Mitochondrial elongation factor 4 modulates energy metabolism and promotes breast cancer metastasis by orchestration of mitochondrial translation

Abstract

To cope with the requirements of energy and building blocks for rapid proliferation, cancer cells reprogram their metabolic pathways profoundly, especially in oxygen- and nutrients-deficient tumor microenvironments. However, functional mitochondria and mitochondria-dependent oxidative phosphorylation are still necessary for the tumorigenesis and metastasis of cancer cells. We show here that mitochondrial elongation factor 4 (mtEF4) is commonly upregulated in breast tumors compared to adjacent non-cancerous tissues, and is relevant to tumor progression and poor prognosis. Down regulation of mtEF4 in breast cancer cells impairs the assembly of mitochondrial respiration complexes, decreases mitochondrial respiration, reduces ATP production, attenuates the formation of lamellipodia, and suppresses cell motility in vitro and cancer metastasis in vivo. On the contrary, upregulation of mtEF4 elevates the mitochondrial oxidative phosphorylation, which contributes to the migratory capacities of breast cancer cells. mtEF4 also increases the potential of glycolysis, probably via an AMPK-related mechanism. In summary, we provide direct evidences that the aberrantly upregulated mtEF4 contributes to the metastasis of breast cancer by coordinating metabolic pathways.

Keywords: Breast cancer; Glycolysis; Metastasis; Mitochondrial elongation factor 4; Oxidative phosphorylation; Tumorigenesis.