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A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy

When ROS production exceeds the cellular antioxidant capacity, the cell needs to eliminate the defective mitochondria responsible for excessive ROS production. It has been proposed that the removal of these defective mitochondria involves mitophagy, but the mechanism of this regulation remains uncle...

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Autores principales: Zeb, Akbar, Choubey, Vinay, Gupta, Ruby, Kuum, Malle, Safiulina, Dzhamilja, Vaarmann, Annika, Gogichaishvili, Nana, Liiv, Mailis, Ilves, Ivar, Tämm, Kaido, Veksler, Vladimir, Kaasik, Allen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607199/
https://www.ncbi.nlm.nih.gov/pubmed/34801863
http://dx.doi.org/10.1016/j.redox.2021.102186
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author Zeb, Akbar
Choubey, Vinay
Gupta, Ruby
Kuum, Malle
Safiulina, Dzhamilja
Vaarmann, Annika
Gogichaishvili, Nana
Liiv, Mailis
Ilves, Ivar
Tämm, Kaido
Veksler, Vladimir
Kaasik, Allen
author_facet Zeb, Akbar
Choubey, Vinay
Gupta, Ruby
Kuum, Malle
Safiulina, Dzhamilja
Vaarmann, Annika
Gogichaishvili, Nana
Liiv, Mailis
Ilves, Ivar
Tämm, Kaido
Veksler, Vladimir
Kaasik, Allen
author_sort Zeb, Akbar
collection PubMed
description When ROS production exceeds the cellular antioxidant capacity, the cell needs to eliminate the defective mitochondria responsible for excessive ROS production. It has been proposed that the removal of these defective mitochondria involves mitophagy, but the mechanism of this regulation remains unclear. Here, we demonstrate that moderate mitochondrial superoxide and hydrogen peroxide production oxidates KEAP1, thus breaking the interaction between this protein and PGAM5, leading to the inhibition of its proteasomal degradation. Accumulated PGAM5 interferes with the processing of the PINK1 in the mitochondria leading to the accumulation of PINK1 on the outer mitochondrial membrane. In turn, PINK1 promotes Parkin recruitment to mitochondria and sensitizes mitochondria for autophagic removal. We also demonstrate that inhibitors of the KEAP1-PGAM5 protein-protein interaction (including CPUY192018) mimic the effect of mitochondrial ROS and sensitize mitophagy machinery, suggesting that these inhibitors could be used as pharmacological regulators of mitophagy. Together, our results show that KEAP1/PGAM5 complex senses mitochondrially generated superoxide/hydrogen peroxide to induce mitophagy.
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spelling pubmed-86071992021-11-29 A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy Zeb, Akbar Choubey, Vinay Gupta, Ruby Kuum, Malle Safiulina, Dzhamilja Vaarmann, Annika Gogichaishvili, Nana Liiv, Mailis Ilves, Ivar Tämm, Kaido Veksler, Vladimir Kaasik, Allen Redox Biol Research Paper When ROS production exceeds the cellular antioxidant capacity, the cell needs to eliminate the defective mitochondria responsible for excessive ROS production. It has been proposed that the removal of these defective mitochondria involves mitophagy, but the mechanism of this regulation remains unclear. Here, we demonstrate that moderate mitochondrial superoxide and hydrogen peroxide production oxidates KEAP1, thus breaking the interaction between this protein and PGAM5, leading to the inhibition of its proteasomal degradation. Accumulated PGAM5 interferes with the processing of the PINK1 in the mitochondria leading to the accumulation of PINK1 on the outer mitochondrial membrane. In turn, PINK1 promotes Parkin recruitment to mitochondria and sensitizes mitochondria for autophagic removal. We also demonstrate that inhibitors of the KEAP1-PGAM5 protein-protein interaction (including CPUY192018) mimic the effect of mitochondrial ROS and sensitize mitophagy machinery, suggesting that these inhibitors could be used as pharmacological regulators of mitophagy. Together, our results show that KEAP1/PGAM5 complex senses mitochondrially generated superoxide/hydrogen peroxide to induce mitophagy. Elsevier 2021-11-11 /pmc/articles/PMC8607199/ /pubmed/34801863 http://dx.doi.org/10.1016/j.redox.2021.102186 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Zeb, Akbar
Choubey, Vinay
Gupta, Ruby
Kuum, Malle
Safiulina, Dzhamilja
Vaarmann, Annika
Gogichaishvili, Nana
Liiv, Mailis
Ilves, Ivar
Tämm, Kaido
Veksler, Vladimir
Kaasik, Allen
A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
title A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
title_full A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
title_fullStr A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
title_full_unstemmed A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
title_short A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
title_sort novel role of keap1/pgam5 complex: ros sensor for inducing mitophagy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607199/
https://www.ncbi.nlm.nih.gov/pubmed/34801863
http://dx.doi.org/10.1016/j.redox.2021.102186
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