Distribution and Apoptotic Function of Outer Membrane Proteins Depend on Mitochondrial Fusion

David Weaver, Verónica Eisner, Xingguo Liu, Péter Várnai, László Hunyady, Atan Gross, György Hajnóczky

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Cells deficient in mitochondrial fusion have been shown to have defects linked to the exchange of inner membrane and matrix components. Because outer-mitochondrial membrane (OMM) constituents insert directly from the cytoplasm, a role for fusion in theirintermitochondrial transfer was unanticipated. Here,we show that fibroblasts lacking the GTPases responsible for OMM fusion, mitofusins 1 and 2 (MFN1 and MFN2), display more heterogeneous distribution of OMM proteins. Proteins with different modes of OMM association display varying degrees of heterogeneity in Mfn1/2-/- cells and different kinetics of transfer during fusion in fusion-competent cells. Proapoptotic Bak exhibits marked heterogeneity, which is normalized upon expression of MFN2. Bak is critical for Bid-induced OMM permeabilization and cytochrome c release, and Mfn1/2-/- cells show dysregulation of Bid-dependent apoptotic signaling. Bid sensitivity of Bak-deficient mitochondria is regained upon fusion with Bak-containing mitochondria. Thus, OMM protein distribution depends on mitochondrial fusion and is a locus of apoptotic dysfunction in conditions of fusion deficiency.

Original languageEnglish
Pages (from-to)870-878
Number of pages9
JournalMolecular Cell
Volume54
Issue number5
DOIs
Publication statusPublished - Jun 5 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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