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.

A network of conserved proteases known as intramitochondrial quality control (IMQC) is critical for normal mitochondrial activities. IMQC proteases were implicated in establishment of signaling cues for interorganellar communication, but understanding of these events is limited. We report that conserved ATP‐independent metalloprotease Oma1 is important for adaptive responses and preservation of normal mitochondrial function under damage‐eliciting conditions. Our data indicate one or more interorganellar communication lines may be compromised in oma1Δ cells. Oxidative stress‐induced nuclear translocation of the transcription factor Yap1 controlling the expression of antioxidant enzymes is impeded in oma1Δ strain. The defect is consistent with attenuation of catalase expression and activity in peroxide‐stressed oma1Δ cells. Oma1‐deficient cells display marked resistance to the TORC1 signaling pathway‐inactivating drug rapamycin, consistent with significant increase in chronological life span in the absence of stress stimuli. Deletion of TORC1 downstream target kinase Sch9 in oma1Δ background results in a positive genetic effect: the mutants demonstrate synergistic increase in rapamycin resistance and improved tolerance to homeostatic insults. We propose that Oma1 is important for integrating IMQC‐mediated mitochondrial stress sensing into pan‐cellular stress response mechanisms. Grant Funding Source: Supported by NIH‐NIGMS P30 GM103335 and University of Nebraska Layman Award