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Mitochondrial dysfunction and cancer metabolites and beyond
Christian Frezza
MRC Cancer Unit, University of Cambridge, Cambridge, UK
Corresponding author: cf366@MRC-CU.cam.ac.uk
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Mitochondrial dysfunction and cancer metabolites and beyond - - PowerPoint PPT Presentation
Mitochondrial dysfunction and cancer metabolites and beyond - - PowerPoint PPT Presentation
Mitochondrial dysfunction and cancer metabolites and beyond Christian Frezza MRC Cancer Unit, University of Cambridge, Cambridge, UK Corresponding author: cf366@MRC-CU.cam.ac.uk 1 OXPHOS suppression Cancer EMT Metastasis EMT mTUNE
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EMT
mTUNE Edoardo Gaude
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A model of primary mitochondrial dysfunction
Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome
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Heteroplasmy shift using mtZFN
mutant mtDNA wt mtDNA
Michal Minczuk & Payam Gammage Mitochondrial Biology Unit, Cambridge, UK Heteroplasmy shift
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Tunable heteroplasmy shift
Michal Minczuk Payam Gammage
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mTune: a model of tunable mitochondrial dysfunction
mutant mtDNA wt mtDNA 143B osteosarcoma
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mTune: a model of tunable mitochondrial dysfunction
mutant mtDNA wt mtDNA
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mTune: a model of tunable mitochondrial dysfunction
mutant mtDNA wt mtDNA
mTUNE: Stable over time Do not undergo selection
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Metabolic defects in mTune
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mTune and cytoskeleton remodeling
Proteomics mT80 vs mT7
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G O _ PO S I T I V E _ R E G U LA T I O N _ O F _ A CT I N _ N U CLE A T I O N G O _ CE LL_ PR O JE CT I O N _ O R G A N I Z A T I O N G O _ R E G U LA T I O N _ O F _ A CT I N _ N U CLE A T I O N G O _ LA M E LLI PO D I U M _ O R G A N I Z A T I O N G O _ PO S I T I V E _ R E G U LA T I O N _ O F _ CY T O S KE LE T O N _ O R G A N I Z A T I O N G O _ PO S I T I V E _ R E G U LA T I O N _ O F _ A CT I N _ F I LA M E N T _ PO LY M E R I Z A T I O N G O _ A CT I N _ N U CLE A T I O N G O _ A R P2 _ 3 _ CO M PLE X_ M E D I A T E D _ A CT I N _ N U CLE A T I O N
- lo g 1 0 p -v a lu e
FDR 0.05
In collaboration with Julio Saez Rodriguez and Aurelien Dugourd, University of Heidelberg
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mTune in wound healing assay
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Migration speed in mTune
m T 7 m T 8 . 0 . 2 . 4 . 6 . 8
v e l o c i t y µ m / m i n * * * *
Sarah Palmer, Norman Lab, Beatson Institute, Glasgow
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GLYCOLYSIS
MITOCHONDRIA
Glycolysis supports cell migration
ATP migration
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Metabolic modelling of mTune
mt7 mt80
METABOLIC MODELLING
ATP production
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Metabolic models of mT7 and mt80
mt7 mt80
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GLYCOLYSIS
Glycolysis is increased in mT80
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Reductive carboxylation of glutamine
Reductive carboxylation
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Reductive carboxylation in mTune
AcCoA Oxaloacetate
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Reductive carboxylation occurs in the cytosol
mT80
AcCoA
- xaloacetate
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MDH1 links reductive carboxylation to glycolysis
Contribution to ATP production
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MDH1 recycles NADH for glycolytic GAPDH
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MDH1 and glycolysis
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MDH1 and glycolysis
s h N T C s h M D H 1 # 1 s h M D H 1 # 2 0 .0 0 0 .0 1 0 .0 2 0 .0 3 0 .0 4
n o rm a lis e d in te n s ity
M+3 lactate
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??? migration
MDH1 and migration
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MDH1 supports cell migration
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migration
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