Mitochondrial control by DRP1 in brain tumor initiating cells

• Published in: Nature neuroscience Vol. 18; no. 4; pp. 501 - 510
• Main Authors: Xie, Qi, Wu, Qiulian, Horbinski, Craig M, Flavahan, William A, Yang, Kailin, Zhou, Wenchao, Dombrowski, Stephen M, Huang, Zhi, Fang, Xiaoguang, Shi, Yu, Ferguson, Ashley N, Kashatus, David F, Bao, Shideng, Rich, Jeremy N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2015; Nature Publishing Group
• Subjects: 13/100; 13/105; 13/106; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 14/19; 45/22; 631/378/1689/1690; 631/378/2183/2581; 631/67; 64/60; Animal Genetics and Genomics; Apoptosis - drug effects; Apoptosis - physiology; Behavioral Sciences; Biological Techniques; Biology; Biomedicine; Brain cancer; Brain Neoplasms - metabolism; Brain research; Brain tumors; Cell cycle; Cell Line, Tumor; Cyclin-dependent kinases; Dynamins; Glioblastoma - metabolism; GTP Phosphohydrolases - antagonists & inhibitors; GTP Phosphohydrolases - metabolism; Humans; Kinases; Metabolism; Microtubule-Associated Proteins - antagonists & inhibitors; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial DNA; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - metabolism; Morphology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neurobiology; Neurosciences; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Physiological aspects; Prognosis; Proteins; Stem cells; United States > US; Ohio
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3960

Glioblastomas contains stem-like tumor cells that display differential metabolic profiles. Here the authors show that brain tumor initiating cells contain fragmented mitochondria owing to activation of the key mediator of mitochondrial fission, DRP1, controlled by a competitive CDK5–CAMK2 axis. Targeting DRP1 activity attenuates growth of stem-like tumor cells, and activated DRP1 informs poor patient prognosis. Brain tumor initiating cells (BTICs) co-opt the neuronal high affinity glucose transporter, GLUT3, to withstand metabolic stress. We investigated another mechanism critical to brain metabolism, mitochondrial morphology, in BTICs. BTIC mitochondria were fragmented relative to non-BTIC tumor cell mitochondria, suggesting that BTICs increase mitochondrial fission. The essential mediator of mitochondrial fission, dynamin-related protein 1 (DRP1), showed activating phosphorylation in BTICs and inhibitory phosphorylation in non-BTIC tumor cells. Targeting DRP1 using RNA interference or pharmacologic inhibition induced BTIC apoptosis and inhibited tumor growth. Downstream, DRP1 activity regulated the essential metabolic stress sensor, AMP-activated protein kinase (AMPK), and targeting AMPK rescued the effects of DRP1 disruption. Cyclin-dependent kinase 5 (CDK5) phosphorylated DRP1 to increase its activity in BTICs, whereas Ca 2+ -calmodulin-dependent protein kinase 2 (CAMK2) inhibited DRP1 in non-BTIC tumor cells, suggesting that tumor cell differentiation induces a regulatory switch in mitochondrial morphology. DRP1 activation correlated with poor prognosis in glioblastoma, suggesting that mitochondrial dynamics may represent a therapeutic target for BTICs.