Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Similar to 2014 11-25 presentación lactrims matute - lima (peru)
Similar to 2014 11-25 presentación lactrims matute - lima (peru) (20)
More from Achucarro-Neuroscience
More from Achucarro-Neuroscience (7)
Recently uploaded
Recently uploaded (20)
2014 11-25 presentación lactrims matute - lima (peru)
- 1. www.excemed.org IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION 2014 Pre LACTRIMS conference on progressive MS 26 November 2014 - Lima, Perù
- 2. 2 Private funding Novartis, Biogen, Merck KGaA Public funding MINECO, CIBERNED, Gobierno Vasco Faculty disclosure Universidad del País Vasco / Euskal Herriko Unibertsitatea Carlos Matute e-mail: carlos.matute@ehu.es
- 3. Mitochondrial alterations in Multiple Sclerosis Outline: • An introduction to mitochondria, the cell powerhouse • Oligodendrocytes supply lactate to myelinated axons • Excitotoxicity in oligodendrocytes damages mitochondria • Mitochondrial defects in MS: neurons, axons and oligodendrocytes
- 4. Oxidative phosphorylation Intermediate metabolism Ca2+ homeostasis Mitochondria: a multi-functional organelle Apoptosis
- 5. Mitochondrial function relevance in white matter • In white matter: axons & oligodendrocytes rely on mitochondrial function to support neurotransmission • In oligodendrocytes, mitochondrial function is essential for viability and myelin synthesis (Acetyl-CoA) • In astrocytes, ATP is critical for the control of glutamate metabolism • Axons → High energy demand (primarily ATP) • N-acetylaspartate (NAA) – Neuronal integrity marker – Synthesized in neuronal mitochondria – Converted to acetate by oligodendrocytes for myelin synthesis
- 6. Three main mitochondrial homeostatic disruptions 1. Energy failure: [ATP]↓↓ 2. Oxidative Stress: ROS > antioxidant systems 3. Ca2+ overload Central features of all neurodegenerative disorders Physiologycal Pathological
- 7. Saab et al (2013) Curr Op Neurobiol Myelin supplies energy substrates to axons
- 8. submitted Oligodendroglial NMDA receptors regulate axonal energy metabolism Demyelination impairs energy supply to axons
- 9. Models of Disease Pathogenesis in Multiple Sclerosis Hauser and Oksenberg 2006 Neuron ATP Demyelination, oligodendrocyte death, axonal damage, neuronal loss, atrophy
- 10. Glutamate and ATP in excess is toxic to oligodendrocytes and myelin MBP TUNEL CNPase CNPase Matute 1998 PNAS USA
- 11. Glutamate levels are elevated in multiple sclerosis Magnetic resonance spectroscopy at 3 T astrogliosis Srinivasan et al 2005 Brain
- 12. Glutamate and ATP toxicity in oligodendrocytes PI – dead cells KAINATE or ATPCONTROL FDA – live cells Matute et al 1997 PNAS USA
- 13. CELL DEATH ROS AIF Nucleus DNA fragmentation PARP-1 Procaspase 8 t-Bid Caspase 3,6,7 Caspase 8 FADD Bid AMPA-RVGCC Na+ Ca2+ m Bcl-2 Cyt c Apaf-1 Caspase 9 CdP P P P Bad Bad 14-3- 3 Bcl-xl KAINATE-R [Ca2+]i Ca2+ VGCC Calpain Bax Sánchez-Gómez et al. J Neurosci 2003 Sánchez-Gómez et al., J Neurosci, 2011 Mitochondria at the crossroads of excitotoxicity in oligodendrocytes
- 14. Butt, Fern, Matute (2014 ) Glia Glutamate and ATP signaling are central to MS pathophysiology Neuroinflammation favors excitotoxic-mediated mitochondrial damage
- 15. • Altered glutamate homeostasis induces mitochondrial damage • Presence of high NO: oxidative stress • Myelin loss-induced trophic imbalance • Expression of mitochondrial respiratory chain complex I, II and III is reduced in MS active lesions and motor cortex • mtDNA defects associated with MS • Abnormal intra-axonal mitochondria prior to axon disruption • Low N-acetyl aspartate levels in acute and chronic lesions and in normal appearing WM Mitochondrial dysfunctions in MS
- 16. Franklin y Ffrench-Constant 2008 Nat Rev Neurosci Persistent demyelination leads to axonal damage Atrophy: loss of axons and neurons
- 17. Axons transiently adapt to demyelination Early response to demyelination Waxman 2006, Nat Rev Neurosci
- 18. Demyelinated axons are more vulnerable to energy failure and therefore to mitochondrial dysfunction → Axonal degeneration in MS Mitochondrial dysfunction → Energy failure → Na+ / K + ATPase↓ → Depolarization → sustained Na+ influx → Reverse activity of the Na+ / Ca2+ exchanger → Ca2+ overload → Axonal damage Non-remyelinated axons ultimately degenerate Late response to demyelination Waxman 2006, Nat Rev Neurosci
- 19. Mechanisms of axonal damage during inflammation and demyelination Waxman 2006, Nat Rev Neurosci
- 20. Ca2+ overload in mitochondria initiates axonal failure in MS Abou-Sleiman et al. 2006 Nat Rev Neurosci
- 21. Ca2+ overload and mPTP opening in MS • Cyclophilin D is a key regulator of the permeability transition pore (mPTP) opening. • CyPD KO neurons were resistant to oxidative stress and NO, and tolerated higher levels of mitochondrial Ca2+ • CyPD KO-EAE mice partially recovered and preserved axonal integrity. Forte et al. 2007, PNAS
- 22. Conclusions 1. White matter is highly dependent on mitochondrial ATP to propagate electric signals, maintain ionic gradients and facilitate axonal transport 2. Inflammation, oxidative stress and Ca2+ homeostasis disruption lead to mitochondrial dysfunction and energy failure in MS 3. Demyelinated axons in MS lesions are more vulnerable to energy failure and mitochondrial dysfunction 4. ROS and Ca2+ damage axons by inducing mitochondrial mPTP opening.
- 23. María Domercq Alberto Pérez Samartín Fernando Pérez Cerdá Fabio Cavaliere Elena Alberdi Vicky Sánchez Olatz Pampliega Olatz Oyanguren Estibaliz Etxeberria Nuria Vázquez Estibaliz Gonzalez Juan Carlos Chara Hospital de Basurto, Bilbao Alfredo Rodríguez-Antigüedad MPI, Göttingen Frank Kirchhoff AECOM, New York Eliana Scemes Universidad del País Vasco, Leioa, Spain Acknowledgments