TRPM7 senses oxidative stress to release Zn²⁺ from unique intracellular vesicles

TRPM7 (transient receptor potential cation channel subfamily M member 7) regulates gene expression and stress-induced cytotoxicity and is required in early embryogenesis through organ development. Here, we show that the majority of TRPM7 is localized in abundant intracellular vesicles. These vesicles (M7Vs) are distinct from endosomes, lysosomes, and other familiar vesicles or organelles. M7Vs accumulate Zn²⁺ in a glutathione-enriched, reduced lumen when cytosolic Zn²⁺ concentrations are elevated. Treatments that increase reactive oxygen species (ROS) trigger TRPM7-dependent Zn²⁺ release from the vesicles, whereas reduced glutathione prevents TRPM7-dependent cytosolic Zn²⁺ influx. These observations strongly support the notion that ROS-mediated TRPM7 activation releases Zn²⁺ from intracellular vesicles after Zn²⁺ overload. Like the endoplasmic reticulum, these vesicles are a distributed system for divalent cation uptake and release, but in this case the primary divalent ion is Zn²⁺ rather than Ca².