A review article recently published in Brain explores the complex role of mitochondrial DNA (mtDNA) release in primary mitochondrial diseases (PMDs), including thymidine kinase 2 deficiency (TK2d).
Recent studies have demonstrated that in PMDs, mitochondrial damage can lead to the release of mtDNA into the cell. This may trigger downstream immune responses that activate inflammation. However, much about these pathways, including how they may differ between PMDs, still remains unknown.
In some cases, released mtDNA and RNA function as damage-associated molecular patterns, which alert cells to injury and stress. This, in turn, activates inflammatory reactions involving numerous signaling molecules that amplify the response. Even in healthy individuals, the authors explained, circulating mtDNA may be a sign of inflammation.
Biopsies of patients with TK2d have revealed inflammatory responses in the skeletal muscle. In these samples, genes that regulate interferons, molecules responsible for fighting off disease, were upregulated. Future research is still needed to understand the exact mechanisms that cause these responses, though.
Read more about TK2d causes and risk factors
Mitochondria are separated from the rest of the cell by both an inner and outer membrane. Research has uncovered numerous PMD-associated genes that play a role in maintaining mitochondrial membrane organization.
When these genes become mutated, membrane integrity may become disrupted, allowing genetic material to leak into the cell. Disease modeling studies have shown that membrane damage may be present in those with ATAD3A, OPA1 and MFN2 mutations, for example.
The machinery required to express and replicate mtDNA can also become disrupted in PMDs. Along with mutations in theTK2 gene, which cause TK2d, mutations in the TFAM, POLG and TOP1MT genes may trigger systemic inflammation. Similarly, genes that help maintain mtDNA quality, like MGME1, can become mutated, increasing the release of inflammatory proteins.
In addition, some evidence suggests that defects in the proteins that carry out cellular respiration might be linked with mtDNA-induced inflammation.
“Together, these findings underscore the potential role of innate immune responses in establishing and modulating mitochondrial disease phenotypes and open avenues for further exploration of inflammation-targeted therapeutic strategies,” the investigators concluded.
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