title: Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy.
abstract: To study effects of mitochondrial complex I (CI, NADH:ubiquinone oxidoreductase) deficiency, we inactivated the Ndufs4 gene, which encodes an 18 kDa subunit of the 45-protein CI complex. Although small, Ndufs4 knockout (KO) mice appeared healthy until approximately 5 weeks of age, when ataxic signs began, progressing to death at approximately 7 weeks. KO mice manifested encephalomyopathy including a retarded growth rate, lethargy, loss of motor skill, blindness, and elevated serum lactate. CI activity in submitochondrial particles from KO mice was undetectable by spectrophotometric assays. However, CI-driven oxygen consumption by intact tissue was about half that of controls. Native gel electrophoresis revealed reduced levels of intact CI. These data suggest that CI fails to assemble properly or is unstable without NDUFS4. KO muscle has normal morphology but low NADH dehydrogenase activity and subsarcolemmal aggregates of mitochondria. Nonetheless, total oxygen consumption and muscle ATP and phosphocreatine concentrations measured in vivo were within normal parameters.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shane E
authors.initials: SE
authors.lastname: Kruse
authors.forename: William C
authors.initials: WC
authors.lastname: Watt
authors.forename: David J
authors.initials: DJ
authors.lastname: Marcinek
authors.forename: Raj P
authors.initials: RP
authors.lastname: Kapur
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Schenkman
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018482:Muscle, Skeletal / Q000166:cytology / Q000648:ultrastructure; D009245:NADH Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D010641:Phenotype; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D009245:NADH Dehydrogenase; D000251:Adenosine Triphosphatases; D042967:Electron Transport Complex I