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

doi:10.1016/j.molcel.2014.10.028

Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis

Mol Cell. 2015 Jan 8;57(1):69-82. doi: 10.1016/j.molcel.2014.10.028. Epub 2014 Dec 4.

Affiliations

¹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
² Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
³ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
⁴ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
⁵ Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
⁶ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
⁷ Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
⁸ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
⁹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹⁰ The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
¹¹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: jerry.chipuk@mssm.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Bcl-2-Like Protein 11
GTP Phosphohydrolases / genetics*
GTP Phosphohydrolases / metabolism
Gene Expression Regulation
Membrane Potential, Mitochondrial / genetics
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mitochondria, Liver / genetics*
Mitochondria, Liver / metabolism
Mitochondria, Liver / ultrastructure
Mitochondrial Dynamics / genetics
Mitochondrial Membranes / metabolism*
Mitochondrial Membranes / ultrastructure
Organelle Shape / genetics*
Permeability
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Signal Transduction
Unilamellar Liposomes / chemistry
Unilamellar Liposomes / metabolism
bcl-2 Homologous Antagonist-Killer Protein / genetics
bcl-2 Homologous Antagonist-Killer Protein / metabolism
bcl-2-Associated X Protein / genetics*
bcl-2-Associated X Protein / metabolism

Substances

Apoptosis Regulatory Proteins
Bak1 protein, mouse
Bax protein, mouse
Bcl-2-Like Protein 11
Bcl2l11 protein, mouse
Membrane Proteins
Proto-Oncogene Proteins
Unilamellar Liposomes
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
GTP Phosphohydrolases
Mfn1 protein, mouse

Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding