CONICET | Buscador de Institutos y Recursos Humanos

INTRODUCTIONCancer cells experience an energetic reprogramming called ?aerobic glycolysis? or ?Warburg effect?. They choose glycolysis over oxidative phosphorylation (OXPHOS) even in the presence of Oxygen. Why this occurs is yet to be completely elucidated. Epigenetic modifications might play a role in this energetic reprogramming. Mitochondrial (MT) diseases have OXPHOS naturally impaired. Our objective was to study whether MT dysfunction could play a role in epigenetic modifications, specifically aberrant methylation of cancer related genes. MATERIALS AND METHODSMethylation of cancer related genes was explored using the Methyl-Specific Multiplex Ligation-dependent Probe amplification assay (MS-MLPA, MRC-Holland®). This was carried out in: 1) 19 samples from 13 MT disease patients using probe kits which covered 94 CpG sites in 55 genes, not methylated in healthy controls. These samples came from low (leukocytes) and high (skeletal muscle and bone marrow) energy demanding tissues that had been used for patient diagnosis. 2) A human skeletal muscle cell line (HSkM) that was used as a high energy demanding tissue model. In these cells, we looked into the methylation status of 24 cancer related genes before and after being treated with an OXPHOS Complex 1 inhibitor (Rotenone). OXPHOS function was determined measuring MT membrane potential using Tetramethylrhodamine Ethyl Ester(TMRE) dye visualized with Confocal Microscopy. RESULTSIn patients´ samples, a gene was considered methylated when the methylation ratio was above 8%. Aberrant methylation profiles were encountered in the majority of the samples (17/19). The mean methylation index (n° of methylated CpG sites/n° of CpG sites explored) differed significantly among tissues with different energy demands (4.9% in leukocytes vs 15.6% in muscle/bone marrow, student test t value= -1.8, p