Abstract
Functional integrity of mitochondria is critical for optimal cellular physiology. A suite of conserved mitochondrial proteases known as intramitochondrial quality control represents one of the mechanisms assuring normal mitochondrial function. We previously demonstrated that ATP-independent metalloprotease Oma1 mediates degradation of hypohemylated Cox1 subunit of cytochrome c oxidase and is active in cytochrome c oxidase-deficient mitochondria. Here we show that Oma1 is important for adaptive responses to various homeostatic insults and preservation of normal mitochondrial function under damage-eliciting conditions. Changes in membrane potential, oxidative stress, or chronic hyperpolarization lead to increased Oma1-mediated proteolysis. The stress-triggered induction of Oma1 proteolytic activity appears to be associated with conformational changes within the Oma1 homo-oligomeric complex, and these alterations likely involve C-terminal residues of the protease. Substitutions in the conserved C-terminal region of Oma1 impair its ability to form a labile proteolytically active complex in response to stress stimuli. We demonstrate that Oma1 genetically interacts with other inner membrane-bound quality control proteases. These findings indicate that yeast Oma1 is an important player in IM protein homeostasis and integrity by acting in concert with other intramitochondrial quality control components.
Highlights
Oma1 is a conserved membrane-bound protease that forms a high molecular mass complex
Studies in yeast and mammalian models indicated that Oma1 might be activated in response to homeostatic insults such as oxidative stress [9] and loss of mitochondrial membrane potential [10, 11]
To confirm that impaired viability of oma1⌬ cells is due to oxidative stress, we examined the genetic relationship between OMA1 and SOD2, the gene encoding the predominantly mitochondrial manganese superoxide dismutase
Summary
Oma is a conserved membrane-bound protease that forms a high molecular mass complex. The stress-triggered induction of Oma proteolytic activity appears to be associated with conformational changes within the Oma homo-oligomeric complex, and these alterations likely involve C-terminal residues of the protease. Substitutions in the conserved C-terminal region of Oma impair its ability to form a labile proteolytically active complex in response to stress stimuli. Studies in yeast and mammalian cells indicate that Oma may be a stress-activated protease (9 –11). Depletion of Oma in coa2⌬ cells leads to stabilization of newly synthesized Cox and allows its maturation to proceed [9, 14] This situation is analogous to the recently reported case where attenuation of the mammalian m-AAA protease led to partial stabilization of a mutant Cox and restoration of cytochrome c oxidase levels [15]. We show here that yeast Oma is an important IMQC component involved in adaptive responses to various stresses and preservation of normal mitochondrial function under damage-eliciting conditions. Our results demonstrate that Oma plays a central role in the preservation of mitochondrial functional integrity
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