Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling

Riccardo Filadi, Elisa Greotti, Gabriele Turacchio, Alberto Luini, Tullio Pozzan, Paola Pizzo

Research output: Contribution to journalArticlepeer-review

Abstract

The organization and mutual interactions between endoplasmic reticulum (ER) and mitochondria modulate key aspects of cell pathophysiology. Several proteins have been suggested to be involved in keeping ER and mitochondria at a correct distance. Among them, in mammalian cells, mitofusin 2 (Mfn2), located on both the outer mitochondrial membrane and the ER surface, has been proposed to be a physical tether between the two organelles, forming homotypic interactions and heterocomplexes with its homolog Mfn1. Recently, this widely accepted model has been challenged using quantitative EM analysis. Using a multiplicity of morphological, biochemical, functional, and genetic approaches, we demonstrate that Mfn2 ablation increases the structural and functional ER-mitochondria coupling. In particular, we show that in different cell types Mfn2 ablation or silencing increases the close contacts between the two organelles and strengthens the efficacy of inositol trisphosphate (IP3)-induced Ca2+ transfer from the ER to mitochondria, sensitizing cells to a mitochondrial Ca2+ overload-dependent death. We also show that the previously reported discrepancy between electron and fluorescence microscopy data on ER-mitochondria proximity in Mfn2-ablated cells is only apparent. By using a different type of morphological analysis of fluorescent images that takes into account (and corrects for) the gross modifications in mitochondrial shape resulting from Mfn2 ablation, we demonstrate that an increased proximity between the organelles is also observed by confocal microscopy when Mfn2 levels are reduced. Based on these results, we propose a new model for ER-mitochondria juxtaposition in which Mfn2 works as a tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles.

Original languageEnglish
Pages (from-to)E2174-E2181
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number17
DOIs
Publication statusPublished - Apr 28 2015

Keywords

  • ER-mitochondria tethering
  • Inter-organellar communication
  • Mitofusin 2

ASJC Scopus subject areas

  • General

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