PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response
Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2025-01-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/102852 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582648658132992 |
|---|---|
| author | Ling Cheng Ian Meliala Yidi Kong Jingyuan Chen Christopher G Proud Mikael Björklund |
| author_facet | Ling Cheng Ian Meliala Yidi Kong Jingyuan Chen Christopher G Proud Mikael Björklund |
| author_sort | Ling Cheng |
| collection | DOAJ |
| description | Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1’s role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction. |
| format | Article |
| id | doaj-art-912f2676979a4ae88e2d2dc9cf1e31f9 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-912f2676979a4ae88e2d2dc9cf1e31f92025-01-29T13:06:35ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.102852PEBP1 amplifies mitochondrial dysfunction-induced integrated stress responseLing Cheng0https://orcid.org/0000-0003-0240-0385Ian Meliala1Yidi Kong2Jingyuan Chen3Christopher G Proud4Mikael Björklund5https://orcid.org/0000-0002-2176-681XCentre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, ChinaCentre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, ChinaCentre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, ChinaCentre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, ChinaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, AustraliaCentre for Cellular Biology and Signalling, Zhejiang University-University of Edinburgh (ZJU-UoE) Institute, Haining, China; University of Edinburgh Medical School, Biomedical Sciences, College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, United KingdomMitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1’s role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.https://elifesciences.org/articles/102852mitochondrial dysfunctionintegrated stress responsePEBP1 |
| spellingShingle | Ling Cheng Ian Meliala Yidi Kong Jingyuan Chen Christopher G Proud Mikael Björklund PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response eLife mitochondrial dysfunction integrated stress response PEBP1 |
| title | PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response |
| title_full | PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response |
| title_fullStr | PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response |
| title_full_unstemmed | PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response |
| title_short | PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response |
| title_sort | pebp1 amplifies mitochondrial dysfunction induced integrated stress response |
| topic | mitochondrial dysfunction integrated stress response PEBP1 |
| url | https://elifesciences.org/articles/102852 |
| work_keys_str_mv | AT lingcheng pebp1amplifiesmitochondrialdysfunctioninducedintegratedstressresponse AT ianmeliala pebp1amplifiesmitochondrialdysfunctioninducedintegratedstressresponse AT yidikong pebp1amplifiesmitochondrialdysfunctioninducedintegratedstressresponse AT jingyuanchen pebp1amplifiesmitochondrialdysfunctioninducedintegratedstressresponse AT christophergproud pebp1amplifiesmitochondrialdysfunctioninducedintegratedstressresponse AT mikaelbjorklund pebp1amplifiesmitochondrialdysfunctioninducedintegratedstressresponse |