Glutamate dehydrogenase (GDH) regulates bioenergetics and redox homeostasis in human glioma

Abstract

The mitochondrial enzyme, glutamate dehydrogenase (GDH), is commonly upregulated in human cancers. Whether and how GDH contributes to the development of glioma remains unknown. Here we report that GDH is a mitochondrial regulator for alpha-ketoglutarate (α-KG) in glioma cells. GDH expression and activity are up-regulated in human glioma cell lines and tissues, and high level of GDH predicts poor outcome. We demonstrate that GDH is an oncogenic factor in vitro and in vivo by using loss-of-function and gain-of-function strategies. GDH is important for bioenergetics (glutamine uptake, ATP production) and redox homeostasis (mitochondria ROS) in glioma cells by controlling the intracellular level of its product α-KG. Finally, we show that inhibiting GDH by overexpression of Sirt4 or by small molecule inhibitors EGCG and R162 leads to attenuated cancer cell proliferation and tumor growth in vitro and in vivo. These findings shed a light that GDH is a new potential target for treatment of human glioma.