Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Mitochondrial complex I dysfunction is a hallmark of Parkinson's disease (PD) pathogenesis.
• Mutations in vacuolar protein sorting 35 (VPS35) are linked to autosomal dominant PD.
• Previous work showed VPS35 mutations induce mitochondrial damage via fragmentation.

Purpose of the Study:

• To investigate the impact of pathogenic VPS35 mutations on mitochondrial complex I activity.
• To elucidate the underlying mechanisms connecting VPS35 mutations, mitochondrial dynamics, and complex I function.

Main Methods:

• Enzymatic activity assays for mitochondrial complex I and II.
• Analysis of protein expression and assembly of respiratory chain complexes and supercomplexes.
• Assessment of mitochondrial morphology and the effect of inhibiting mitochondrial fission.

Main Results:

• VPS35 D620N mutation decreased complex I and II enzymatic activity and respiratory function in patient fibroblasts.
• Reduced levels of assembled complex I, complex II, and supercomplexes were observed in D620N fibroblasts.
• Inhibiting mitochondrial fission ameliorated the assembly defects and functional deficits in complex I and II.

Conclusions:

• Pathogenic VPS35 D620N mutation leads to excessive mitochondrial fission.
• This fission disrupts the assembly of mitochondrial complex I and supercomplexes.
• These disruptions result in bioenergetic deficits, contributing to Parkinson's disease pathogenesis.