Blood cell gene mutations affect mitochondria, increasing cardiovascular disease risk

A newly discovered link between mitochondria, inflammation and two genes required for blood cell growth could provide new therapeutic options to treat atherosclerosis and other inflammation-associated diseases.

Researchers in California identified an inflammatory response when studying the effects of mutations in the DNMT3A and TET2 genes during clonal haematopoiesis - the process of mutated blood stem cells developing into a population of mature blood cells possessing identical mutations (see BioNews 1146). In particular, the team found that loss of DNMT3A and TET2 gene expression in macrophages was linked to the inflammatory pathways which lead to atherosclerosis. However, the exact mechanism through which DNMT3A and TET2 could contribute to inflammation was undetermined.

'The problem was we couldn't work out how DNMT3A and TET2 were involved because the proteins they [en]code do seemingly opposite things regarding DNA regulation,' said Professor Christopher Glass from the University of California San Diego School of Medicine, co-author of the research published in the journal Immunity.

Mitochondria, the organelles responsible for cellular respiration, contain a unique class of mitochondrial DNA which must be organised and packaged correctly to facilitate normal functioning. Previous work led by co-author Professor Gerald Shadel of the Salk institute in La Jolla, California, demonstrated that deletion of the TFAM gene responsible for accurate packaging of mitochondrial DNA led to the ejection of the mitochondrial DNA into the cell interior. This triggered the activation of the same cell signalling pathways responsible for defending against bacterial and viral invasion, resulting in a cellular inflammatory response.

By combining the efforts of the two research groups, the collaborative project characterised the mechanism through which DNMT3A and TET2 mutations could promote inflammation. The team demonstrated that cells with reduced expression of DNMT3A and TET2 had an inflammatory profile comparable to that of cells taken from patients with atherosclerosis. Further investigation showed that reducing the expression of DNMT3A and TET2 leads to a loss of TFAM expression and subsequent dysfunctional packaging of mitochondrial DNA, triggering DNA ejection and inflammation. Moreover, low levels of DNMT3A and TET2 expression were associated with greater interferon signalling, a cell signalling pathway associated with enhanced atherosclerosis.

'It's very exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now has direct relevance for a disease like atherosclerosis,' said Professor Shadel.

This study demonstrates the importance of mitochondrial DNA stress in regulating cellular inflammation. The characterisation of this novel molecular mechanism could lead to the development of therapeutics which block the pathways that promote atherosclerosis in patients with DNMT3A and TET2 defects.

The researchers plan to continue their collaboration to explore this pathway further and investigate the potential role of mitochondrial DNA stress in other human diseases.