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{middle dot}), and these reactive oxygen species (ROS) are detrimental to mitochondria. Mitochondrial damage is linked to a broad spectrum of pathologies such as Alzheimer's disease, hemochromatosis, and diabetes. Mitochondria contain several enzymes for rapidly removing superoxide anion and hydrogen peroxide, but how they antagonize HO{middle dot} 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{middle dot}. Surprisingly, hydrogen sulfide (H2S) promotes HO{middle dot} production through stimulating the Fenton reaction, leading to increased DNA damage. Our study may reveal an ex-ante mean for antagonizing HO{middle dot}, patching the loophole of the anti-ROS system in mitochondria.