Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis

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

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

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, invivo, and exvivo 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.

Original languageEnglish (US)
Pages (from-to)69-82
Number of pages14
JournalMolecular cell
Volume57
Issue number1
DOIs
StatePublished - Jan 8 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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