Next Article in Journal
Supramolecular Approaches to Nanoscale Morphological Control in Organic Solar Cells
Previous Article in Journal
Phylogeography of Thlaspi arvense (Brassicaceae) in China Inferred from Chloroplast and Nuclear DNA Sequences and Ecological Niche Modeling
Previous Article in Special Issue
Trans-Membrane Area Asymmetry Controls the Shape of Cellular Organelles
Article Menu
Issue 6 (June) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2015, 16(6), 13356-13380; doi:10.3390/ijms160613356

Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells

Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol BS81TD, UK
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Jeremy C. Simpson
Received: 28 March 2015 / Revised: 4 June 2015 / Accepted: 5 June 2015 / Published: 11 June 2015
View Full-Text   |   Download PDF [6875 KB, uploaded 11 June 2015]   |  

Abstract

Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial autophagy (mitophagy), mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER) and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1), as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT) and the IP3-receptors (IP3Rs) as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R-mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU) primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R-mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis. View Full-Text
Keywords: autophagy; mitophagy; Parkin; SIGMAR1; IP3Rs; ATG5; LC3; calcium autophagy; mitophagy; Parkin; SIGMAR1; IP3Rs; ATG5; LC3; calcium
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

MacVicar, T.D.B.; Mannack, L.V.J.C.; Lees, R.M.; Lane, J.D. Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells. Int. J. Mol. Sci. 2015, 16, 13356-13380.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top