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.