Mitochondria are well known as the powerhouses of the cell because of their energy generating capabilities. These little organelles are very special, because they also carry their own tiny little genomes. This mitochondrial DNA is completely separate from the rest of the human genome, which is kept inside the nucleus of cells. Mutations in mitochondrial DNA can lead to a variety of very serious disorders.
Researchers have now found that a mitochondrial DNA mutation has a surprising impact on the whole body: it can alter immune function. This study, which focused on an animal model of mitochondrial disease, still needs to be confirmed with additional research. But it suggests that mitochondrial DNA mutations can have a significant effect on the functions of immune cells. The findings have been reported in Nature Communications.
This work could also help explain why people who have inherited mitochondrial diseases have issues with multiple organ systems and often experience repeated infections and a deadly complication of infection known as sepsis. The research could also help scientists develop therapies for these patients.
Inherited primary mitochondrial disorder patients seem to be more vulnerable to recurrent infections and sepsis. This can trigger or exacerbate various symptoms, and can lead to death. “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,” noted senior study author Dr. Dylan Ryan, an Assistant Professor at Trinity College Dublin.
"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,” added first study author Dr. Eloïse Marques, a research associate at Trinity. "However, we have uncovered a number of pieces of the puzzle that support 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."
The mutation that this study focused on is known as m.5019A>G mt-tRNAAla. It is used in mouse models to mimic human mitochondrial mutations. When the immune systems of these mice were challenged with a toxin, illness was aggravated and immunity was disrupted.
The researchers determined that this mutation led to a major shift in the balance of immune cells called macrophages, and caused problems with immune signaling. When the mitochondria in mouse macrophages carried this mutation, a signaling pathway was impaired by an early "interferon burst,” followed by a later phase in which mitochondrial DNA and RNA activated another signaling cascade.
Problems in mitochondria were linked to chronic activity in interferons, which launch immune defenses during infection. But excessive immune activity can seriously harm the body, and overactive interferons may lead to major problems.
"The significance of this is that by showing this single inherited [mitochondrial DNA] 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," Ryan added.
"The work suggests that if we could therapeutically restore mitochondrial function or modulate interferon signaling, such approaches could one day be helpful for mitigating inflammation and sepsis risk."
Sources: Trinity College Dublin, Nature Communications