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Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation
Cytochrome c (Cytc) is a multifunctional protein, acting as an electron carrier in the electron transport chain (ETC), where it shuttles electrons from bc(1) complex to cytochrome c oxidase (COX), and as a trigger of type II apoptosis when released from the mitochondria. We previously showed that Cy...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825195/ https://www.ncbi.nlm.nih.gov/pubmed/31676852 http://dx.doi.org/10.1038/s41598-019-52101-z |
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author | Wan, Junmei Kalpage, Hasini A. Vaishnav, Asmita Liu, Jenney Lee, Icksoo Mahapatra, Gargi Turner, Alice A. Zurek, Matthew P. Ji, Qinqin Moraes, Carlos T. Recanati, Maurice-Andre Grossman, Lawrence I. Salomon, Arthur R. Edwards, Brian F. P. Hüttemann, Maik |
author_facet | Wan, Junmei Kalpage, Hasini A. Vaishnav, Asmita Liu, Jenney Lee, Icksoo Mahapatra, Gargi Turner, Alice A. Zurek, Matthew P. Ji, Qinqin Moraes, Carlos T. Recanati, Maurice-Andre Grossman, Lawrence I. Salomon, Arthur R. Edwards, Brian F. P. Hüttemann, Maik |
author_sort | Wan, Junmei |
collection | PubMed |
description | Cytochrome c (Cytc) is a multifunctional protein, acting as an electron carrier in the electron transport chain (ETC), where it shuttles electrons from bc(1) complex to cytochrome c oxidase (COX), and as a trigger of type II apoptosis when released from the mitochondria. We previously showed that Cytc is regulated in a highly tissue-specific manner: Cytc isolated from heart, liver, and kidney is phosphorylated on Y97, Y48, and T28, respectively. Here, we have analyzed the effect of a new Cytc phosphorylation site, threonine 58, which we mapped in rat kidney Cytc by mass spectrometry. We generated and overexpressed wild-type, phosphomimetic T58E, and two controls, T58A and T58I Cytc; the latter replacement is found in human and testis-specific Cytc. In vitro, COX activity, caspase-3 activity, and heme degradation in the presence of H(2)O(2) were decreased with phosphomimetic Cytc compared to wild-type. Cytc-knockout cells expressing T58E or T58I Cytc showed a reduction in intact cell respiration, mitochondrial membrane potential (∆Ψ(m)), ROS production, and apoptotic activity compared to wild-type. We propose that, under physiological conditions, Cytc is phosphorylated, which controls mitochondrial respiration and apoptosis. Under conditions of stress Cytc phosphorylations are lost leading to maximal respiration rates, ∆Ψ(m) hyperpolarization, ROS production, and apoptosis. |
format | Online Article Text |
id | pubmed-6825195 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68251952019-11-12 Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation Wan, Junmei Kalpage, Hasini A. Vaishnav, Asmita Liu, Jenney Lee, Icksoo Mahapatra, Gargi Turner, Alice A. Zurek, Matthew P. Ji, Qinqin Moraes, Carlos T. Recanati, Maurice-Andre Grossman, Lawrence I. Salomon, Arthur R. Edwards, Brian F. P. Hüttemann, Maik Sci Rep Article Cytochrome c (Cytc) is a multifunctional protein, acting as an electron carrier in the electron transport chain (ETC), where it shuttles electrons from bc(1) complex to cytochrome c oxidase (COX), and as a trigger of type II apoptosis when released from the mitochondria. We previously showed that Cytc is regulated in a highly tissue-specific manner: Cytc isolated from heart, liver, and kidney is phosphorylated on Y97, Y48, and T28, respectively. Here, we have analyzed the effect of a new Cytc phosphorylation site, threonine 58, which we mapped in rat kidney Cytc by mass spectrometry. We generated and overexpressed wild-type, phosphomimetic T58E, and two controls, T58A and T58I Cytc; the latter replacement is found in human and testis-specific Cytc. In vitro, COX activity, caspase-3 activity, and heme degradation in the presence of H(2)O(2) were decreased with phosphomimetic Cytc compared to wild-type. Cytc-knockout cells expressing T58E or T58I Cytc showed a reduction in intact cell respiration, mitochondrial membrane potential (∆Ψ(m)), ROS production, and apoptotic activity compared to wild-type. We propose that, under physiological conditions, Cytc is phosphorylated, which controls mitochondrial respiration and apoptosis. Under conditions of stress Cytc phosphorylations are lost leading to maximal respiration rates, ∆Ψ(m) hyperpolarization, ROS production, and apoptosis. Nature Publishing Group UK 2019-11-01 /pmc/articles/PMC6825195/ /pubmed/31676852 http://dx.doi.org/10.1038/s41598-019-52101-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wan, Junmei Kalpage, Hasini A. Vaishnav, Asmita Liu, Jenney Lee, Icksoo Mahapatra, Gargi Turner, Alice A. Zurek, Matthew P. Ji, Qinqin Moraes, Carlos T. Recanati, Maurice-Andre Grossman, Lawrence I. Salomon, Arthur R. Edwards, Brian F. P. Hüttemann, Maik Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation |
title | Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation |
title_full | Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation |
title_fullStr | Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation |
title_full_unstemmed | Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation |
title_short | Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation |
title_sort | regulation of respiration and apoptosis by cytochrome c threonine 58 phosphorylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825195/ https://www.ncbi.nlm.nih.gov/pubmed/31676852 http://dx.doi.org/10.1038/s41598-019-52101-z |
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