期刊
CELL DEATH & DISEASE
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2013.522
关键词
apoptosis; oxidative stress; reactive oxygen species; signal transduction; hepatocytes; HeLa cells
类别
资金
- NIH [RO1DK067215, RO1-AA014428]
- USC Research Center for Liver Disease Cellular and Tissue Imaging, Cell Separation and Culture, and Analytical/Metabolic/Instrumentation Cores [P30-DK48522]
- Southern California Research Center for Alcoholic Liver and Pancreatic Disease [P30-AA11999]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK067215, P30DK048522] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [P50AA011999, R01AA014428] Funding Source: NIH RePORTER
Our aim was to better understand the mechanism and importance of sustained c-Jun N-terminal kinase (JNK) activation in endoplasmic reticulum (ER) stress and effects of ER stress on mitochondria by determining the role of mitochondrial JNK binding protein, Sab. Tunicamycin or brefeldin A induced a rapid and marked decline in basal mitochondrial respiration and reserve-capacity followed by delayed mitochondrial-mediated apoptosis. Knockdown of mitochondrial Sab prevented ER stress-induced sustained JNK activation, impaired respiration, and apoptosis, but did not alter the magnitude or time course of activation of ER stress pathways. P-JNK plus adenosine 50-triphosphate (ATP) added to isolated liver mitochondria promoted superoxide production, which was amplified by addition of calcium and inhibited by a blocking peptide corresponding to the JNK binding site on Sab (KIM1). This peptide also blocked tunicamycin-induced inhibition of cellular respiration. In conclusion, ER stress triggers an interaction of JNK with mitochondrial Sab, which leads to impaired respiration and increased mitochondrial reactive oxygen species, sustaining JNK activation culminating in apoptosis.
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