Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER

Mol Cell. 2021 Sep 16;81(18):3866-3876.e2. doi: 10.1016/j.molcel.2021.07.014. Epub 2021 Aug 4.

Abstract

The emerging role of mitochondria as signaling organelles raises the question of whether individual mitochondria can initiate heterotypic communication with neighboring organelles. Using fluorescent probes targeted to the endoplasmic-reticulum-mitochondrial interface, we demonstrate that single mitochondria generate oxidative bursts, rapid redox oscillations, confined to the nanoscale environment of the interorganellar contact sites. Using probes fused to inositol 1,4,5-trisphosphate receptors (IP3Rs), we show that Ca2+ channels directly sense oxidative bursts and respond with Ca2+ transients adjacent to active mitochondria. Application of specific mitochondrial stressors or apoptotic stimuli dramatically increases the frequency and amplitude of the oxidative bursts by enhancing transient permeability transition pore openings. Conversely, blocking interface Ca2+ transport via elimination of IP3Rs or mitochondrial calcium uniporter channels suppresses ER-mitochondrial Ca2+ feedback and cell death. Thus, single mitochondria initiate local retrograde signaling by miniature oxidative bursts and, upon metabolic or apoptotic stress, may also amplify signals to the rest of the cell.

Keywords: Ca2+ microdomain; Inositol-1,4,5-trisphosphate receptor; Mitochondrial retrograde signaling; Organelle contacts; Redox nanodomain.

Publication types

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

MeSH terms

  • Calcium / metabolism
  • Calcium Channels
  • Calcium Signaling / physiology
  • Cell Membrane Permeability / physiology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Oxidation-Reduction
  • Protein Transport / physiology*
  • Respiratory Burst / genetics
  • Respiratory Burst / physiology*
  • Single-Cell Analysis / methods

Substances

  • Calcium Channels
  • Inositol 1,4,5-Trisphosphate Receptors
  • mitochondrial calcium uniporter
  • Calcium