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Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis
Thibaud T Renault1, Konstantinos V Floros2, Rana Elkholi3
1Department 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.
Molecular Cell
|December 9, 2014
Summary
Mitochondrial size is critical for apoptosis initiation. The study shows that BAX protein needs a specific mitochondrial size to trigger outer mitochondrial membrane permeabilization (MOMP) and cell death.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Proapoptotic BCL-2 proteins induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis.
- The precise mechanisms linking mitochondrial morphology to MOMP are not fully understood.
Purpose of the Study:
- To investigate the mechanistic relationship between mitochondrial shape and MOMP.
- To determine if mitochondrial size is a prerequisite for BAX-mediated MOMP.
Main Methods:
- Utilized the terminal unfolded protein response pathway to define proapoptotic BCL-2 protein composition.
- Employed complementary biochemical, cellular, in vivo, and ex vivo studies.
- Interrogated the requirement for specific mitochondrial size for BCL-2 family function.
Main Results:
- Mitochondrial fusion protein Mfn1 establishes a mitochondrial size permissive for BCL-2 family function.
- Hyperfragmented mitochondria and size-restricted models impair BAX membrane association and permeabilization.
- Inability to stabilize BAXα9·membrane interactions occurs in mitochondria of restricted size.
Conclusions:
- Mitochondrial size is a mechanistic determinant of BAX activation, MOMP, and apoptosis.
- Mitochondrial fusion is crucial for establishing a size that supports BAX-dependent MOMP.
- This work reveals a novel role for mitochondrial morphology in regulating programmed cell death.
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