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In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
08:40

In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice

Published on: November 22, 2017

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ER-mitochondria signaling regulates autophagy

Patricia Gomez-Suaga1, Sebastien Paillusson1, Christopher C J Miller1

  • 1a Department of Basic and Clinical Neuroscience , Institute of Psychiatry, Psychology and Neuroscience, Kings College London , London , UK.

Autophagy
|May 27, 2017
PubMed

Insights

Endoplasmic reticulum-mitochondria tethers regulate autophagy. Loosening these contacts via VAPB/RMDN3 knockdown stimulates autophagosome formation, while tightening inhibits it, involving calcium signaling.

Area of Science:

  • Cell Biology
  • Organelle Communication

Background:

  • Endoplasmic reticulum (ER) and mitochondria form crucial functional contacts regulated by tethering proteins.
  • VAMP associated protein B and C (VAPB) and regulator of microtubule dynamics 3 (RMDN3/PTPIP51) form ER-mitochondria tethers.
  • These tethers are implicated in regulating cellular processes, including autophagy.

Purpose of the Study:

  • To investigate the role of VAPB-RMDN3 tethers in regulating macroautophagy/autophagy.
  • To elucidate the mechanisms by which ER-mitochondria contacts influence autophagosome formation.

Main Methods:

  • Small interfering RNA (siRNA) knockdown of VAPB and RMDN3.
  • Overexpression of VAPB and RMDN3.
  • Utilizing a synthetic linker protein for artificial ER-mitochondria tethering.
  • Assessing autophagosome formation.
  • Investigating the role of inositol 1,4,5-trisphosphate receptor (ITPR)-mediated calcium signaling.

Main Results:

  • siRNA-mediated knockdown of VAPB or RMDN3, which loosens ER-mitochondria contacts, stimulates autophagosome formation.
  • Overexpression of VAPB or RMDN3, which tightens contacts, inhibits autophagosome formation.
  • Artificial tethering reduces autophagy, and this effect is rescued by VAPB/RMDN3 siRNA.
  • ER-mitochondria contact-mediated autophagy regulation involves ITPR-dependent calcium delivery to mitochondria.

Conclusions:

  • VAPB-RMDN3 tethers play a critical role in modulating autophagy.
  • The extent of ER-mitochondria contact influences autophagosome formation.
  • Calcium signaling via ITPR is a key mechanism linking ER-mitochondria contacts to autophagy regulation.
Keywords:
PTPIP51VAPBautophagycalciumendoplasmic reticulummitochondriamitochondria-associated membranes

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