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RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion
The receptor-interacting protein kinase 3 (RIP3) has been reported to regulate programmed necrosis–necroptosis forms of cell death with important functions in inflammation. We investigated whether RIP3 translocates into mitochondria in response to renal ischemia–reperfusion (I/R) to interact with in...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220894/ https://www.ncbi.nlm.nih.gov/pubmed/35741025 http://dx.doi.org/10.3390/cells11121894 |
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author | Feng, Yansheng Imam Aliagan, Abdulhafiz Tombo, Nathalie Draeger, Derrick Bopassa, Jean C. |
author_facet | Feng, Yansheng Imam Aliagan, Abdulhafiz Tombo, Nathalie Draeger, Derrick Bopassa, Jean C. |
author_sort | Feng, Yansheng |
collection | PubMed |
description | The receptor-interacting protein kinase 3 (RIP3) has been reported to regulate programmed necrosis–necroptosis forms of cell death with important functions in inflammation. We investigated whether RIP3 translocates into mitochondria in response to renal ischemia–reperfusion (I/R) to interact with inner mitochondrial protein (Mitofilin) and promote mtDNA release into the cytosol. We found that release of mtDNA activates the cGAS–STING pathway, leading to increased nuclear transcription of pro-inflammatory markers that exacerbate renal I/R injury. Monolateral C57/6N and RIP3(−/−) mice kidneys were subjected to 60 min of ischemia followed by either 12, 24, or 48 h of reperfusion. In WT mice, we found that renal I/R injury increased RIP3 levels, as well as its translocation into mitochondria. We observed that RIP3 interacts with Mitofilin, likely promoting its degradation, resulting in increased mitochondria damage and mtDNA release, activation of the cGAS–STING–p65 pathway, and increased transcription of pro-inflammatory markers. All of these effects observed in WT mice were decreased in RIP3(−/−) mice. In HK-2, RIP3 overexpression or Mitofilin knockdown increased cell death by activating the cGAS–STING–p65 pathway. Together, this study point to an important role of the RIP3–Mitofilin axis in the initiation and development of renal I/R injury. |
format | Online Article Text |
id | pubmed-9220894 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-92208942022-06-24 RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion Feng, Yansheng Imam Aliagan, Abdulhafiz Tombo, Nathalie Draeger, Derrick Bopassa, Jean C. Cells Article The receptor-interacting protein kinase 3 (RIP3) has been reported to regulate programmed necrosis–necroptosis forms of cell death with important functions in inflammation. We investigated whether RIP3 translocates into mitochondria in response to renal ischemia–reperfusion (I/R) to interact with inner mitochondrial protein (Mitofilin) and promote mtDNA release into the cytosol. We found that release of mtDNA activates the cGAS–STING pathway, leading to increased nuclear transcription of pro-inflammatory markers that exacerbate renal I/R injury. Monolateral C57/6N and RIP3(−/−) mice kidneys were subjected to 60 min of ischemia followed by either 12, 24, or 48 h of reperfusion. In WT mice, we found that renal I/R injury increased RIP3 levels, as well as its translocation into mitochondria. We observed that RIP3 interacts with Mitofilin, likely promoting its degradation, resulting in increased mitochondria damage and mtDNA release, activation of the cGAS–STING–p65 pathway, and increased transcription of pro-inflammatory markers. All of these effects observed in WT mice were decreased in RIP3(−/−) mice. In HK-2, RIP3 overexpression or Mitofilin knockdown increased cell death by activating the cGAS–STING–p65 pathway. Together, this study point to an important role of the RIP3–Mitofilin axis in the initiation and development of renal I/R injury. MDPI 2022-06-11 /pmc/articles/PMC9220894/ /pubmed/35741025 http://dx.doi.org/10.3390/cells11121894 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Feng, Yansheng Imam Aliagan, Abdulhafiz Tombo, Nathalie Draeger, Derrick Bopassa, Jean C. RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion |
title | RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion |
title_full | RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion |
title_fullStr | RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion |
title_full_unstemmed | RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion |
title_short | RIP3 Translocation into Mitochondria Promotes Mitofilin Degradation to Increase Inflammation and Kidney Injury after Renal Ischemia–Reperfusion |
title_sort | rip3 translocation into mitochondria promotes mitofilin degradation to increase inflammation and kidney injury after renal ischemia–reperfusion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9220894/ https://www.ncbi.nlm.nih.gov/pubmed/35741025 http://dx.doi.org/10.3390/cells11121894 |
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