Mitigation of the age-dependent decline in mitochondrial genome integrity

Abstract

AbstractUnknown processes promote accumulation of mitochondrial DNA mutations during aging. Accumulation of defective mitochondrial genomes is thought to promote progression of heteroplasmic mitochondrial diseases and degenerative changes with natural aging. We used a heteroplasmic Drosophila model to test 1) whether purifying 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 mutations, and 4) whether improved quality control improves healthspan. 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 mutation during growth and development. Flies with nuclear genotypes that enhanced purifying selection sustained higher genome quality, retained more vigorous climbing activity and lost fewer dopaminergic neurons. Pharmacological enhancement of quality 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 wellbeing in a Drosophila model of heteroplasmic mitochondrial disease.Significance StatementIn contrast to the orderly segregation of nuclear DNA, mitochondrial genomes compete for replication and segregation. The abundance of mutants that emerge in a cell depends on their success in this competition. We show that quality control mechanisms put deleterious mutations at a disadvantage, but these mechanisms become ineffective during aging. The resulting rise in mutant genomes, which compromises vigor, can be suppressed using genetic backgrounds that enhance quality control. Feeding kinetin to adult Drosophila or mice also reduced the load of mutant mitochondrial genomes. This pharmacological reversal of the age associated deterioration of mtDNA quality suggests possible therapies to alleviate mitochondrial diseases and normal aging.