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

• Published in: Molecular cell Vol. 63; no. 2; pp. 240 - 248
• Main Authors: Booth, David M., Enyedi, Balázs, Geiszt, Miklós, Várnai, Péter, Hajnóczky, György
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.07.2016
• Subjects: Calcium - metabolism; Calcium Channels - drug effects; Calcium Channels - metabolism; Calcium Signaling - drug effects; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Genes, Reporter; Hep G2 Cells; Humans; Hydrogen Peroxide - pharmacology; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Membrane Microdomains - ultrastructure; Microscopy, Fluorescence; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondria, Liver - ultrastructure; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Mitochondrial Membranes - ultrastructure; Oxidation-Reduction; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Time Factors; Transfection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.05.040

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. [Display omitted] •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 During Ca2+ signals, elevated Ca2+ microdomains form at the ER-mitochondrial interface. Booth et al. demonstrate that a nanodomain of H2O2 is also present. This is produced by Ca2+-induced mobilization of ROS from the mitochondrial cristae and functions to sensitize ER Ca2+ channels.