Mitochondrial thioredoxin system is required for enhanced stress resistance and extended longevity in long-lived mitochondrial mutants

Mild impairment of mitochondrial function has been shown to increase lifespan in genetic model organisms including worms, flies and mice. To better understand the mechanisms involved, we analyzed RNA sequencing data and found that genes involved in the mitochondrial thioredoxin system, trx-2 and trxr-2, are specifically upregulated in long-lived mitochondrial mutants but not other non-mitochondrial, long-lived mutants. Upregulation of trx-2 and trxr-2 is mediated by activation of the mitochondrial unfolded protein response (mitoUPR). While we decided to focus on the genes of the mitochondrial thioredoxin system for this paper, we identified multiple other antioxidant genes that are upregulated by the mitoUPR in the long-lived mitochondrial mutants including sod-3, prdx-3, gpx-6, gpx-7, gpx-8 and glrx-5. In exploring the role of the mitochondrial thioredoxin system in the long-lived mitochondrial mutants, nuo-6 and isp-1, we found that disruption of either trx-2 or trxr-2 significantly decreases their long lifespan, but has no effect on wild-type lifespan, indicating that the mitochondrial thioredoxin system is specifically required for their longevity. In contrast, disruption of the cytoplasmic thioredoxin gene trx-1 decreases lifespan in nuo-6, isp-1 and wild-type worms, indicating a non-specific detrimental effect on longevity. Disruption of trx-2 or trxr-2 also decreases the enhanced resistance to stress in nuo-6 and isp-1 worms, indicating a role for the mitochondrial thioredoxin system in protecting against exogenous stressors. Overall, this work demonstrates an important role for the mitochondrial thioredoxin system in both stress resistance and lifespan resulting from mild impairment of mitochondrial function.