Characterization Of The Ncor1 Complex And Its Association With The Molecular Control Of The Mitochondrial Biogenesis Process

Metabolic homeostasis is regulated transcriptionally through the interaction between transcription factors, co‐regulators and proteins of the basal transcriptional complex. Nuclear co‐regulators work either as transcriptional repressors or as transcriptional activators and, therefore, are strictly regulated to synchronize metabolic pathways to environmental stimuli. Preliminary results from our laboratory have indicated that the NCoR1 co‐repressor plays an important role in the regulation of mitochondrial biogenesis and oxidative metabolism in muscle cells. During the differentiation process of C2C12 muscle cells, the expression of the NCoR1 repressor is reduced favoring the process of mitochondrial biogenesis. While, overexpression of NCoR1 negatively affects the oxidative characteristics of these cells. These observations suggest that NCoR1 plays a central role in binding the nuclear receptor to the transcriptional program of mitochondrial biogenesis. In this way, we are proposing here study to identify and characterize NCoR1 protein (s) involved in the regulation of mitochondrial biogenesis in MEF cells. Thus, we hope to identify potential therapeutic targets in the management of obesity and diabetes. The design will be performed through the following experimental steps: 1) Co‐immunoprecipitation/proteome of the NCoR1 complex; 2) In silico analysis of target candidates; 3) Identification of the target through functional/biochemical tests. Finally we intend to explore the target interface/NCoR1 as therapeutic potential in experimental models of insulin resistance/obesity. The overexpression of NCoR1 was confirmed by PCR and western blotting (Figure 1). After NCoR1 co‐imunoprecipitation (Fig. 2), cellular extract was submitted to mass spectrometry (LC‐MS/MS ) analysis and at least 15 targets were identified (Table 1). The identified proteins were listed according to (A) cellular components; (B) Molecular function; (C) Biological process (Fig. 3). Interactome analysis also demonstrated physical interaction among NcoR1 and indentified proteins including Hdac3, Tbl1xr1, GPS2 and Chd8 (Fig. 4). This analysis revealed potential candidates to control mitochondrial function/biogenesis in MEF cells. Support or Funding Information This work was supported by grant from Fundação de Amparo à Pesquisa do estado de São Paulo – FAPESP (2016/23008‐5), Capes and CNpq. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .