OMA1 is a mitochondrial inner membrane zinc metallopeptidase that functions as a stress-activated quality control protease 1234. Upon mitochondrial stress—including membrane depolarization and reactive oxygen species accumulation—OMA1 cleaves critical substrates including OPA1, DELE1, and UQCC3 34. OMA1-mediated OPA1 cleavage regulates mitochondrial inner membrane fusion and cristae remodeling; excess soluble OPA1 production prevents hyperfusion during stress or facilitates cytochrome c release during apoptosis 5. A key stress-signaling pathway involves OMA1-dependent DELE1 proteolysis, generating a soluble form that translocates to the cytosol and activates HRI kinase to trigger the integrated stress response via eIF2α phosphorylation 34. OMA1 may also degrade PINK1 in depolarized mitochondria as a backup mechanism 6. Beyond canonical mitochondrial quality control, OMA1 regulates lipid metabolism, thermogenesis, and respiratory supercomplex stability. Dysregulated OMA1 activity associates with disease: elevated OMA1 in glioblastoma promotes PD-L1 expression and immune escape through HSPA9-mediated mitophagy and cGAS-STING activation 7, while altered OMA1 function in intervertebral disc degeneration correlates with cell senescence 8. OMA1 emerges as a multifaceted therapeutic target in cancer and neurodegeneration 9.