OMA1 is a mitochondrial protease. Among its substrates are DELE1, a signaling peptide, which can elicit the integrated stress response, as well as the membrane-shaping dynamin-related GTPase OPA1, which can drive mitochondrial outer membrane permeabilization. OMA1 is dormant under physiological conditions but rapidly activated upon mitochondrial stress, such as loss of membrane potential or excessive reactive oxygen species. Accordingly, OMA1 was found to be activated in a number of disease conditions, including cancer and neurodegeneration. OMA1 has a predicted transmembrane domain and is believed to be tethered to the mitochondrial inner membrane. Yet, its structure has not been resolved and its context-dependent regulation remains obscure. Here, I review the literature with focus on OMA1's biochemistry. I provide a good homology model of OMA1's active site with a root-mean-square deviation of 0.9 Å and a DALI Z-score of 19.8. And I build a case for OMA1 actually being an integral membrane protease based on OMA1's role in the generation of small signaling peptides, its functional overlap with PARL, and OMA1's homology with ZMPSTE24. The refined understanding of this important enzyme can help with the design of tool compounds and development of chemical probes in the future.

OMA1 是一种线粒体蛋白酶。其底物包括 DELE1（一种信号肽，可引发综合应激反应）以及膜成形动力相关的 GTPase OPA1（可驱动线粒体外膜透化）。 OMA1 在生理条件下处于休眠状态，但在线粒体应激（例如膜电位丧失或活性氧过多）时迅速激活。因此，OMA1被发现在许多疾病中被激活，包括癌症和神经退行性疾病。 OMA1 具有预测的跨膜结构域，并被认为与线粒体内膜相连。然而，其结构尚未解决，其与环境相关的监管仍然模糊。在这里，我重点回顾了 OMA1 生物化学方面的文献。我提供了 OMA1 活性位点的良好同源模型，均方根偏差为 0.9 Å，DALI Z分数为 19.8。基于 OMA1 在小信号肽生成中的作用、其与 PARL 的功能重叠以及 OMA1 与 ZMPSTE24 的同源性，我构建了 OMA1 实际上是一种完整膜蛋白酶的案例。对这种重要酶的深入了解有助于未来工具化合物的设计和化学探针的开发。