Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome.
To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by approximately 7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. Neurons, particularly in these brain regions, had aberrant mitochondrial morphology. Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.
Quintana
Albert
A
Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Kruse
Shane E
SE
Kapur
Raj P
RP
Sanz
Elisenda
E
Palmiter
Richard D
RD
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007888:Leigh Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype
C534449:Ndufs4 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8; D042967:Electron Transport Complex I