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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Elsevier
2021
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oai:doaj.org-article:d02ca99c8f53492ab9e9ee6e461b836c2021-11-20T05:05:56ZA novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy2213-231710.1016/j.redox.2021.102186https://doaj.org/article/d02ca99c8f53492ab9e9ee6e461b836c2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2213231721003463https://doaj.org/toc/2213-2317When 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.Akbar ZebVinay ChoubeyRuby GuptaMalle KuumDzhamilja SafiulinaAnnika VaarmannNana GogichaishviliMailis LiivIvar IlvesKaido TämmVladimir VekslerAllen KaasikElsevierarticleOxidative stressNRF2/KEAP1 pathwayMitophagyPINK1/Parkin pathwayNeurodegenerative diseasesMedicine (General)R5-920Biology (General)QH301-705.5ENRedox Biology, Vol 48, Iss , Pp 102186- (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Oxidative stress NRF2/KEAP1 pathway Mitophagy PINK1/Parkin pathway Neurodegenerative diseases Medicine (General) R5-920 Biology (General) QH301-705.5 |
| spellingShingle |
Oxidative stress NRF2/KEAP1 pathway Mitophagy PINK1/Parkin pathway Neurodegenerative diseases Medicine (General) R5-920 Biology (General) QH301-705.5 Akbar Zeb Vinay Choubey Ruby Gupta Malle Kuum Dzhamilja Safiulina Annika Vaarmann Nana Gogichaishvili Mailis Liiv Ivar Ilves Kaido Tämm Vladimir Veksler Allen Kaasik A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy |
| 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. |
| format |
article |
| author |
Akbar Zeb Vinay Choubey Ruby Gupta Malle Kuum Dzhamilja Safiulina Annika Vaarmann Nana Gogichaishvili Mailis Liiv Ivar Ilves Kaido Tämm Vladimir Veksler Allen Kaasik |
| author_facet |
Akbar Zeb Vinay Choubey Ruby Gupta Malle Kuum Dzhamilja Safiulina Annika Vaarmann Nana Gogichaishvili Mailis Liiv Ivar Ilves Kaido Tämm Vladimir Veksler Allen Kaasik |
| author_sort |
Akbar Zeb |
| title |
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_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_sort |
novel role of keap1/pgam5 complex: ros sensor for inducing mitophagy |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/d02ca99c8f53492ab9e9ee6e461b836c |
| work_keys_str_mv |
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