Journal article
Mitochondrial control by DRP1 in brain tumor initiating cells
Nature neuroscience, Vol.18(4), pp.501-510
04/01/2015
DOI: 10.1038/nn.3960
PMCID: PMC4376639
PMID: 25730670
Abstract
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 Ca2+-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.
Details
- Title: Subtitle
- Mitochondrial control by DRP1 in brain tumor initiating cells
- Creators
- Qi Xie - Cleveland Clinic Lerner College of MedicineQiulian Wu - Cleveland Clinic Lerner College of MedicineCraig M. Horbinski - University of KentuckyWilliam A. Flavahan - Cleveland Clinic Lerner College of MedicineKailin Yang - Cleveland Clinic Lerner College of MedicineWenchao Zhou - Cleveland Clinic Lerner College of MedicineStephen M. Dombrowski - Cleveland ClinicZhi Huang - Cleveland Clinic Lerner College of MedicineXiaoguang Fang - Cleveland Clinic Lerner College of MedicineYu Shi - Cleveland Clinic Lerner College of MedicineAshley N. Ferguson - University of VirginiaDavid F. Kashatus - University of VirginiaShideng Bao - Cleveland Clinic Lerner College of MedicineJeremy N. Rich - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience, Vol.18(4), pp.501-510
- DOI
- 10.1038/nn.3960
- PMID
- 25730670
- PMCID
- PMC4376639
- NLM abbreviation
- Nat Neurosci
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Publisher
- Springer Nature
- Number of pages
- 12
- Grant note
- James S. McDonnell Foundation Peter and Carmen Lucia Buck Training Program in Translational Clinical Oncology P20RR020171 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Research Programs Committees of Cleveland Clinic University of Kentucky College of Medicine Physician Scientist Program P30CA177558 / University of Kentucky Markey Cancer Center R01NS087913 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R01CA169117 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) CA154130; CA169117; CA171652; NS087913; NS089272; CA155764; 2P20 RR020171; NS070315 / US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 04/01/2015
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696725902771
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