Fungal oxidative stress tolerance depends on peroxiredoxin PrxA-mediated redox signaling to mitochondrial cytochrome c peroxidase Ccp1.

Oxidative stress represents a central challenge to cellular survival. Although multiple antioxidant enzymes participate in oxidative defense, peroxiredoxins (Prxs) have long been regarded as key determinants of oxidative stress tolerance. However, this view is largely based on the oxidative sensitivity of Prx-deficient mutants and lacks direct experimental evidence demonstrating that Prxs function as terminal antioxidant effectors determining cellular tolerance to oxidative stress. In this study, through transcriptomic screening combined with systematic genetic and functional analyses, we define the key effector within the oxidative defense system and identify the mitochondrial cytochrome c peroxidase Ccp1 as a core determinant of oxidative stress tolerance. In Aspergillus nidulans, the peroxiredoxin PrxA activates the oxidative-stress transcription factor NapA, mediating Ccp1 induction. Our results indicate that the apparent requirement for Prx in oxidative stress tolerance does not arise from its role as a terminal antioxidant effector, but instead reflects its function as an upstream redox signaling factor regulating activation of the key effector enzyme Ccp1. Further functional analyses show that loss of Ccp1 or catalytic inactivation leads to dissipation of mitochondrial membrane potential, compromised mitochondrial DNA integrity, and reduced iron-sulfur enzyme activity, thereby impairing cellular tolerance to oxidative stress. Redirecting other peroxidases to mitochondria functionally substitutes for Ccp1 and restores oxidative stress tolerance. Together, these findings demonstrate that mitochondria-targeted antioxidant protection mediated by Ccp1 acts as a key defensive process for oxidative stress tolerance, while mechanistically clarifying the functional role of PrxA as an upstream redox signaling factor within the oxidative defense network of this fungus.