Mitochondrial levels determine variability in cell death by modulating apoptotic gene expression

Abstract

Fractional killing is the main cause of tumour resistance to chemotherapy. This phenomenon is observed even in genetically identical cancer cells in homogeneous microenvironments. To understand this variable resistance, here we investigate the individual responses to TRAIL in a clonal population of HeLa cells using live-cell microscopy and computational modelling. We show that the cellular mitochondrial content determines the apoptotic fate and modulates the time to death, cells with higher mitochondrial content are more prone to die. We find that all apoptotic protein levels are modulated by the mitochondrial content. Modelling the apoptotic network, we demonstrate that these correlations, and especially the differential control of anti- and pro-apoptotic protein pairs, confer mitochondria a powerful discriminatory capacity of apoptotic fate. We find a similar correlation between the mitochondria and apoptotic proteins in colon cancer biopsies. Our results reveal a different role of mitochondria in apoptosis as the global regulator of apoptotic protein expression.The Spanish Ministry of Economy and Competitiveness (MINECO) supported this research under grants BFU2013-45918-R and BFU2016-79127-R. F.J.I. acknowledges a grant from the European Sequencing and Genotyping Infrastructure (ESGI), Grant Agreement no. 262055. J.D.C. is a recipient of a Ph.D. fellowship ‘Severo Ochoa’ Excellence Program from MINECO. R.G. acknowledges funding from the AIRBIOTACM project of Comunidad Autónoma de Madrid (S2013/MAE-2874)