Marada A, Allu PK, Murari A, Pullareddy B, Tammineni P, Thiriveedi VR, Danduprolu J, Sepuri NB

Despite the growing evidence of the role of oxidative stress in diseases, its molecular mechanism of action remains poorly understood. Yeast Saccharomyces cerevisiae provides a valuable model system to elucidate the effects of oxidative stress on mitochondria in higher eukaryotes. Dimeric yeast Mge1, the cochaperone of Heat shock protein 70 ...

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(Hsp70), is essential for exchanging ATP for ADP on Hsp70 and thus for recycling of Hsp70 for mitochondrial protein import and folding. Here we show an oxidative stress dependent decrease in Mge1 dimer formation accompanied by a concomitant decrease in Mge1-Hsp70 complex formation in vitro. Mge1-M155L substitution mutant stabilizes both Mge1 dimer and Mge1-Hsp70 complex formation. Most importantly, the Mge1-M155L mutant rescues the slow growth phenomenon associated with the wild type Mge1 strain in presence of H(2)O(2) in vivo, stimulation of ATPase activity of Hsp70 and protein import defect during oxidative stress in vitro. Furthermore, cross linking studies reveal that Mge1-Hsp70 complex formation in mitochondria isolated from wild type Mge1 cells is more susceptible to reactive oxygen species compared with mitochondria from Mge1-M155L cells. This novel oxidative sensor capability of yeast Mge1 may represent an evolutionarily conserved function as human recombinant dimeric Mge1 is also sensitive to H(2)O(2).

Date: Jan. 23, 2013

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