Mitigation of age-dependent accumulation of defective mitochondrial genomes

Unknown processes promote the accumulation of mitochondrial DNA (mtDNA) muta-tions during aging. Accumulation of defective mitochondrial genomes is thought to pro-mote the progression of heteroplasmic mitochondrial diseases and degenerative changes with natural aging. We used a heteroplasmic Drosophila model to test 1) whether purify-ing selection acts to limit the abundance of deleterious mutations during development and aging, 2) whether quality control pathways contribute to purifying selection, 3) whether activation of quality control can mitigate accumulation of deleterious muta-tions, and 4) whether improved quality control improves health span. We show that purifying selection operates during development and growth but is ineffective during aging. Genetic manipulations suggest that a quality control process known to enforce purifying selection during oogenesis also suppresses accumulation of a deleterious muta-tion during growth and development. Flies with nuclear genotypes that enhance purify-ing selection sustained higher genome quality, retained more vigorous climbing activity, and lost fewer dopaminergic neurons. A pharmacological agent thought to enhance qual-ity control produced similar benefits. Importantly, similar pharmacological treatment of aged mice reversed age-associated accumulation of a deleterious mtDNA mutation. Our findings reveal dynamic maintenance of mitochondrial genome fitness and reduction in the effectiveness of purifying selection during life. Importantly, we describe interventions that mitigate and even reverse age-associated genome degeneration in flies and in mice. Furthermore, mitigation of genome degeneration improved well-being in a Drosophila model of heteroplasmic mitochondrial disease.

Automated summary

Unknown processes lead to accumulation of mitochondrial DNA mutations, which promote heteroplasmic mitochondrial diseases and degenerative changes with aging. Purifying selection operates during development and growth, but loses effectiveness during aging. Quality control pathways and pharmacological interventions can mitigate accumulation of deleterious mutations and improve health span.