Cells react to the presence of DNA in the cytoplasm by triggering inflammatory signaling, an evolved defense mechanism against viral and bacterial threats. When mitochondria malfunction, their own DNA (mtDNA) may escape into the cytoplasm, linking mitochondrial dysfunction to age-related chronic inflammation. The extent to which this phenomenon contributes to unresolved inflammatory signaling is still unknown. Can this unwanted response be blocked without fixing all dysfunctional mitochondria? Further research is necessary to uncover potential solutions.
Mitochondrial DNA (mtDNA) serves as an essential component of the oxidative phosphorylation system but also acts as a danger signal that triggers immune responses when it exits cells, leading to inflammation in various disease scenarios. Stress on mtDNA, caused by factors like TFAM depletion or viral infections, results in the release of mtDNA into the cytoplasm and activation of immune signaling pathways. However, the mechanisms linking abnormal mitochondria, mtDNA release, and immune activation remain unclear.
Research indicates that under conditions of mtDNA replication stress or viral infections, enlarged nucleoids attached to TFAM move out of mitochondria. These enlarged nucleoids form due to replication stress, leading to nucleoid clustering and eventual disposal through endosomal pathways. Endosomal rupture during this process ultimately triggers immune system activation. This suggests a mitochondria-endosomal quality control pathway that could be a target for preventing mtDNA-mediated inflammation during infections and diseases.
Link: https://doi.org/10.1038/s41556-023-01343-1
