Anion-Responsive Manganese Porphyrin Facilitates Chloride Transport and Induces Immunogenic Cell Death

Abstract

Chloride is the most abundant anion in living systems. Most natural or synthetic chloride anionophores function via hydrogen-bonding interactions. However, dynamic metal-anion coordination can also be an efficient way of transporting chloride across membranes. Here, we investigate anion transport by manganese(III) meso-tetraphenylporphyrin chloride {[Mn(TPP)Cl], TPP = meso-tetraphenylporphyrin} complex that exhibits labile axial coordination. [Mn(TPP)Cl] showed high chloride transport activity in a bilayer vesicle model with an EC50 value of 4.42 × 10−3 mol %. In living cells, [Mn(TPP)Cl] induced rapid chloride influx and autophagy. The release of Ca2+ and adenosine 5′-triphosphate (ATP), as well as the relocation of calreticulin, revealed that [Mn(TPP)Cl] caused immunogenic cell death. Proteomic analysis indicated that [Mn(TPP)Cl] impaired several physiological processes, including DNA synthesis, transcription, mitochondrial respiration, RNA translation, and immune response. Our study suggests that dynamic metal-anion interactions across membranes might provide a practical strategy for the interference of chloride homeostasis.