Antioxidant and anti-aging properties of a Zn-complex in Saccharomyces cerevisiae: A non-canonical protective mechanism

Zinc is essential for cellular homeostasis, but its role in oxidative stress resistance and aging remains incompletely understood. We evaluated the antioxidant and anti-aging effects of the zinc(II) coordination compound [Zn₂(μ-Cl)₂(HPClNOL)₂](ClO₄)₂, (HPClNOL: 1-(bis-pyridin-2-ylmethylamino)-3-chloropropan-2-ol), in Saccharomyces cerevisiae. The crystal structure of this Zn-complex revealed a distorted octahedral geometry around both Zn(II) centers. The equatorial plane comprised one tertiary amine, one alcohol, in the protonated form, and two chloro, which bridge the two Zn(II) centers, resulting in the binuclear arrangement. Two pyridine nitrogen atoms occupy the axial sites. Pre-treatment with this Zn-complex increased yeast survival under oxidative stress and reduced lipid peroxidation, effects preserved in sod1Δ and ctt1Δ strains. Protection persisted in yap1Δ cells and did not induce thermotolerance or trehalose accumulation, suggesting Yap1/Hsf1/Msn2/4-independent action. The Zn-complex remained protective in the presence of cycloheximide, indicating no requirement for de novo protein synthesis. Chronological lifespan was extended in wild-type and antioxidant-deficient strains treated with the Zn-complex, with aged cells showing reduced lipid peroxidation and protein carbonylation. Together, these results demonstrate that the Zn-complex promotes redox balance and longevity via noncanonical, transcription-independent mechanisms despite lacking a redox-active metal center, highlighting its potential as a modulator of oxidative stress and aging in eukaryotic cells.