Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions

Area of Science:

• Mitochondrial genetics
• Neuroscience
• Animal modeling

Background:

• Mutations in nuclear-encoded mitochondrial DNA (mtDNA) polymerase (POLG) cause autosomal dominant chronic progressive external ophthalmoplegia (adCPEO) with mtDNA deletions.
• An established animal model for heterozygous Polg mutations and CPEO symptoms is lacking.
• Understanding the age and tissue-specific effects of Polg mutations on mtDNA is crucial for elucidating CPEO pathogenesis.

Purpose of the Study:

• To establish and characterize a mouse model with a heterozygous Polg mutation.
• To investigate the age dependency and tissue specificity of mtDNA impairment in this model.
• To assess the potential of this model for studying adCPEO.

Main Methods:

• Generation of heterozygous Polg (D257A) knock-in mice with a proofreading-deficient mutation.
• Assessment of behavioral phenotypes using a rotarod test.
• Analysis of tissue-specific mtDNA deletion accumulation and its age dependency.

Main Results:

• Heterozygous Polg (D257A) mice displayed motor dysfunction.
• Significant accumulation of multiple mtDNA deletions occurred in Polg (+/D257A) mice, enhanced in muscles and brain with age.
• No significant mtDNA point mutation accumulation or depletion was observed in the brain.

Conclusions:

• Heterozygous Polg (D257A) mice exhibit tissue-specific, age-dependent mtDNA deletions, suggesting a link to neuromuscular symptoms.
• These mice represent a valuable animal model for studying adCPEO and impaired mtDNA maintenance.