Mitochondrial dysfunction triggers a pro-survival adaptive response.

C. GARCÍA SAMARTINO; G. GUTIERREZ; L. MAYORGA; M.A. LOOS; P. ROMANO; B. N. SALASSA; H. D. EIROA; M. ROQUE

Washington

Congreso; UMDF Symposium: Mitochondrial Medicine 2017.; 2017

Background: Mitochondrias occupy a central role in cells, sustaining the energy level, controlling metabolic processes, and regulating apoptosis. Mitochondrial retrograde signaling (MRS) is considered a stress responsive pathway by which mitochondrias communicate with the nucleus and induce changes in gene expression. Different cellular pathways are triggered in response to stress through specific gene-environment interactions mediated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling and small noncoding RNAs. The epigenetic stress response can be due to low intensity/short term or high intensity/long term stress. In the first case, histone modifications are mainly involved and cause transient changes that lead to cell death through apoptosis. In the second setting, the epigenetic response leads to a more permanent pro-survival adaptive state in which DNA methylation plays an important role. Mitochondrial diseases are genetic disorders that involve primary mitochondrial dysfunction causing high intensity chronic stress. We hypothesized that this stressor triggers an epigenetically mediated pro-survival response, specifically through DNA methylation of nuclear genes. To test this our aims were: 1) To study the differential DNA methylation of nuclear tumor suppressor genes from mitochondrial disease patients and controls. 2) Explore this in healthy cultured skeletal muscle cells treated with mitochondrial inhibitors. 3) Investigate cellular stress mediated responses, such as cell death and autophagy in both models.Results: Skeletal muscle and blood samples were obtained from mitochondrial disease patients and controls. DNA methylation assays of 94 CpG sites from 55 tumor suppressor genes were performed using MS MLPA (MRC-Holland®). The comparison of means in patients and controls revealed that the patients´ muscles had more methylation than controls when comparing global mean methylation (Unpaired t test, p