Mitochondria is a cell's energy hub. It is of a prokaryotic (simple bacterial) origin. It has its own DNA. However, prokaryotic DNA can activate innate immune system. So, what would happen if our mtDNA undergo misfolding stress?
This is exactly what the new Nature paper tried to uncover. This study led by Gerald Shadel at the Yale School of Medicine, has examined the outcome of mitochondrial DNA (mtDNA) packaging abnormality by studying mouse model heterozygous for mitochondrial transcription factor A (TFAM-/+), a protein responsible for mtDNA higher-order nucleoid organization.
Gene expression profiling revealed that cells in TFAM-/+ mice showed enrichment in IFN-stimulated pathway genes.
The authors showed that this type I IFN response was significantly abrogated in cGAS, STING, IRF3 and TBK1 deficient backgrounds indicating that in TFAM-/+ mice aberrant mtDNA released into cytosol activates cGAS-STING-IRF3 pathway leading to type IFN production.
Additional experiments showed that such heightened type I IFN response in TFAM-/+ mice reduced viral cellular burden.
Finally, the authors showed that viruses from herpesviridae family could induce mtDNA misfolding (by TFAM depletion via viral-encoded UL12 M185 molecule) and mtDNA dependent type I IFN response in wild type mice, mimicking TFAM-/+ mice, suggesting physiological function of mtDNA stress response.
In summary, these results highlight how mitochondrial DNA stress could activate innate immune system and cause inflammation (in human disorders such as systemic lupus erythematosus, cancer, multiple sclerosis, etc).
This study provides additional support for recently described immunological function of mtDNA and its detection by cGAS-STING-IRF3-type I IFN pathway. It is of note that many cellular abnormalities analysed from immunological point of view are converging on type I IFN response.
David Usharauli
Gene expression profiling revealed that cells in TFAM-/+ mice showed enrichment in IFN-stimulated pathway genes.
The authors showed that this type I IFN response was significantly abrogated in cGAS, STING, IRF3 and TBK1 deficient backgrounds indicating that in TFAM-/+ mice aberrant mtDNA released into cytosol activates cGAS-STING-IRF3 pathway leading to type IFN production.
Finally, the authors showed that viruses from herpesviridae family could induce mtDNA misfolding (by TFAM depletion via viral-encoded UL12 M185 molecule) and mtDNA dependent type I IFN response in wild type mice, mimicking TFAM-/+ mice, suggesting physiological function of mtDNA stress response.
In summary, these results highlight how mitochondrial DNA stress could activate innate immune system and cause inflammation (in human disorders such as systemic lupus erythematosus, cancer, multiple sclerosis, etc).
This study provides additional support for recently described immunological function of mtDNA and its detection by cGAS-STING-IRF3-type I IFN pathway. It is of note that many cellular abnormalities analysed from immunological point of view are converging on type I IFN response.
David Usharauli
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