Disruption of cytochrome c oxidase function induces the Warburg effect and metabolic reprogramming

Abstract

Defects in mitochondrial oxidative phosphorylation complexes, altered bioenergetics and metabolic shift are often seen in cancers. Here we show a role for the dysfunction of the electron transport chain component cytochrome c oxidase (CcO) in cancer progression. We show that genetic silencing of the CcO complex by shRNA expression and loss of CcO activity in multiple cell types from the mouse and human sources resulted in metabolic shift to glycolysis, loss of anchorage-dependent growth and acquired invasive phenotypes. Disruption of the CcO complex caused loss of transmembrane potential and induction of Ca2+/Calcineurin-mediated retrograde signaling. Propagation of this signaling includes activation of PI3-kinase, IGF1R and Akt, Ca2+-sensitive transcription factors and also TGFβ1, MMP16 and periostin, which are involved in oncogenic progression. Whole-genome expression analysis showed the upregulation of genes involved in cell signaling, extracellular matrix interactions, cell morphogenesis, cell motility and migration. The transcription profiles reveal extensive similarity to retrograde signaling initiated by partial mitochondrial DNA depletion, although distinct differences are observed in signaling induced by CcO dysfunction. The possible CcO dysfunction as a biomarker for cancer progression was supported by data showing that esophageal tumors from human patients show reduced CcO subunits IVi1 and Vb in regions that were previously shown to be the hypoxic core of the tumors. Our results show that mitochondrial electron transport chain defect initiates a retrograde signaling. These results suggest that a defect in the CcO complex can potentially induce tumor progression.

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Acknowledgements

This work was supported by NIH grants CA-22762 and GM-34883, and an endowment from the Harriet Ellison Woodward Trust to NGA and a grant to SS from Mitochondria research affinity group, Children’s hospital of Philadelphia. We also acknowledge the help of the Imaging Core facility at the School of Veterinary Medicine and the NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases (P30DK050306) and its Molecular Pathology and Imaging Core facilities at the Perelman School of Medicine.

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Correspondence to N G Avadhani.

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Srinivasan, S., Guha, M., Dong, D. et al. Disruption of cytochrome c oxidase function induces the Warburg effect and metabolic reprogramming. Oncogene 35, 1585–1595 (2016). https://doi.org/10.1038/onc.2015.227

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