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Amazing mitochondria: inner DNA and its mutated cognates would spark inflammation and lead to a-thero-sclerosis

Scientists from the Salk Institute and UC San Diego published new findings in the journal Immunity, where they examined human blood cells and discovered a surprising link between mitochondria, inflammation and two genes that normally help regulate blood cell growth: DNMT3A and TET2. When mutated these proteins are also associated with an increased risk of cancer. And now acoording to their data, they might also be somehow involved in a higher risk of atherosclerosis. The study started when researchers at UC San Diego noted a specific inflammatory response while investigating the roles of DNMT3A and TET2 mutations in clonal hematopoiesis: this is because when mutated immature blood cells give rise to a population of mature blood cells with identical mutations. They reported that abnormal inflammatory signaling was also related to DNMT3A and TET2 deficiency in blood cells that play a major role in inflammation response that promotes the progression of atherosclerosis. But how the DNMT3A and TET2 genes were involved in inflammation, and possibly atherosclerosis, was unknown.

Scientist found difficulties to figure it out how DNMT3A and TET2 were involved, because these two proteins do seemingly opposite things regarding DNA regulation. Their antagonistic activity led us to believe there may be other mechanisms at play, so left researchers doubtful of the simultaneous participation. This prompted them to take a different approach taking example from the same inflammatory pathway uncovered years earlier, while scientists were examining responses to mitochondrial DNA stress. Mitochondria have their own DNA that must be organized and condensed correctly to sustain normal function. Previously it was investigated the effects of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged correctly. They found that when TFAM levels are reduced, mitochondrial DNA is expelled from the mitochondria into the cytoplasm. This sets off the same molecular alarm that tells the cell there is a bacterial or viral invader, and triggers a defensive molecular pathway that promotes inflammation.

Scientists needed help from another lab and worked together, to better understand why DNMT3A and TET2 mutations led to inflammation responses similar to those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to examine cells from people with normal cells, those with loss of function mutations in DNMT3A or TET2 expression, and those with atherosclerosis. They found that experimentally reducing the expression of DNMT3A or TET2 in the normal blood cells had similar results to blood cells that had loss of function mutations and blood cells from atherosclerosis patients––an increased inflammatory response. Remarkably, low levels of DNMT3A and TET2 expression in blood cells leads to reduced TFAM expression, which in turn leads to abnormal mitochondria DNA packaging, instigating inflammation due to released mitochondrial DNA. And the trick is a forward feedback: DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene. The subsequent missing or reducing this binding activity leads to mitochondrial DNA release.

The result is an overactive mitochondrial inflammation response, and this is what scientists believe may exacerbate plaque buildup in atherosclerosis. DNA and cellular proteins once released are recognized by surface receptors of the Toll family (TLRs). For each of them, there is one or more physically bulky ligand. The member called TLR9 is positioned onto inner membranes (endosomes) and is activated by DNA or its fragments. Upon docking with roaming DNA, TLR9 uses the MyD88 transducer to activate a downstream signaling platform that lead to a type I interferon gene response. The phenomenon could be permanent as far as the biological damage progresses. In a collateral work of professor Shadel, wich coworked with UC San Diego scientists, it was demonstrated that oxidated/fragmented mitochondrial DNA activate the cGAS-STING cytosolic pathway, again funnelling towad type I interferon response. Therapeutics that target inflammatory pathways already exist for many other diseases, including new molecules targeting the cGAS-STING signal transduction.

Researches, therefore, deem that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations could form the basis for new treatments.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Xian H et a. Immunity 2022 Jul 7:S1074-7613(22)00280-1.

Tadepalle N, Shadel GS. Mol Cell. 2021; 81(9):1863-1865.

Shemiakova T et al. Biomedicines. 2020; 8(6):166.

Sobenin IA et al. Gerontology. 2015 ;61(4):343-349.

Shadel GS, Horvath TL. Cell. 2015; 163(3):560-69.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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