Rhodanese Rdl2 produces reactive sulfur species to scavenge hydroxyl radical and protect mitochondria

During aerobic respiration, mitochondria generate superoxide anion (O2*-), hydrogen peroxide (H2O2), and hydroxyl radical (HO*), and these reactive oxygen species (ROS) are detrimental to mitochondria. Mitochondrial damage is linked to a broad spectrum of pathologies such as Alzheimers disease, hemochromatosis, and diabetes. Mitochondria contain several enzymes for rapidly removing superoxide anion and hydrogen peroxide, but how they antagonize HO* is elusive, representing a loophole in the anti-ROS system. Herein, we discovered that Rhodanese 2 (Rdl2) is critical for maintaining the functionality and integrity of mitochondria under sub-lethal ROS stress in Saccharomyces cerevisiae. Rdl2 converts stable sulfur species (thiosulfate and dialkyl polysulfide) to reactive sulfane sulfur including persulfide that protects mitochondrial DNA via scavenging HO*. Surprisingly, hydrogen sulfide (H2S) promotes HO* production through stimulating the Fenton reaction, leading to increased DNA damage. Our study may reveal an ex-ante mean for antagonizing HO*, patching the loophole of the anti-ROS system in mitochondria.