Mitochondrial control by DRP1 in brain tumor initiating cells.
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.
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
Qi
Q
Xie
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
Qiulian
Q
Wu
Department of Pathology, University of Kentucky, Lexington, Kentucky, USA.
Craig M
CM
Horbinski
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
William A
WA
Flavahan
1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA. [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Kailin
0000000159686738
K
Yang
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
Wenchao
W
Zhou
Department of Neurological Surgery, Cleveland Clinic, Cleveland, Ohio, USA.
Stephen M
SM
Dombrowski
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
Zhi
Z
Huang
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
Xiaoguang
X
Fang
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
Yu
Y
Shi
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
Ashley N
AN
Ferguson
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
David F
DF
Kashatus
1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA. [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Shideng
S
Bao
1] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland, Ohio, USA. [2] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
Jeremy N
JN
Rich
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011379:Prognosis
D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins