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Zemanovic, Sara; Ivanov, Maxim V.; Ivanova, Lena V.; Bhatnagar, Amogh; Michalkiewicz, Teresa; Teng, Ru-Jeng; Kumar, Suresh; Rathore, Rajendra; Pritchard, Kirkwood A.; Konduri, Girija G.; Afolayan, Adeleye J.
Cell reports, 11/2018, Letnik: 25, Številka: 9Journal Article
The import of superoxide dismutase-2 (SOD2) into mitochondria is vital for the survival of eukaryotic cells. SOD2 is encoded within the nuclear genome and translocated into mitochondria for activation after translation in the cytosol. The molecular chaperone Hsp70 modulates SOD2 activity by promoting import of SOD2 into mitochondria. In turn, the activity of Hsp70 is controlled by co-chaperones, particularly CHIP, which directs Hsp70-bound proteins for degradation in the proteasomes. We investigated the mechanisms controlling the activity of SOD2 to signal activation and maintain mitochondrial redox balance. We demonstrate that Akt1 binds to and phosphorylates the C terminus of Hsp70 on Serine631, which inhibits CHIP-mediated SOD2 degradation thereby stabilizing and promoting SOD2 import. Conversely, increased mitochondrial-H2O2 formation disrupts Akt1-mediated phosphorylation of Hsp70, and non-phosphorylatable Hsp70 mutants decrease SOD2 import, resulting in mitochondrial oxidative stress. Our findings identify Hsp70 phosphorylation as a physiological mechanism essential for regulation of mitochondrial redox balance. Display omitted •SOD2 is synthesized in the cytosol and imported into mitochondria for activation•Inducible Hsp70 transports newly made SOD2 to mitochondria for subsequent import•Phosphorylation of the C terminus of Hsp70 by Akt1 facilitates SOD2 import•Hsp70 dephosphorylation promotes SOD2 degradation to terminate SOD2 import SOD2 is synthesized on free cytosolic ribosomes as an inactive precursor and must be imported into mitochondria for activation. Zemanovic et al. report that the phosphorylation-dephosphorylation cycle of Hsp70 is an essential physiological mechanism controlling SOD2 activity.
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