IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Mitochondrial dysfunction triggers a pro-survival adaptive response through distinct DNA methylation of nuclear genes.
Autor/es:
MAYORGA, LÍA; LOOS, MARIANA A.; GARCÍA SAMARTINO, CLARA; SALASSA, BETIANA N; EIROA, HERNÁN D.; ROMANO, PATRICIA S; MARZESE, DIEGO M.; LUBIENIECKI, FABIANA; ROQUÉ, MARÍA
Lugar:
Mendoza
Reunión:
Congreso; World Muscle Society Congress 2018; 2019
Institución organizadora:
https://www.nmd-journal.com/article/S0960-8966(18)30791
Resumen:
Epigenetics can modulate cellular responses to stress and DNA methylation has been associated to high intensity stress adaptive responses. Wehypothesized that mitochondrial (MT) dysfunction could trigger an epigenetically mediated adaptive response. To test this, we studied stress responsesin an in vitro and in vivo model of MT dysfunction and explored their epigenetic modulation. In vitro: human skeletal myoblasts exposed to the MTcomplex I inhibitor Rotenone(Rot) showed that high doses of the drug(Rot1&10microM) managed to keep cell death to the control level, whereaslower doses(Rot-0.1microM) increased their cell death through apoptosis(AnnexinV+TO-PRO-3 flow cytometry). Autophagy was increased in theRot-10microM condition (LC3 IIF+WB) and we proved that this processwas necessary for cell survival. DNA methylation inhibition with 5-Aza-2-deoxycytidine(5-Aza) evidenced that methylation was also necessary for this?pro-survival? state since cells showed enhanced apoptosis and inhibition ofautophagy when treated with Rot-10microM+5-Aza. In vivo: Skeletal muscle and blood samples were obtained from MT disease patients and healthycontrols. Autophagy was explored in muscle samples by LC3 WB revealingincreased autophagy in patients. DNA methylation assays of tumor suppressor genes (MS-MLPA) was enhanced in both of patients? tissues. Reducedrepresentative bisulfite sequencing(RRBS) also evidenced hypermethylationof CpG rich regions in patients? muscles. With G.R.E.A.T analysis of theRRBS data, we found that the pathways altered by distinct methylation correlated with the ones known to be dysregulated at a transcriptional level.Therefore, the transcriptome could be driven by DNA methylation in this MTdysfunctional scenario. We highlight the methylation and transcriptional alteration of the ?Nutrient sensing network? key for autophagy and cell survivalregulation. MT dysfunction leads to a ?pro-survival? response that seems tobe triggered by the differential methylation of nuclear genes.