title: Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis.
abstract: Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial electron transport component, the cytochrome c oxidase (CcO), leads to increased glycolysis and carcinogenesis. Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm) increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca (2+) sensitive Calcineurin (Ppp3ca) and the expression of PI3-kinase (Pik3r4 and Pik3cb) increased by two folds. This Ca (2+)/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01) between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10(- 5)). Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.
authors.affiliation: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States ; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, PA, United States.
authors.forename: Dawei W
authors.initials: DW
authors.lastname: Dong
authors.affiliation: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States.
authors.forename: Satish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States.
authors.forename: Manti
authors.initials: M
authors.lastname: Guha
authors.affiliation: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States.
authors.forename: Narayan G
authors.initials: NG
authors.lastname: Avadhani
keywords: Cytochrome c oxidase defects; Functional analysis; Genome expression; Mitochondrial metabolic dysfunction; Tumor progression