Dual Redox Behavior of Mitochondria‐Targeting Antioxidant: Prooxidant Activity Through Light‐Induced Redox Active Triplet State

Mitochondria‐targeting neutral small molecules are promising candidates for redox modulation and diagnostic imaging in mammalian cells. A deeper understanding of how the properties of these molecules affect mitochondria is essential for these applications. Herein, we present an interesting ergothioneine‐based mitochondria‐targeted neutral molecule. This molecule was originally designed using a fragment‐based approach for simultaneous mitochondrial imaging and targeted antioxidant activity. However, it forms a charge‐separated state within 10 ps under visible light, leading to triplet‐state formation upon charge recombination. This redox active triplet state (E red = 0.27 V) is first reduced by mitochondrial biomolecules (E red = −0.30 V to 0.25 mV), to its reduced form (E red = −1.85 V), which in turn mediates one‐electron reduction of molecular oxygen (O 2 ) to form superoxide radical anion (O 2 • − ) selectively inside mitochondria. This leads to mitochondrial lipid peroxidation, persistent mitochondrial membrane permeability transition pore opening, mitochondrial depolarization, and eventually, apoptotic cell death. Interestingly, the molecule did not induce hemolysis even upon photoexcitation. These findings provide insights into the role of triplet and ground state reduction potentials in O 2 • − generation. In mammalian cells, mitochondria targeting charge neutral molecule (compound 1 ) shows antioxidant properties in dark but becomes prooxidant in presence of visible light to induce apoptosis. Mechanistic investigations reveal that upon light irradiation compound 1 leads to ultrafast triplet state formation. The reduction potentials of triplet and ground state enable superoxide radical formation in mitochondria using biomolecular substrates.