Microenvironmental mitochondria transfer support chemo-resistance in cancer cells

Authors

• Y Liu
• Y Lu
• A Li
• H Song
• W Zhang
• MR Gilbert
• C Yang

Abstract

Mitochondria is the powerhouse in eukaryotic cells that plays vital roles in cellular metabolism. Emerging evidence indicates that in addition to inherited from parent cell, mitochondria could be transferred among different cell lineages, which not only supports metabolism but also relieve metabolic stress in recipient cells. Cancer cells exploit mitochondrial function by diverting ATP generation to synthetic pathways, as such to meet the substantial demands for fast cellular proliferation and redox balance. However, it is still obscure on whether microenvironment-derived mitochondria affect cancer biology and disease outcome. In this study, we established in vitro and in vivo model to explore the mitochondria transfer in tumor microenvironment. By co-culture and conditional media system, we demonstrated that mitochondria are released from normal human astrocyte (NHA) via extracellular vesicles (EVs). Microenvironment-derived mitochondria could be internalized by glioma cells that shared the same microenvironment. Mitochondria transfer support metabolism in recipient glioma cells, characterized by significantly increased oxidative metabolism and glycolysis. Moreover, mitochondria transfer supports the synthesis of macromolecules with biologic importance, such as ATP and NADH/NAD+, and therefore potentiates the cellular resistance against chemotherapies by prompting PARP-associated base excision DNA repair (BER) pathway. Our findings suggest that EVs-derived mitochondria component in microenvironment benefit cancer cells with both metabolic capability and chemo-resistance. Targeting microenvironment-derived mitochondria transfer may become a novel avenue in cancer therapies which not only diminish crucial metabolic pathways in cancer cells, but also augment the therapeutic effect with combination with other anti-cancer agents.

Scientific Focus Area: Cell Biology

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