Rhodanese Rdl2 produces reactive sulfur species to protect mitochondria from reactive oxygen species

Mitochondria damage is related to a broad spectrum of pathologies including Alzheimer's, Parkinson's disease, and carcinogenesis. Recently, it has been found that reactive sulfur species (RSS) has a close connection with mitochondrial health. However, the enzyme involving in mitochondrial RSS generation and the mechanism of how RSS affects mitochondrial health are not well understood. In this study, we discovered that rhodanese 2 (Rdl2) is the main enzyme responsible for RSS generation in S. cerevisiae mitochondria, in which no sulfide:quinone oxidoreductase (Sqr) is present. Rdl2 releases sulfane sulfur atoms (S⁰) from stable S⁰ carriers (thiosulfate and dialkyl polysulfide) to produce RSS. Rdl2 deletion leads to morphological change, dysfunction, and DNA degradation of mitochondria. Rdl2-generated RSS can protect DNA from HO^• attack. The reaction rate between RSS and HO^• is ∼10¹⁰ M^-1s^-1, two magnitudes higher than that of HO^• reacting with DNA. Surprisingly, hydrogen sulfide (H₂S) promotes HO^• production through stimulating the Fenton reaction, leading to increased DNA damage. This study highlights the antioxidation function of RSS in vivo and sheds a light on the elusive connection between RSS biogenesis and mitochondrial health.