Redox Nanodomains Are Induced by and Control Calcium Signaling at the ER-Mitochondrial Interface

Highlights

• The ER-mitochondrial interface hosts a dynamic H₂O₂ nanodomain

• ER-mitochondrial Ca²⁺ transfer stimulates ROS mobilization from mitochondria

• The oxidized cristae volume is the source of interface H₂O₂ transients

• H₂O₂ transients sensitize ER Ca²⁺ release to maintain Ca²⁺ oscillations

Summary

The ER-mitochondrial interface is central to calcium signaling, organellar dynamics, and lipid biosynthesis. The ER and mitochondrial membranes also host sources and targets of reactive oxygen species (ROS), but their local dynamics and relevance remained elusive since measurement and perturbation of ROS at the organellar interface has proven difficult. Employing drug-inducible synthetic ER-mitochondrial linkers, we overcame this problem and demonstrate that the ER-mitochondrial interface hosts a nanodomain of H₂O₂, which is induced by cytoplasmic [Ca²⁺] spikes and exerts a positive feedback on calcium oscillations. H₂O₂ nanodomains originate from the mitochondrial cristae, which are compressed upon calcium signal propagation to the mitochondria, likely due to Ca²⁺-induced K⁺ and concomitant water influx to the matrix. Thus, ER-mitochondrial H₂O₂ nanodomains represent a component of inter-organelle communication, regulating calcium signaling and mitochondrial activities.