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Stress-Triggered Activation of the Metalloprotease Oma1 Involves Its University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Biochemistry -- Faculty Publications Biochemistry, Department of 2014 Stress-triggered Activation of the Metalloprotease Oma1 Involves Its C-terminal Region and Is Important for Mitochondrial Stress Protection in Yeast Iryna Bohovych University of Nebraska- Lincoln, [email protected] Garrett onD aldson University of Nebraska- Lincoln Sara Christianson University of Nebraska-Lincoln Nataliya Zahayko University of Nebraska-Lincoln Oleh Khalimonchuk University of Nebraska-Lincoln, [email protected] Follow this and additional works at: http://digitalcommons.unl.edu/biochemfacpub Part of the Biochemistry Commons, Biotechnology Commons, and the Other Biochemistry, Biophysics, and Structural Biology Commons Bohovych, Iryna; Donaldson, Garrett; Christianson, Sara; Zahayko, Nataliya; and Khalimonchuk, Oleh, "Stress-triggered Activation of the Metalloprotease Oma1 Involves Its C-terminal Region and Is Important for Mitochondrial Stress Protection in Yeast" (2014). Biochemistry -- Faculty Publications. 167. http://digitalcommons.unl.edu/biochemfacpub/167 This Article is brought to you for free and open access by the Biochemistry, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Biochemistry -- Faculty Publications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 289, NO. 19, pp. 13259–13272, May 9, 2014 © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Stress-triggered Activation of the Metalloprotease Oma1 Involves Its C-terminal Region and Is Important for Mitochondrial Stress Protection in Yeast* Received for publication, December 13, 2013, and in revised form, March 13, 2014 Published, JBC Papers in Press, March 19, 2014, DOI 10.1074/jbc.M113.542910 Iryna Bohovych, Garrett Donaldson, Sara Christianson, Nataliya Zahayko, and Oleh Khalimonchuk1 From the Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska-Lincoln, Lincoln, Nebraska 68588 Background: Oma1 is a conserved membrane-bound protease that forms a high molecular mass complex. Results: Oma1 activity is induced by stress stimuli and required for survival. The activation is linked to changes in Oma1 oligomer stability and involves its C-terminal region. Conclusion: Oma1 function is activated by mitochondrial stress and is important for stress tolerance. Significance: Novel insights into Oma1 function and a potential stress activation mechanism are provided. Functional integrity of mitochondria is critical for optimal drial membrane (IM)2 arising from the bigenomic nature of cellular physiology. A suite of conserved mitochondrial pro- mitochondrial proteome is an additional homeostatic chal- teases known as intramitochondrial quality control represents lenge (2). Over time, these factors can lead to oxidative damage one of the mechanisms assuring normal mitochondrial func- of polypeptides, protein misfolding, mismatches in the stoichi- tion. We previously demonstrated that ATP-independent met- ometry of respiratory complexes, and, subsequently, mitochon- alloprotease Oma1 mediates degradation of hypohemylated drial dysfunction (2, 3). Normal mitochondrial function is Cox1 subunit of cytochrome c oxidase and is active in cyto- maintained through several functionally intertwined mecha- chrome c oxidase-deficient mitochondria. Here we show that nisms commonly known as mitochondrial quality control Oma1 is important for adaptive responses to various homeo- (reviewed in Refs. 3–5). One such mechanism, the intramito- static insults and preservation of normal mitochondrial func- chondrial quality control (IMQC), comprises an intricate net- tion under damage-eliciting conditions. Changes in membrane work of evolutionary conserved proteases and molecular chap- potential, oxidative stress, or chronic hyperpolarization lead to erones (3–5). The IMQC proteases are distributed throughout increased Oma1-mediated proteolysis. The stress-triggered mitochondrial subcompartments, where they survey folding induction of Oma1 proteolytic activity appears to be associated and assembly status of proteins and selectively degrade mis- with conformational changes within the Oma1 homo-oligo- folded, damaged, or nonassembled polypeptides (3, 4). The best meric complex, and these alterations likely involve C-terminal studied IMQC components are AAA family proteases localized residues of the protease. Substitutions in the conserved C-ter- to the IM (m-AAA and i-AAA) and mitochondrial matrix (ClpP minal region of Oma1 impair its ability to form a labile proteo- and Lon proteases) (3–5). In addition to elimination of mis- lytically active complex in response to stress stimuli. We dem- folded/damaged proteins, these enzymes are involved in a num- onstrate that Oma1 genetically interacts with other inner ber of key mitochondrial processes by degrading/processing membrane-bound quality control proteases. These findings regulatory proteins or acting as molecular chaperones (4). indicate that yeast Oma1 is an important player in IM protein Despite the significant progress