Opposing action of NCoR1 and PGC-1 alpha in mitochondrial redox homeostasis

The ability to respond to fluctuations of reactive oxygen species (ROS) within the cell is a central aspect of mammalian physiology. This dynamic process depends on the coordinated action of transcriptional factors to promote the expression of genes encoding for antioxidant enzymes. Here, we demonstrate that the transcriptional coregulators, PGC-1 alpha and NCoR1, are essential mediators of mitochondrial redox homeostasis in skeletal muscle cells. Our findings reveal an antagonistic role of these coregulators in modulating mitochondrial antioxidant induction through Sod2 transcriptional control. Importantly, the activation of this mechanism by either PGC-1 alpha overexpression or NCoR1 knockdown attenuates mitochondrial ROS levels and prevents cell death caused by lipid overload in skeletal muscle cells. The opposing actions of coactivators and corepressors, therefore, exert a commanding role over cellular antioxidant capacity143203208FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2017/04377-2; 2016/23008-5; 2017/21628-9; 2017/011849The work in Leonardo Silveira lab was supported by grants from FAPESP (2016/23008-5). The work in the Johan Auwerx lab was supported by grants from the Ecole Polytechnique Fédérale de Lausanne (EPFL), and the Swiss National Science Foundation. The work in Marcelo Mori lab was supported by grants from FAPESP (2017/01184-9). Tanes Lima was supported by grants from FAPESP (2017/21628-9). Silas Pinto was supported by grants from FAPESP (2017/04377-2