Analysis of mouse models of cytochrome c oxidase deficiency owing to mutations in Sco2
Hua Yang1, Sonja Brosel, Rebeca Acin-Perez
1Department of Neurology, Columbia University Medical Center, Berrie-303A, New York, NY 10032, USA.
Abstract:
Mutations in SCO2, a protein required for the proper assembly and functioning of cytochrome c oxidase (COX; complex IV of the mitochondrial respiratory chain), cause a fatal infantile cardioencephalomyopathy with COX deficiency. We have generated mice harboring a Sco2 knock-out (KO) allele and a Sco2 knock-in (KI) allele expressing an E-->K mutation at position 129 (E129K), corresponding to the E140K mutation found in almost all human SCO2-mutated patients. Whereas homozygous KO mice were embryonic lethals, homozygous KI and compound heterozygous KI/KO mice were viable, but had muscle weakness; biochemically, they had respiratory chain deficiencies as well as complex IV assembly defects in multiple tissues. There was a concomitant reduction in mitochondrial copper content, but the total amount of copper in examined tissues was not reduced. These mouse models should be of use in further studies of Sco2 function, as well as in testing therapeutic approaches to treat the human disorder.
Insights
Mice with SCO2 gene mutations, crucial for cellular respiration, show muscle weakness and complex IV assembly defects. These models aid in understanding and treating human SCO2-related disorders.
Area of Science:
- Mitochondrial biology
- Genetics
- Biochemistry
Background:
- Mutations in SCO2 impair cytochrome c oxidase (COX) assembly and function.
- SCO2 deficiency causes fatal infantile cardioencephalomyopathy with COX deficiency.
- The E140K mutation in human SCO2 is common in patients.
Purpose of the Study:
- To generate and characterize mouse models of SCO2 deficiency.
- To investigate the in vivo consequences of SCO2 mutations.
- To provide tools for studying SCO2 function and therapeutic development.
Main Methods:
- Generation of Sco2 knock-out (KO) and knock-in (KI) mouse models.
- Phenotypic analysis of KO and KI mice, including viability and muscle function.
- Biochemical assessment of mitochondrial respiratory chain and complex IV assembly.
- Measurement of copper content in tissues and mitochondria.
Main Results:
- Homozygous KO mice were embryonic lethal.
- Homozygous KI and compound heterozygous KI/KO mice exhibited muscle weakness.
- These mice displayed respiratory chain deficiencies and complex IV assembly defects.
- Mitochondrial copper content was reduced, but total tissue copper remained unchanged.
Conclusions:
- Sco2 mutations lead to mitochondrial dysfunction and complex IV assembly defects in vivo.
- The generated mouse models recapitulate key features of human SCO2 deficiency.
- These models are valuable for further research into SCO2 function and potential therapies.
