Myelinated axons are the primary target of hemin-mediated oxidative damage in a model of the central nervous system

Baldacchino, K. et al. (2022) Myelinated axons are the primary target of hemin-mediated oxidative damage in a model of the central nervous system. Experimental Neurology, 354, 114113. (doi: 10.1016/j.expneurol.2022.114113) (PMID:35569511)

Abstract

Iron released from oligodendrocytes during demyelination or derived from haemoglobin breakdown products is believed to amplify oxidative tissue injury in multiple sclerosis (MS). However, the pathophysiological significance of iron-containing haemoglobin breakdown products themselves is rarely considered in the context of MS and their cellular specificity and mode of action remain unclear. Using myelinating cell cultures, we now report the cytotoxic potential of hemin (ferriprotoporphyrin IX chloride), a major degradation product of haemoglobin, is 25-fold greater than equimolar concentrations of free iron in myelinating cultures; a model that reproduces the complex multicellular environment of the CNS. At low micro molar concentrations (3.3 - 10 μM) we observed hemin preferentially binds to myelin and axons to initiate a complex detrimental response that results in targeted demyelination and axonal loss but spares neuronal cell bodies, astrocytes and the majority of oligodendroglia. Demyelination and axonal loss in this context are executed by a combination of mechanisms that include iron-dependent peroxidation by reactive oxygen species (ROS) and ferroptosis. These effects are microglial-independent, do not require any initiating inflammatory insult and represent a direct effect that compromises the structural integrity of myelinated axons in the CNS. Our data identify hemin-mediated demyelination and axonal loss as a novel mechanism by which intracerebral degradation of haemoglobin may contribute to lesion development in MS.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Muecklisch, Dr Katja and Komarek, Miss Lina and Sherrard Smith, rebecca and Baldacchino, Mr Karl and Barnett, Professor Susan and Lindsay, Dr Susan and Linington, Professor Christopher and Peveler, Dr William and Edgar, Professor Julia and Hayden, Lorna and Lemgruber Soares, Dr Leandro
• Authors: Baldacchino, K., Peveler, W. J., Lemgruber, L., Sherrard Smith, R., Scharler, C., Hayden, L., Komarek, L., Lindsay, S. L., Barnett, S. C., Edgar, J. M., Linington, C., and Thümmler, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Science and Engineering > School of Chemistry
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Experimental Neurology
• Publisher: Elsevier
• ISSN: 0014-4886
• ISSN (Online): 1090-2430
• Published Online: 13 May 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Experimental Neurology 354: 114113
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
304445		EPSRC Capital Award emphasising support for Early Career Researchers	Muffy Calder	Engineering and Physical Sciences Research Council (EPSRC)	EP/S017984/1	S&E - College Senior Management
310553		Screening for potent inhibitors of neurodegeneration in progressive multiple sclerosis: the role of altered iron homeostasis in oxidative injury of the central nervous system.	Katja Muecklisch	Tenovus Scotland (TENOVUS)	S20-06	III - Immunology