Pathogenesis of primary defects in mitochondrial ATP synthesis
E A Schon1, S Santra, F Pallotti
1Columbia University College of Physicians and Surgeons, New York, NY, USA. pas3@columbia.edu
Seminars in Cell & Developmental Biology
|December 12, 2001
Summary
Maternally inherited mutations in ATPase 6 subunit of complex V cause severe brain disorders like NARP and MILS. Specific mutations at codons 156 and 217 are linked to these conditions, and a new model explains their pathogenicity.
Area of Science:
- Mitochondrial genetics
- Biochemistry
- Neuroscience
Background:
- Maternally inherited mutations in the mtDNA-encoded ATPase 6 subunit of complex V (ATP synthase) are linked to severe neurological disorders.
- These disorders, including NARP, MILS, and FBSN, primarily affect the brain, particularly the striatum.
Purpose of the Study:
- To propose a model explaining the pathogenicity of specific mutations in the ATPase 6 subunit.
- To elucidate the structural and mechanistic basis for mutations at codons 156 and 217 leading to disease.
Main Methods:
- Review and synthesis of existing data on ATP synthase structure and function.
- Analysis of known pathogenic mutations at codons 156 and 217.
Main Results:
- Four out of five known pathogenic mutations occur at codons 156 and 217.
- These mutations convert a conserved leucine to arginine or proline.
Conclusions:
- A proposed model integrates ATP synthase structure and rotary catalysis mechanism.
- This model may explain why specific mutations at codons 156 and 217 are pathogenic and lead to severe mitochondrial disorders.
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