Turning an Antioxidant into a Prooxidant: Light-induced Mitochondrial Apoptosis in Mammalian Cells by an Ergothioneine-based Neutral Small Molecule

Abstract

Mitochondria-targeted compounds gained significant interest due to their applications in fundamental research, diagnostics, and therapeutics. In this work, we present a detailed investigation of the ergothioneine-based mitochondria-targeted neutral molecule, which is an antioxidant in the dark and turns prooxidant in light inside mammalian cells. This molecule was designed using a fragment-based approach for simultaneous mitochondrial imaging and targeted antioxidant activity. However, it forms a charge-separated state within 10 picoseconds under visible light, leading to triplet-state formation upon charge recombination. Mitochondrial biomolecules first reduce this redox-active triplet state to its one-electron reduced form, which reduces molecular oxygen via one-electron transfer to form superoxide radicals selectively inside mitochondria. This leads to mitochondrial lipid peroxidation, increased mitochondrial membrane permeability transition pore formation, mitochondrial depolarization, and eventually, apoptotic cell death.