Age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics

An age-related decline in mitochondrial function is a multi-factorial hallmark of aging, driven partly by increased lipid hydroperoxide levels that impair mitochondrial respiration in skeletal muscle, leading to atrophy. Although pharmacological and genetic manipulations to counteract increased lipid hydroperoxide levels represent a promising strategy to treat sarcopenia, the mechanisms driving such phenotypes remain understudied. Peroxiredoxin 6 (Prdx6) is a multifunctional enzyme that contributes to peroxidized membrane repair via its phospholipid hydroperoxidase and phospholipase A₂ activities. Here, we show decreased mitochondrial Prdx6 levels, increased mitochondrial lipid peroxidation, and dysregulated muscle bioenergetics in aged mice and muscle cells derived from older humans. Mechanistically, we found that Prdx6 supports optimal mitochondrial function and prevents mitochondrial fragmentation by limiting mitochondrial lipid peroxidation via its membrane remodeling activities. Our results suggest that age-related declines in mitochondrial Prdx6 contribute to dysregulated muscle bioenergetics, thereby opening the door to therapeutic modulation of Prdx6 to counteract diminished mitochondrial function in aging.