期刊
MOLECULAR CELL
卷 57, 期 1, 页码 69-82出版社
CELL PRESS
DOI: 10.1016/j.molcel.2014.10.028
关键词
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资金
- NIH [CA157740, DK074873, DK083568, DK082724, P20AA017067]
- JJR Foundation
- William A. Spivak Fund
- Fridolin Charitable Trust
- American Cancer Society Research Scholar Award
- ADA career development award
- March of Dimes Foundation [5-FY11-74, 1-FY13-416]
- Albert Einstein Research Fellowship
- American Skin Association Medical Students Grant
- Department of Oncological Sciences at Mount Sinai
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, aGTPase 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 BAX alpha 9.membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis.
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