues in an animal model after its immune response is sparked into action.

Although the scientists stress the research is at a relatively early stage, it is one of the first pieces of work to show that a heritable mitochondrial DNA mutation can independently remodel immune cell function and inflammatory signalling. 

It thus offers a plausible hypothesis as to why individuals with inherited primary mitochondrial disorders often experience problems with multiple organs and suffer repeated infections and sepsis. Additionally, it puts a potential target on specific links in the immune response chain that offer the greatest potential for therapeutic success.

Dylan Ryan, Assistant Professor in Trinity’s School of Biochemistry and Immunology, formerly based at the MRC Mitochondrial Biology Unit, University of Cambridge, is the senior author of the research article, which has just been published in leading journal Nature Communications. 

Dr Ryan said: “Many patients living with inherited primary mitochondrial disorders appear to be more susceptible to recurrent infections and sepsis, which can trigger the onset of symptoms, worsen developed symptoms or cause significant mortality. The precise mechanistic basis for this has been unclear, which of course hampers any attempt to develop effective therapies. These are badly needed as there is currently no cure for these debilitating disorders.”

Dr Eloïse Marques, research associate in the MRC Mitochondrial Biology Unit and first author of the study, said: “Given the rare nature of these disorders, we performed this work in an experimentally tractable mouse model, so we don’t want to overstate the findings. However, we have uncovered a number of pieces of the puzzle that supports descriptive reporting in human patients. This is helping us better understand what is likely happening on a mechanistic level when immune systems are triggered in the context of mitochondrial defects and running away with themselves.” 

“Ultimately we must be cautious, given this is early stage research, but we are excited as to what it could one day mean for mitochondrial disease patients.”

Specifically, in this study, the scientists showed that the m.5019A>G mt-tRNAAla mutation in mice, which models certain patient mutations, drives a fundamental shift in macrophage immune balance, linking bioenergetic failure directly to innate immune signalling defects.

Macrophages (key immune cells) with this specific mutation exhibit an early “interferon burst” via a specific signalling pathway, which is then followed by a delayed phase driven by the release of mitochondrial DNA and RNA that activates another specific signalling pathway. Interferons act to kickstart our immune systems into gear when pathogens or viruses are detected, but this causes the release of toxic reactive oxygen species which, if unchecked, can cause an over-the-top response and a suite of knock-on problems.

This newly discovered dual mechanism connects mitochondrial damage to chronic interferon activity and represents an “antiviral alarm” – a key (but not well-understood) feature of many autoimmune and inflammatory disorders.

Mice with the mitochondrial mutation showed excessive interferon signalling and aggravated sickness behaviour when their immune systems were triggered by a toxin, which revealed that this mitochondrial defect disrupted immune homeostasis at the whole-body level during inflammation.

“The significance of this is that by showing this single inherited mtDNA mutation is sufficient to disturb innate immunity, our work may help to reframe primary mitochondrial disorders as not only being an inborn error of metabolism syndrome but also a disorder of immune regulation,” added Dr Ryan, who is based in the Trinity Biomedical Sciences Institute (TBSI).

“The work suggests that if we could therapeutically restore mitochondrial function or modulate interferon signalling such approaches could one day be helpful for mitigating inflammation and sepsis risk.”

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