Mitochondrial Shape Governs BAX-induced Membrane Permeabilization and Apoptosis

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Dec 9

PMID 25482509

Citations 99

Authors

Thibaud T Renault

Konstantinos V Floros

Rana Elkholi

Kelly-Ann Corrigan

Yulia Kushnareva

Shira Y Wieder

Claudia Lindtner

Madhavika N Serasinghe

James J Asciolla

Christoph Buettner

Donald D Newmeyer

Jerry E Chipuk

Affiliations

Soon will be listed here.

Abstract

Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX requires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mitochondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, a GTPase involved in mitochondrial fusion, establishes a mitochondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAXα9·membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis.

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