Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy

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 Cl complex. Although small, Ndufs4 knockout (KO) mice appeared healthy until similar to 5 weeks of age, when ataxic signs began, progressing to death at similar to 7 weeks. KO mice manifested encepha-lomyopathy including a retarded growth rate, lethargy, loss of motor skill, blindness, and elevated serum lactate. Cl activity in submitochondrial particles from KO mice was undetectable by spectrophotometric assays. However, Cl-driven oxygen consumption by intact tissue was about half that of controls. Native gel electrophoresis revealed reduced levels of intact Cl. These data suggest that Cl 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.