Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes

Iryna Ziabreva,Hans Lassmann,Graham Campbell,Robin J M Franklin,Joanna Rorbach,Mateusz M Wydro,Jessica Zambonin,Don Mahad,Julia Rist

doi:10.1002/glia.21052

Abstract

Oligodendrocyte lineage cells are susceptible to a variety of insults including hypoxia, excitotoxicity, and reactive oxygen species. Demyelination is a well-recognized feature of several CNS disorders including multiple sclerosis, white matter strokes, progressive multifocal leukoencephalopathy, and disorders due to mitochondrial DNA mutations. Although mitochondria have been implicated in the demise of oligodendrocyte lineage cells, the consequences of mitochondrial respiratory chain defects have not been examined. We determine the in vitro impact of established inhibitors of mitochondrial respiratory chain complex IV or cytochrome c oxidase on oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes as well as on differentiation capacity of OPCs from P0 rat. Injury to mature oligodendrocytes following complex IV inhibition was significantly greater than to OPCs, judged by cell detachment and mitochondrial membrane potential (MMP) changes, although viability of cells that remained attached was not compromised. Active mitochondria were abundant in processes of differentiated oligodendrocytes and MMP was significantly greater in differentiated oligodendrocytes than OPCs. MMP dissipated following complex IV inhibition in oligodendrocytes. Furthermore, complex IV inhibition impaired process formation within oligodendrocyte lineage cells. Injury to and impaired process formation of oligodendrocytes following complex IV inhibition has potentially important implications for the pathogenesis and repair of CNS myelin disorders. © 2010 Wiley-Liss, Inc.

Highlights

Mature oligodendrocytes remaining on the slides decreased significantly in a dose dependent manner when exposed to complex IV inhibitor whereas (Fig. 2i,j) the number of oligodendrocyte progenitor cells (OPCs) identified by PDGFRA or NG2 was unchanged, except with the highest concentration of the inhibitor at 24 h where both OPC and oligodendrocyte numbers were reduced (Fig. 2g–j)
Potassium cyanide caused a similar degree of complex IV inhibition (Cooper and Brown, 2008) and preferential loss of MBP expressing cells compared with OPCs
The complex IV activity of mitochondria isolated from differentiated oligodendrocyte lineage cells persistently exposed to 1 lM and 10 lM of sodium azide for the 5 days decreased by 35.3% and 65.7%, In this study, we identified mature oligodendrocytes differentiated from P0 rat as more prone to mitochondrial respiratory chain complex IV inhibitor mediated injury than OPCs

Summary

Introduction

Demyelination is a cardinal neuropathological feature of several central nervous system (CNS) disorders including multiple sclerosis (MS), white matter strokes (WMS), progressive multifocal leukoencephalopathy (PML), periventricular leukomalacia (PVL), and certain primary mitochondrial disorders due to mitochondrial DNA (mtDNA) mutations (Aboul-Enein et al, 2003; Barnett and Prineas, 2004; Betts et al, 2004; Gendelman et al, 1985; Lucchinetti et al, 2000; Tanji et al, 2001). Complex IV defects in acute MS lesions, based on the loss of the main catalytic subunit (COX-I), affected oligodendrocytes, astrocytes, and axons (Mahad et al, 2008). Well-established complex IV inhibitors, sodium azide and potassium cyanide, have been used to induce chemical hypoxia in vitro and in vivo the Additional supporting information may be found in the online version of this article

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