Diminished YAP1 affects mitochondrial dynamics in IDH1 mutant glioma

Mutation in isocitrate dehydrogenase 1 (IDH1) gene, leading to the production of oncometabolite D-2-hydroxyglutarate (2-HG) from α-ketoglutarate, is associated with better prognosis in glioma. As Yes-associated protein 1 (YAP1) is an important regulator of tumor progression, its role in glioma expressing IDH1 R132H mutation was investigated. Diminished nuclear YAP1 in IDH1 mutant patient gliomas and cell lines was accompanied by decreased TFAM levels. Luciferase reporter assays and chromatin immunoprecipitation indicated the functionality of TEAD2 site on TFAM promoter in mediating its YAP1-dependent expression. YAP1-dependent mitochondrial fragmentation and ROS generation was accompanied by decreased TERT levels and increased mitochondrial TERT localization in IDH1 R132H cells. Treatment with Bosutinib that prevents extranuclear TERT shuttle, further elevated ROS in IDH1 R132H cells and triggered apoptosis. Importantly, Bosutinib elevated ROS levels and induced apoptosis in IDH1 WT cells upon concurrent depletion of YAP1. These findings highlight the involvement of YAP1 in coupling mitochondrial dysfunction with TERT mitochondrial shuttle to constitute an essential non-canonical function of YAP1 in regulating redox homeostasis.