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

Weaver, David; Eisner, Veronica; Liu, Xingguo; Vamai, Peter; Hunyady, Laszlo; Gross, Atan; Hajnoczky, Gyorgy


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 their intermitochondrial 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.

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Título según WOS: ID WOS:000340626100015 Not found in local WOS DB
Título de la Revista: MOLECULAR CELL
Volumen: 54
Número: 5
Editorial: Cell Press
Fecha de publicación: 2014
Página de inicio: 870
Página final: 878


Notas: ISI