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Mitochondrial Fusion in Adult Myelinated Axons Justin Robert Schultz.

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1 Mitochondrial Fusion in Adult Myelinated Axons Justin Robert Schultz

2 Acknowledgements Local Mitochondrial Fusion in Adult Myelinated Axons In Vivo by Chuan-Li Zhang1, Lance Rodenkirch, Justin R Schultz and Shing Yan Chiu Dept. of Physiology, W. M. Keck Laboratory for Biological Imaging 1300 University Avenue, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706

3 Background Axons act as information highways The brain will send out signals that travel along axons Axons of adults are coated with myelin Protects axon from being damaged Bundles of axons are called nerves Mitochondria are mobile organelles Travel along the axon Key for providing energy to the axons


5 Mitochondria Importance Necessary for providing energy to axon If mitochondria die or become immobile the axon will die If axon dies signals from the brain are distorted

6 Demyelination Myelin can be damaged or stripped from the axon This is the case in different diseases Our focus is how it effects Multiple Sclerosis patients Signals are not sent correctly



9 Mitochondrial Remodeling Is it possible that mitochondria have the ability to help rebuild other mitochondria? This is our focus for the paper We are one of the first labs to actually study this In- vivo


11 Mitochondrial Remodeling Fusion occurring in the cell soma

12 Mitochondrial Remodeling Local Fusion Fusion occurring between two mitochondria within the axon

13 Finding Local Fusion Actually we have a simple concept Using two different dyes Two-color coded mitochondrial populations labeled spatially apart in sciatic nerve Colors used Red (MitoTracker-Red-CMXRos ) Green (MitoTracker-Green-FM)

14 Finding Local Fusion If Fusion does occur locally in the axon the two colors will mix Green + Red = Yellow On imaging system when yellow is seen this means fusion occurred

15 Arguments Many researchers will argue that this is only a 2-D rendering of the image It is possible that a yellow mitochondria is not actually fused There could be two mitochondria on two different z planes This would produce a yellow image Lucky for us we were able to fight these arguments Using a $500,000 Nikon imaging system and Nikon $30,000 software Able to do 3-D rendering


17 Complete Fusion Nikon Imaging system 3-D Rendering of the axon and mitochondria Important Note: Need thin optical z-sections This shows that on a specific z-section there is nothing below or above the mitochondria No longer can argue that it isn’t Fusion



20 Movies

21 Significance to Multiple Sclerosis In last 5 years: Mitochondrial dysfunction has been increasingly linked to axonal death in MS Essential subunits of the respiratory complexes I, III, IV are encoded by mtDNA Myelinated axons can possibly locally repair their damaged mtDNA Mitochondrial fusion stabilizes mtDNA and allows cells to tolerate runaway mtDNA mutations

22 Significance to Multiple Sclerosis Mitochondrial fusion is neuroprotective in various neurodegenerative diseases Our focus is Multiple Sclerosis Mitochondrial fusion might allow two high-energy mitochondria to join forces and “thwart” axonal death

23 Significance to Multiple Sclerosis Current thinking in mitochondrial targeting in MS therapy has focused on blocking free radicals Our lab suggests a novel approach: boost ongoing axonal mitochondrial fusion to repair damaged mitochondria in MS

24 Relevance to Patients with MS Recently our lab was recognized for work done 30 years ago A drug called Amprya was just approved by the FDA in March 2010 The drug allows blockage of potassium channels when myelin is damaged This allows for a more smooth transition of signals to and from the brain

25 Relevance to Patients with MS Brian White thought he might benefit from taking Ampyra. White, a 45-year-old from the Antigo area, was diagnosed with relapsing-remitting MS in 1999. Since then, his strength, balance and walking longevity have declined. “I couldn’t walk more than 100 feet without getting really tired,” he said. “And I wasn’t that quick.” His troubles walking were impacted by his inability to see cracks and unevenness in pavement.

26 Questions

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