Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes.
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.
Ziabreva
Iryna
I
The Mitochondrial Research Group, Newcastle University, Framlington Place, Newcastle upon Tyne, United Kingdom.
Campbell
Graham
G
Rist
Julia
J
Zambonin
Jessica
J
Rorbach
Joanna
J
Wydro
Mateusz M
MM
Lassmann
Hans
H
Franklin
Robin J M
RJ
Mahad
Don
D
D000818:Animals; D000831:Animals, Newborn; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001921:Brain / Q000166:cytology; D053453:Caspase 9 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling / Q000379:methods; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D019810:Sodium Azide / Q000494:pharmacology; D013053:Spectrophotometry / Q000379:methods; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D051033:Apoptosis Inducing Factor; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019810:Sodium Azide; D003576:Electron Transport Complex IV; D053453:Caspase 9