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08:44
Isolating Potentiated Hsp104 Variants Using Yeast Proteinopathy Models
Published on: November 11, 2014
A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy
Isla Ogilvie1, Nancy G Kennaway, Eric A Shoubridge
1Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
The Journal of Clinical Investigation
|October 4, 2005
Summary
NADH:ubiquinone oxidoreductase (complex I) deficiency, a cause of mitochondrial disease, is linked to assembly defects. Researchers identified B17.2L as a crucial molecular chaperone essential for complex I assembly and nervous system function.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- NADH:ubiquinone oxidoreductase (complex I) deficiency is a frequent cause of mitochondrial oxidative phosphorylation disorders.
- Clinical manifestations in infants include Leigh syndrome, cardiomyopathy, and encephalomyopathy.
- Assembly defects of the complex I holoenzyme are implicated in at least 50% of patient cases, with unknown molecular chaperones.
Observation:
- Whole genome subtraction of yeast identified B17.2L, a paralogue of the B17.2 structural subunit, as a candidate assembly factor.
- A null mutation in B17.2L was identified in a patient with progressive encephalopathy.
- Retroviral expression of B17.2L rescued the complex I assembly defect in patient fibroblasts.
Findings:
- B17.2L acts as a molecular chaperone essential for mammalian complex I assembly.
- An anti-B17.2L antibody recognized an 830-kDa subassembly in patients with complex I assembly defects.
- B17.2L coimmunoprecipitated with complex I structural subunits from human heart mitochondria.
Implications:
- B17.2L is critical for the assembly and function of complex I.
- Understanding B17.2L's role opens new avenues for diagnosing and potentially treating complex I assembly defects.
- This discovery is vital for comprehending the molecular basis of mitochondrial diseases affecting the nervous system.
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