Oxidative damage to mitochondria at the nodes of Ranvier precedes axon degeneration in ex vivo transected axons

摘要

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 mitochondria! transport. These mitochondrial changes expanded from the nodes of Ranvier bidirectionally towards both intemodes 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.