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

Mol Cell. 2016 Jul 21;63(2):240-248. doi: 10.1016/j.molcel.2016.05.040. Epub 2016 Jul 7.


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 [Ca(2+)] 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 Ca(2+)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Calcium Channels
  • Recombinant Fusion Proteins
  • Hydrogen Peroxide
  • Calcium