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 Edoardo Gaude

A model of primary mitochondrial dysfunction Neuropathy, ataxia and retinitis pigmentosa ( NARP ) syndrome

Heteroplasmy shift using mtZFN Heteroplasmy shift mutant mtDNA wt mtDNA Michal Minczuk & Payam Gammage Mitochondrial Biology Unit, Cambridge, UK

Tunable heteroplasmy shift Michal Minczuk Payam Gammage

mTune: a model of tunable mitochondrial dysfunction 143B osteosarcoma mutant mtDNA wt mtDNA

mTune: a model of tunable mitochondrial dysfunction mutant mtDNA wt mtDNA

mTune: a model of tunable mitochondrial dysfunction mTUNE: Stable over time Do not undergo selection mutant mtDNA wt mtDNA

Metabolic defects in mTune

mTune and cytoskeleton remodeling Proteomics mT80 vs mT7 FDR 0.05 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 G O _ A CT I N _ N U CLE 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 _ 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 _ LA M E LLI PO D I U M _ 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 _ CE LL_ PR O JE CT I 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 _ N U CLE A T I O N 0 1 2 3 4 -lo g 1 0 p -v a lu e In collaboration with Julio Saez Rodriguez and Aurelien Dugourd, University of Heidelberg

mTune in wound healing assay

Migration speed in mTune 0 . 8 * * * * 0 . 6 i n / m m µ 0 . 4 c i t y l o v e 0 . 2 0 . 0 m T 7 m T 8 0 Sarah Palmer, Norman Lab, Beatson Institute, Glasgow

Glycolysis supports cell migration MITOCHONDRIA GLYCOLYSIS ATP migration

Metabolic modelling of mTune METABOLIC MODELLING mt7 mt80 ATP production

Metabolic models of mT7 and mt80 mt7 mt80

Glycolysis is increased in mT80 GLYCOLYSIS

Reductive carboxylation of glutamine Reductive carboxylation

Reductive carboxylation in mTune AcCoA Oxaloacetate

Reductive carboxylation occurs in the cytosol mT80 AcCoA oxaloacetate

MDH1 links reductive carboxylation to glycolysis Contribution to ATP production

MDH1 recycles NADH for glycolytic GAPDH

MDH1 and glycolysis

MDH1 and glycolysis M+3 lactate 0 .0 4 n o rm a lis e d in te n s ity 0 .0 3 0 .0 2 0 .0 1 0 .0 0 s h M D H 1 # 1 s h M D H 1 # 2 s h N T C

MDH1 and migration ??? migration

MDH1 supports cell migration

migration

migration For more details check Gaude et al, Mol Cell 2018 Follow us at Twitter: @FrezzaLab