Wednesday, 2 July 2014

Damage to the energy factories may afect damage

Bros H, Millward JM, Paul F, Niesner R, Infante-Duarte C. Oxidative damage to mitochondria at the nodes of Ranvier precedes axon degeneration in ex vivo transected axons. Exp Neurol. 2014 . pii: S0014-4886(14)00214-3.

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 mouse 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. Mitochondria at the nodes became depolarized (depolarization is a positive-going change in a cell's membrane potential, making it more positive, or less negative, and thereby removing the polarity that arises from the accumulation of negative charges on the inner membrane and positive charges on the outer membrane of the cell. Inneurons and some other cells, a large enough depolarization may result in an action potential. Hyperpolarization is the opposite of depolarization, and inhibits the rise of an action potential), followed by alterations of the external morphology and disruption of the cristae (folds in the inner membrane of a mitochondrion. The cristae give the inner mitochondrial membrane its characteristic wrinkled shape providing a large amount of surface area for chemical reactions to occur on. This aids aerobic cellular respiration (since the mitochondrion requires oxygen), along with reduced mitochondrial transport. These mitochondrial changes expanded from the nodes of Ranvier bidirectionally towards both internodes (Space between the nodes of Ranvier) 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.

Mitochondira are the energy factories of cells and can move up and down nerves to produce energy to keep nerves going. If the mitochondria fail it can lead to nerve damage and death and may be a problem in progressive MS. In this study of peripheral nerves it suggests that damaging chemicals.produced within the nerves can act on the mitochondria in the nerves. This occurs at the Nodes of Ranvier which is the place on nerves between myelin sheets This set of damaging chemicals relate to changes in oxidative function. 

This alters the REDOX balance, which is critical for normal cell function.The term "redox" comes from two concepts involved with electron transfer: reduction and oxidation. It can be explained in simple terms: Oxidation is the loss of electrons or an increase in oxidation state by a molecule, atom, or ion. Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion. They use chemicals to block this effect. Will they limit Nerve damage in MS?

 This was studied in EAE as part of the pre-clinical work up to MS-SMART.

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