Abstract

Introduction: Respiratory supercomplexes are dynamic assemblies of complex I, III and IV within the inner mitochondrial membrane, allowing the adjustment of respiratory control to cell´s energy demands. Assembly factors are then required for the configuration and stability of supercomplexes. In this regard, HIG2A has been recently described and it was shown that HIG2A knocking down impaired supercomplex formation. However, how HIG2A is regulated at the level of gene expression is not known. Our current objective is to study the regulation of the higd2a gene that encode for HIG2A. Methodology: We performed bioinformatics analyses of HIG2A; higd2a gene expression by qRT-PCR; and reporter assays. Tests were performed in cell lines and C57BL/6 mice. Results: HIG2A has a hypoxia-inducible domain and higd2a expression was increased significantly in C2C12 cells after hypoxia exposure. Promoter region of higd2a possesses binding sites for PPAR-α and E2F1 transcription factors. We modulated chemically PPAR-α and E2F-1 in C2C12 and HEK293 cells and this induced significant changes on higd2a expression. In mice, higd2a expression showed differential tissue expression, which was higher in bone marrow than in liver and spleen. Furthermore, we observed that mice injected with quercetin, a modulator of energetic metabolism, displayed a tissue-differential expression of higd2a. In spleen and bone marrow, higd2a expression increased significantly, while in liver decreased significantly as compared with control mice. Conclusions: Alterations in cellular metabolism lead to changes in higd2a gene expression. HIG2A protein might function as a regulator of respiratory supercomplexes in response to changes in cellular metabolism.