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GSK3 inactivation is involved in mitochondrial complex IV defect in transforming growth factor (TGF) β1-induced senescence

Authors
Byun, Hae-ok; Jung, Hyun-Jung; Seo, Yong-Hak; Lee, Young-Kyoung; Kim, You-Mie; Yoon, Gyesoon
Department
Department of Biochemistry & Molecular Biology
Abstract
Transforming growth factor β1 (TGF β1) induces Mv1Lu cell senescence by persistently producing mitochondrial reactive oxygen species (ROS) through decreased complex IV activity. Here, we investigated the molecular mechanism underlying the effect of TGF β1 on mitochondrial complex IV activity. TGF β1 progressively phosphorylated the negative regulatory sites of both glycogen synthase kinase 3 (GSK3) α and β, corresponding well to the intracellular ROS generation profile.Interestingly,pharmacological inhibition of GSK3 by SB415286 significantly increased mitochondrial ROS,decreased complex IV activity and cellular respiration rate, implying that GSK3 phosphorylation is an upstream event of the ROS generation. Interestingly, we found that active GSK3 exists within mitochondria and binds subunit 6b1 of complex IV which is known to be topologically located in mitochondrial intermembrane space. silencing of the subunit 6b1 significantly decreased complex IV activity and overall respiration rate. Finally, TGF β1 treatment decreased the binding of the subunit 6b to GSK3 and subunit 6b phosphorylation. Our results suggest that GSK3 inactivation is involved in TGF β1-induced complex IV defects by binding the subunit 6b1, thereby persistently generating senescence-associated ROS.
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