Huntington's disease affects mitochondrial network dynamics predisposing to pathogenic mitochondrial DNA mutations

Area of Science:

• Neuroscience
• Genetics
• Mitochondrial Biology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder affecting brain and skeletal muscle.
• Mitochondrial dysfunction is implicated in HD models and patient-derived cells.
• Mutant huntingtin protein (mutHTT) can accelerate mitochondrial aging and impair quality control.

Purpose of the Study:

• To investigate the mitochondrial phenotype in human skeletal muscle from Huntington's disease patients.
• To examine the impact of mutant huntingtin protein expression on mitochondrial DNA (mtDNA) stability and mitophagy.

Main Methods:

• Ultra-deep mtDNA sequencing of human skeletal muscle.
• Tissue proteomics to assess mtDNA maintenance and oxidative phosphorylation.
• Analysis of mitophagy in primary cell lines expressing varying levels of mutHTT.

Main Results:

• Accumulation of mtDNA mutations affecting oxidative phosphorylation was observed in HD skeletal muscle.
• Impaired mtDNA maintenance and increased biogenesis of less efficient oxidative phosphorylation complexes (I and IV) were detected.
• High levels of N-terminal mutHTT fragments impaired mitophagy and mitochondrial dynamics.

Conclusions:

• Lifelong expression of mutant huntingtin causes mtDNA instability in human skeletal muscle.
• Somatic HTT CAG instability and mutHTT fragments can disrupt mitochondrial network dynamics and mitophagy.
• Targeting mitochondrial health may be a complementary therapeutic strategy for Huntington's disease.