OPA1, or Optic atrophy 1, is a mitochondrial dynamin-like GTPase. It is crucial for mitochondrial morphogenesis, controlling mitochondrial fusion, especially of the inner mitochondrial membrane, and is involved in maintaining mitochondrial energetics, mtDNA maintenance, and cristae integrity. It participates in pathways related to cell death, energy metabolism, and angiogenesis, thus being of great biological importance. Genetic models, such as KO/CKO mouse models, have been valuable in studying its functions [2,4,5,6,7,8,9].

Cells lacking OPA1 are resistant to ferroptosis, indicating OPA1 promotes ferroptosis by maintaining mitochondrial homeostasis, contributing to mitochondrial lipid ROS generation and suppressing an ATF4-mediated integrated stress response [1]. In skeletal and cardiac muscle, OPA1 regulates inner mitochondrial membrane fusion, influencing oxidative phosphorylation, and is a potential target for treating muscle atrophy and heart failure [2]. In adipocytes, OPA1 facilitates browning, improving glucose tolerance and insulin sensitivity, with urea cycle metabolites as effectors [3]. In angiogenesis, endothelial OPA1 is required for developmental and tumor angiogenesis, and a specific inhibitor can curtail tumor growth [6]. Empagliflozin alleviates renal ischemia-reperfusion injury by upregulating OPA1 through the AMPK-OPA1 pathway [7]. Paeonol promotes OPA1-mediated mitochondrial fusion via the CK2α-Stat3 pathway, protecting against diabetic cardiomyopathy [9].

In summary, OPA1 is essential for multiple biological processes, including mitochondrial dynamics, energy metabolism, cell death regulation, and angiogenesis. Studies using KO/CKO mouse models have revealed its role in diseases such as ferroptosis-related pathologies, muscle-related disorders, obesity-associated metabolic diseases, tumor angiogenesis, renal ischemia-reperfusion injury, and diabetic cardiomyopathy, providing insights into potential therapeutic strategies for these conditions.

References:

1. Liang, Felix G, Zandkarimi, Fereshteh, Lee, Jaehoon, Stockwell, Brent R, Kitsis, Richard N. 2024. OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response. In Molecular cell, 84, 3098-3114.e6. doi:10.1016/j.molcel.2024.07.020. https://pubmed.ncbi.nlm.nih.gov/39142278/

2. Noone, John, O'Gorman, Donal J, Kenny, Helena C. 2022. OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle. In Trends in endocrinology and metabolism: TEM, 33, 710-721. doi:10.1016/j.tem.2022.07.003. https://pubmed.ncbi.nlm.nih.gov/35945104/

3. Bean, Camilla, Audano, Matteo, Varanita, Tatiana, Mitro, Nico, Scorrano, Luca. 2021. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites. In Nature metabolism, 3, 1633-1647. doi:10.1038/s42255-021-00497-2. https://pubmed.ncbi.nlm.nih.gov/34873337/

4. Nyenhuis, Sarah B, Wu, Xufeng, Strub, Marie-Paule, Hammer, John A, Hinshaw, Jenny E. 2023. OPA1 helical structures give perspective to mitochondrial dysfunction. In Nature, 620, 1109-1116. doi:10.1038/s41586-023-06462-1. https://pubmed.ncbi.nlm.nih.gov/37612506/

5. Chen, Jiaqi, Shao, Jianan, Wang, Yaoyao, Wu, Kangxiang, Huang, Mingyuan. 2023. OPA1, a molecular regulator of dilated cardiomyopathy. In Journal of cellular and molecular medicine, 27, 3017-3025. doi:10.1111/jcmm.17918. https://pubmed.ncbi.nlm.nih.gov/37603376/

6. Herkenne, Stéphanie, Ek, Olivier, Zamberlan, Margherita, Graupera, Mariona, Scorrano, Luca. 2020. Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1. In Cell metabolism, 31, 987-1003.e8. doi:10.1016/j.cmet.2020.04.007. https://pubmed.ncbi.nlm.nih.gov/32315597/

7. Yang, Wenbo, Li, Xiaoli, He, Liujie, Cui, Chunping, Wang, Qiang. 2023. Empagliflozin improves renal ischemia-reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK-OPA1 pathway promotion. In Cellular & molecular biology letters, 28, 42. doi:10.1186/s11658-023-00457-6. https://pubmed.ncbi.nlm.nih.gov/37202752/

8. Del Dotto, Valentina, Fogazza, Mario, Lenaers, Guy, Carelli, Valerio, Zanna, Claudia. 2018. OPA1: How much do we know to approach therapy? In Pharmacological research, 131, 199-210. doi:10.1016/j.phrs.2018.02.018. https://pubmed.ncbi.nlm.nih.gov/29454676/

9. Liu, Chaoyang, Han, Yuehu, Gu, Xiaoming, Fu, Feng, Ding, Mingge. 2021. Paeonol promotes Opa1-mediated mitochondrial fusion via activating the CK2α-Stat3 pathway in diabetic cardiomyopathy. In Redox biology, 46, 102098. doi:10.1016/j.redox.2021.102098. https://pubmed.ncbi.nlm.nih.gov/34418601/