Oma1 is a mitochondrial protease with a predicted transmembrane domain, believed to be tethered to the mitochondrial inner membrane [2]. It plays crucial roles in mitochondrial quality control, redox activity, and stress responses [5]. Oma1 is involved in pathways such as the integrated stress response (ISR) via the Oma1-Dele1-Atf4 axis, and it can cleave substrates like DELE1 and the membrane-shaping dynamin-related GTPase OPA1 [2,4].

In mitochondrial cardiomyopathy, cardiac-specific loss of the cytochrome c oxidase assembly factor Cox10 in mice activates Oma1, leading to mitochondrial fragmentation and induction of ISR. Ablation of Oma1 or Dele1 in these Cox10 -/- mice aggravates cardiomyopathy, and ISR inhibition promotes ferroptosis, demonstrating a protective role of the Oma1-Dele1-mediated ISR [1]. In colorectal cancer, Oma1 knockout suppresses cancer development in AOM/DSS and xenograft mice models. Hypoxia activates the Oma1-OPA1 axis, increasing mitochondrial ROS to stabilize HIF-1α and promote glycolysis, while Oma1 depletion under hypoxia promotes the accumulation of certain OXPHOS components, indicating its role in coordinating glycolysis and OXPHOS [3].

In conclusion, Oma1 is a key regulator in mitochondria-related biological processes. Gene knockout (KO) mouse models have revealed its significance in mitochondrial cardiomyopathy and colorectal cancer, highlighting its potential as a therapeutic target in these disease areas. Its role in regulating mitochondrial dynamics, stress responses, and metabolism is essential for maintaining cellular homeostasis [1,3].

References:

1. Ahola, Sofia, Rivera Mejías, Pablo, Hermans, Steffen, Nolte, Hendrik, Langer, Thomas. 2022. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. In Cell metabolism, 34, 1875-1891.e7. doi:10.1016/j.cmet.2022.08.017. https://pubmed.ncbi.nlm.nih.gov/36113464/

2. Alavi, Marcel V. 2020. OMA1-An integral membrane protease? In Biochimica et biophysica acta. Proteins and proteomics, 1869, 140558. doi:10.1016/j.bbapap.2020.140558. https://pubmed.ncbi.nlm.nih.gov/33130089/

3. Wu, Zhida, Zuo, Meiling, Zeng, Ling, Lu, Bin, Song, Zhiyin. 2020. OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development. In EMBO reports, 22, e50827. doi:10.15252/embr.202050827. https://pubmed.ncbi.nlm.nih.gov/33314701/

4. Guo, Xiaoyan, Aviles, Giovanni, Liu, Yi, Correia, M Almira, Kampmann, Martin. 2020. Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. In Nature, 579, 427-432. doi:10.1038/s41586-020-2078-2. https://pubmed.ncbi.nlm.nih.gov/32132707/

5. Purohit, Gunjan, Ghosh, Polash, Khalimonchuk, Oleh. 2024. Mitochondrial metallopeptidase OMA1 in cancer. In Advances in cancer research, 162, 75-97. doi:10.1016/bs.acr.2024.05.001. https://pubmed.ncbi.nlm.nih.gov/39069370/