Hyperosmolarity Triggers the Warburg Effect in Chinese Hamster Ovary Cells and Reveals a Reduced Mitochondria Horsepower

Abstract

Tumor cells are known to favor a glycolytic metabolism over oxidative phosphorylation (OxPhos), which takes place in mitochondria, to produce the energy and building blocks essential for cell maintenance and cell growth. This phenotypic property of tumor cells gives them several advantages over normal cells and is known as the Warburg effect. Tumors can be treated as a metabolic disease by targeting their bioenergetics capacity. Alpha-lipoic acid (ALA) and calcium hydroxycitrate (HCA) are two drugs known to target the Warburg effect in tumor cells and hence induce the mitochondria for ATP production. However, tumor cells, known to have an increased flux through glycolysis, are not able to handle the activation of their mitochondria by drugs or any other condition, leading to decoupling of gene regulation. In this study, these drug effects were studied by mimicking an inflammatory condition through the imposition of a hyperosmotic condition in Chinese hamster ovary (CHO) cells, which behave similarly to tumor cells. Indeed, CHO cells grown in high osmolarity conditions, using 200 mM mannitol, showed a pronounced Warburg effect phenotype. Our results show that hyperosmolar conditions triggered high-throughput glycolysis and enhanced glutaminolysis in CHO cells, such as during cancer cell proliferation in inflammatory tissue. Finally, we found that the hyperosmolar condition was correlated with increased mitochondrial membrane potential (ΔΨm) but mitochondrial horsepower seemed to vanish (h = Δp/ΔΨm), which may be explained by mitochondrial hyperfusion.

Keywords

• CHO cells
• Warburg effect
• hyperosmolarity
• lipoic acid
• hydroxycitrate
• mitochondrial hyperfusion