A novel role of KEAP1/PGAM5 complex: ROS sensor for inducing mitophagy
Akbar Zeb,
Vinay Choubey,
Ruby Gupta,
Malle Kuum,
Dzhamilja Safiulina,
Annika Vaarmann,
Nana Gogichaishvili,
Mailis Liiv,
Ivar Ilves,
Kaido Tämm,
Vladimir Veksler,
Allen Kaasik
Affiliations
Akbar Zeb
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Vinay Choubey
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia; Corresponding author.
Ruby Gupta
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Malle Kuum
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Dzhamilja Safiulina
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Annika Vaarmann
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Nana Gogichaishvili
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Mailis Liiv
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia
Ivar Ilves
Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia
Kaido Tämm
Institute of Chemistry, University of Tartu, Ravila 14a, 50411, Tartu, Estonia
Vladimir Veksler
University Paris-Saclay, INSERM UMR-S 1180, Laboratory of Signaling and Cardiovascular Pathophysiology, 92296, Châtenay-Malabry, France
Allen Kaasik
Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, 50411, Tartu, Estonia; Corresponding author.
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.
