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

Silvia Márquez-Jurado, Juan Díaz-Colunga, Ricardo Pires Neves, Antonio Martinez-Lorente, Fernando Almazán, Raúl Guantes () and Francisco J. Iborra ()
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Silvia Márquez-Jurado: Campus de Cantoblanco
Juan Díaz-Colunga: Campus de Cantoblanco
Ricardo Pires Neves: Center of Innovation in Biotechnology
Antonio Martinez-Lorente: Department of Pathology of Torrevieja and Vinalopó Hospitals
Fernando Almazán: Campus de Cantoblanco
Raúl Guantes: Universidad Autónoma de Madrid, Campus de Cantoblanco
Francisco J. Iborra: Campus de Cantoblanco

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02787-4

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