in understanding IMQC func- homeostasis and integrity by acting in concert with other tions, many aspects thereof remain unclear. Among these intramitochondrial quality control components. aspects are the exact roles of less characterized conserved IMQC components and the mechanisms by which IMQC senses mitochondrial damage. In addition to being a hub for a number of vital cellular func- Oma1 (overlapping activities with m-AAA 1) is a conserved tions, mitochondria are also a potent source of reactive oxygen ATP-independent M48-type zinc metalloprotease, a member species generated as the by-products of respiration (1). The of the metazincins family (6, 7). Oma1 is intrinsic to the IM, complex protein folding environment in the inner mitochon- where it exists as a high molecular weight complex (8, 9). Stud- ies in yeast and mammalian cells indicate that Oma1 may be a stress-activated protease (9–11). Likewise, HtpX, the bacterial ortholog of Oma1, has been implicated as a stress-inducible * This work was supported, in whole or in part, by National Institutes of Health Grants P20 RR-017675 and P30GM103335 (to the Nebraska Redox Biology molecule (12, 13). In response to impaired Cox1 hemylation Center) and ES03817. This work was also supported by a University of and related heme A-mediated stress, Oma1 was shown to selec- Nebraska-Lincoln Lyman Award (to O. K.) and funds from the University of tively mediate the rapid turnover of newly synthesized cyto- Nebraska UCARE program (to G. D. and S. C.). 1 To whom correspondence should be addressed: Dept. of Biochemistry and Nebraska Redox Biology Center, University of Nebraska-Lincoln, 1901 Vine 2 The abbreviations used are: IM, inner mitochondrial membrane; IMQC, St., N230 BEAD, Lincoln, NE 68588. Tel.: 402-472-8060; Fax: 402-472-7842; intramitochondrial quality control; CCCP, carbonyl cyanide m-chlorophe- E-mail: [email protected]. nylhydrazone; BN, blue native; MBP, maltose-binding peptide. MAY 9, 2014•VOLUME 289•NUMBER 19 JOURNAL OF BIOLOGICAL CHEMISTRY 13259 Oma1 in Mitochondrial Stress Protection TABLE 1 Yeast strains used in this study Strain Genotype Reference W303-1B MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 [rhoϩ] R. Rothstein DY5113 MATa ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1[rhoϩ] D. Winge W303-2A MATa ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 [rhoϩ] A. Barrientos oma1⌬ (OKY90) MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1 oma1⌬::CaURA3 [rhoϩ] Ref. 14 oma1⌬ (OKY199) MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 oma1⌬::TRP1 [rhoϩ] This study oma1⌬ (OKY207) MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 oma1⌬::HIS3MX6 [rhoϩ] This study coa2⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coa2⌬::KanMX4 [rhoϩ] Ref. 34 sod2⌬ MATa ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 sod2⌬::KanMX4 [rhoϩ] A. Barrientos YMN503 MATa ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 yta10⌬::KanMX4 mrpl32⌬::NatMX4 (pSu9-MRPL32)[rhoϩ] Ref. 35 yme1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 yme1⌬::HIS3MX6 [rhoϩ] This study pcp1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 pcp1⌬::TRP1 [rhoϩ] This study coa2⌬ oma1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coa2⌬::KanMX4 oma1⌬::CaURA3 [rhoϩ] 14 sod2⌬ oma1⌬ MATa ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 sod2⌬::KanMX4 oma1⌬::URA3MX [rhoϩ] This study YMN503 oma1⌬ MATa ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 yta10⌬::KanMX4 mrpl32⌬::NatMX4 This study (pSu9-MRPL32) oma1⌬::TRP1 [rhoϩ] yta10⌬ oma1⌬ MATa ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 yta10⌬::HIS3MX6 oma1⌬::TRP1 This study yme1⌬ oma1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 yme1⌬::HIS3MX6 oma1⌬::CaURA3 [rhoϩ] This study pcp1⌬ oma1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 pcp1⌬::TRP1 oma1⌬::URA3MX [rhoϩ] This study OMA1-13Myc MATa ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1 COA2-3HA::TRP1 OMA1-13Myc::HIS3MX6 [rhoϩ] Ref. 9 OMA1-TEV-MBP MATa ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1 OMA1-TEV-MBP::HIS3MX6 [rhoϩ] Ref. 9 OMA1-TEV-MBP coa2⌬ MATa ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1 OMA1-TEV-MBP::HIS3MX6 coa2⌬::URA3MX [rhoϩ] Ref. 9 Htt46Q-GFP MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 YIp-GAL1-HTT46Q-GFP::LEU2 [rhoϩ] This study Htt103Q-GFP MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 YIp351-GAL1-HTT103Q-GFP::LEU2 [rhoϩ] This study Htt46Q-GFP oma1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 YIp351-GAL1-HTT46Q-GFP::LEU2 oma1⌬::TRP1 [rhoϩ] This study Htt103Q-GFP oma1⌬ MAT␣ ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 YIp351-GAL1-HTT103Q-GFP::LEU2 oma1⌬::TRP1 [rhoϩ] This study OMA1-13Myc MATa ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1 COA2-3HA::TRP1 OMA1-13Myc::HIS3MX6 Htt46Q-GFP YIp351-GAL1-HTT46Q-GFP::LEU2 [rhoϩ] This study OMA1-13Myc MATa ade2-1 his3-1,15 leu2-3,112 trp1⌬ ura3-1 COA2-3HA::TRP1 OMA1-13Myc::HIS3MX6 Htt103Q-GFP YIp351-GAL1-HTT103Q-GFP::LEU2 [rhoϩ] This study chrome c oxidase subunit Cox1, in yeast cells lacking the Coa2 agement.
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