Role of STING complex in differential retrograde signaling in cybrids with K versus H haplogroup mtDNA


Mitochondrial (mt) DNA haplogroups, defined by specific single nucleotide polymorphism (SNPs) patterns, represent populations of diverse geographic origins and may play a role in disparate disease susceptibilities found in different ethnic/racial populations. The most common European haplogroup is H, while the K haplogroup is highly associated with Ashkenazi Jewish populations. Studies using transmitochondrial cybrids (cell lines with identical nuclei but mitochondria from either H or K haplogroup subjects) demonstrated significant molecular and biological differences but mechanisms for these disparities are unclear. In this study, we hypothesized that there is differential retrograde signaling occurring between the Stimulator of Interferon Genes (STING) pathway and H versus K mtDNA haplogroups. Results showed that K cybrids exhibit increased levels of cytoplasmic mtDNA fragments. After STING Knock-Down, H cybrids had lower expression levels for EGFR, BRCA1, DNMT3A, DNMT3B, HDAC1, and IFNα genes, but upregulated DNMT3A compared to control H cybrids. The STING-KD K cybrids showed downregulation of EGFR, DNMT3A, HDAC1, HCAD9, CFH, and CHI, along with upregulation of DNMT1 and IL-6 compared to control K cybrids. Since all cybrids have identical nuclei, the STING DNA sensor system interacts differently with K haplogroup mtDNA compared to H mtDNA for genes related to cancer (EGFR, BRCA1), methylation (DNMT1, DNMT3A, DNMT3B), acetylation (HDAC1, HDCA9), complement (CFH, CHI) and inflammation (IFNα, IL-6). In summary, in non-pathologic conditions, (a) STING is an important retrograde signaling mechanism(s) and (b) cybrids possessing Ashkenazi Jewish mtDNA (K haplogroup) interact with the STING complex differently compared to H cybrids which affects various disease-related pathways.

It would be interesting to see how this increase/decrease in DNA methylation, acetylation and immune genes like Interferon α affect various diseases like cancer and general immunity to viral and bacterial infections. As they say:

"It is recognized that pathological conditions (e.g., viral and bacterial infections) are often associated with DNA304 fragmentation and STING activation that modulates the immune responses."

If I understood well, mtDNA H increases DNA methylation and acetylation as well as the expression of IFNα. The latter is important against viral infections and tumours.

Haplogroup K upregulates histone acetylation (to increase or decrease gene expression, as in epigenetics), but also complement factor H and I.

Factor H protects host cells from complement-mediated damage. An overactive factor H reduces complement activity and increases susceptibility to microbial infections. An underactive factor H may cause autoimmune diseases.

L Factor I influences levels of IgG and is particularly important against bacterial infections.

In other words and simplifying a lot, haplogroup H may confer better viral immunity and protect against tumours, while haplogroup K would increase bacterial immunity and protect against autoimmunity.

The paper also mentions:

"Interestingly, in the STING-KD K cybrids the HDAC9 transcription was significantly lower (p = 0.02) while the285 STING-KD H cybrids showed a trend for lower HDAC9 levels but it did not reach significant (p = 0.18) due to larger286 variations within the H cybrids. HDAC9, which is important for mitochondrial functions, has highest expression in brain."

Haplogroup K has been linked to higher IQ, apparently due to higher brain pH which improves neural connectivity and transmission. Could this be linked to the upregulated histone acetylation of HDAC9?