title: Oxidative damage to mitochondria at the nodes of Ranvier precedes axon degeneration in ex vivo transected axons.
abstract: Oxidative stress and mitochondrial dysfunction appear to contribute to axon degeneration in numerous neurological disorders. However, how these two processes interact to cause axonal damage-and how this damage is initiated-remains unclear. In this study we used transected motor axons from murine peripheral roots to investigate whether oxidative stress alters mitochondrial dynamics in myelinated axons. We show that the nodes of Ranvier are the initial sites of mitochondrial damage induced by oxidative stress. There, mitochondria became depolarized, followed by alterations of the external morphology and disruption of the cristae, along with reduced mitochondrial transport. These mitochondrial changes expanded from the nodes of Ranvier bidirectionally towards both internodes and eventually affected the entire mitochondrial population in the axon. Supplementing axonal bioenergetics by applying nicotinamide adenine dinucleotide and methyl pyruvate, rendered the mitochondria at the nodes of Ranvier resistant to these oxidative stress-induced changes. Importantly, this inhibition of mitochondrial damage protected the axons from degeneration. In conclusion, we present a novel ex vivo approach for monitoring mitochondrial dynamics within axons, which proved suitable for detecting mitochondrial changes upon exogenous application of oxidative stress. Our results indicate that the nodes of Ranvier are the site of initial mitochondrial damage in peripheral axons, and suggest that dysregulation of axonal bioenergetics plays a critical role in oxidative stress-triggered mitochondrial alterations and subsequent axonal injury. These novel insights into the mechanisms underlying axon degeneration may have implications for neurological disorders with a degenerative component.
authors: Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Experimental and Clinical Research Center, a joint cooperation between the Charité-Universitätsmedizin Berlin and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany; NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: elena.bros@charite.de.
authors: Helena
authors: H
authors: Bros
authors: Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Experimental and Clinical Research Center, a joint cooperation between the Charité-Universitätsmedizin Berlin and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany. Electronic address: jason.millward@charite.de.
authors: Jason M
authors: JM
authors: Millward
authors: Experimental and Clinical Research Center, a joint cooperation between the Charité-Universitätsmedizin Berlin and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany; NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: friedemann.paul@charite.de.
authors: Friedemann
authors: F
authors: Paul
authors: Deutsches Rheuma-Forschungszentrum, Charitéplatz 1, 10117 Berlin, Germany. Electronic address: niesner@drfz.de.
authors: Raluca
authors: R
authors: Niesner
authors: Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Experimental and Clinical Research Center, a joint cooperation between the Charité-Universitätsmedizin Berlin and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany. Electronic address: carmen.infante@charite.de.
authors: Carmen
authors: C
authors: Infante-Duarte
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D004734:Energy Metabolism; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000473:pathology* / Q000648:ultrastructure; D009243:NAD / Q000494:pharmacology; D009410:Nerve Degeneration / Q000473:pathology* / Q000517:prevention & control; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011773:Pyruvates / Q000494:pharmacology; D011901:Ranvier's Nodes / Q000473:pathology* / Q000648:ultrastructure*; D019051:Rhizotomy / Q000009:adverse effects; D013126:Spinal Nerve Roots / Q000601:surgery; D018709:Statistics, Nonparametric
chemical_list: D011773:Pyruvates; D009243:NAD; C104813:methyl pyruvate; D006861:Hydrogen Peroxide
keywords: Axonal degeneration; Mitochondria; NAD(+); Neurodegenerative disease; Node of Ranvier; Oxidative stress