MiR-181a Promotes Hypoxia-Induced Apoptosis and Mitochondrial Damage Through Regulating Higd-1a

Yan Pang1, *, Junshen Lu4, Jianqi Lu1, Chaoxin Pan1, Zhihao Wen1, Zhide Zhu3, Qi Xiang3, Hao Lin2, Meiling Tang1
1The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning 530023, China
2Geriatrics Department, Danzhou Hospital of Traditional Chinese Medicine, Danzhou 571799, China
3Museum, Guangxi University of Traditional Chinese Medicine Attached Chinese Medicine School, Nanning 530001, China
4Academic Affairs Section, Guangxi University of Traditional Chinese Medicine Attached Chinese Medicine School, Nanning 530001,
China
*Corresponding email: doctoryfy@yeah.net

Aberrant microRNAs are strongly associated with cardiac diseases. However, the regulation mechanism of MiR-181a in hypoxia-induced cardiomyocytes apoptosis and mitochondrial fragmentation have not been clarified. In the present study, we investigated the function of miR-181a in cardiomyocytes under hypoxic conditions. Cell viability, apoptosis, mitochondrial fragmentation, ROS level, activity of caspase 3 and 9, mitochondrial membrane potential, as well as primary antibodies Bcl-2, Bax, Drp1, MFN2, and Higd-1a levels in treated cells were tested. The results showed that overexpression of miR-181a led to an increase in apoptosis, ROS production, and mitochondrial membrane potential loss. Mechanistically, miR-181a promotes mitochondrial fission through targeting Higd-1a, and the effects of miR-181a could be rescued by Higd-1a. Collectively, our results are beneficial to understand the function of miR-181a in hypoxia-induced apoptosis and mitochondrial damage, which might become a novel direction for related diseases.

References
[1] Hoppins, S., Lackner, L., Nunnari, J. (2007) The machines that divide and fuse mitochondria. Annual Review of Biochemistry, 76(1), 751-780.
[2] Bertholet, A. M., Delerue, T., Millet, A. M., Moulis, M. F., David, C., Daloyau, M., Arnaun Pelloquin, L., Davezac, N., Mils, V., Miquel, M. C., Rojo, M., Belenguer, P. (2016) Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiology of Disease, 90, 3-19.
[3] Dorn, G. W., Kitsis, R. N. (2015) The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circulation Research, 116(1), 167-182.
[4] Bose, A., Beal, M. F. (2016) Mitochondrial dysfunction in Parkinson’s disease. Journal of Neurochemistry, 139(1), 216-231.
[5] Smirnova, E., Griparic, L., Shurland, D. L., Van Der Bliek, A. M. (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Molecular Biology of the Cell, 12(8), 2245-2256.
[6] Koshiba, T., Detmer, S. A., Kaiser, J. T., Chen, H., McCaffery, J. M., Chan, D. C. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science, 305(5685), 858-862.
[7] Cipolat, S., de Brito, O. M., Dal Zilio, B., Scorrano, L. (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proceedings of the National Academy of Sciences, 101(45), 15927-15932.
[8] Prabhakar, N. R., Peng, Y. J., Nanduri, J. (2020) Hypoxia-inducible factors and obstructive sleep apnea. The Journal of Clinical Investigation, 130(10), 5042-5051.
[9] Parra, V., Bravo-Sagua, R., Norambuena-Soto, I., Hernández-Fuentes, C. P., Gómez-Contreras, A. G., Verdejo, H. E., Mellado, R., Chiong, M., Lavandero, S., Castro, P. F. (2017) Inhibition of mitochondrial fission prevents hypoxia-induced metabolic shift and cellular proliferation of pulmonary arterial smooth muscle cells. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1863(11), 2891-2903.
[10] Wang, J., Cao, Y., Chen, Y., Chen, Y., Gardner, P., Steiner, D. F. (2006) Pancreatic β cells lack a low glucose and O2-inducible mitochondrial protein that augments cell survival. Proceedings of the National Academy of Sciences, 103(28), 10636-10641.
[11] Pang, Y., Zhu, Z., Wen, Z., Lu, J., Lin, H., Tang, M., Xu, Z., Lu, J. (2021) HIGD‑1B inhibits hypoxia‑induced mitochondrial fragmentation by regulating OPA1 cleavage in cardiomyocytes. Molecular Medicine Reports, 24(2), 1-11.
[12] Bartel, D. P. (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116(2), 281-297.
[13] Karshovska, E., Wei, Y., Subramanian, P., Mohibullah, R., Geißler, C., Baatsch, I., Campos, J. C., Exner, N., Schober, A. (2020) HIF-1α (hypoxia-inducible factor-1α) promotes macrophage necroptosis by regulating miR-210 and miR-383. Arteriosclerosis, Thrombosis, and Vascular Biology, 40(3), 583-596.
[14] Zhao, Y., Ponnusamy, M., Dong, Y., Zhang, L., Wang, K., Li, P. (2017) Effects of mi RNA son myocardial apoptosis by modulating mitochondria related proteins. Clinical and Experimental Pharmacology and Physiology, 44(4), 431-440.
[15] Garg, A., Foinquinos, A., Jung, M., Janssen-Peters, H., Biss, S., Bauersachs, J., Gupta, S. K., Thum, T. (2020) MiRNA-181a is a novel regulator of aldosterone-mineralocorticoid receptor-mediated cardiac remodelling. European Journal of Heart Failure, 22(8), 1366-1377.
[16] Li, C., Zhang, Y., Tang, Y., Xiao, J., Gao, F., Ouyang, Y., Cheng, X. (2020) LncRNA CRNDE modulates cardiac progenitor cells’ proliferation and migration via the miR-181a/LYRM1 axis in hypoxia. Journal of Thoracic Disease, 12(5), 2614.
[17] An, H. J., Cho, G., Lee, J. O., Paik, S. G., Kim, Y. S., Lee, H. (2013) Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria. Proceedings of the National Academy of Sciences, 110(32), 13014-13019.
[18] Qi, M., He, L., Ma, X., Li, Z. (2020) MiR-181a-5p is involved in the cardiomyocyte’s apoptosis induced by hypoxia-reoxygenation through regulating SIRT1. Bioscience, Biotechnology, and Biochemistry, 84(7), 1353-1361.
[19] Zhou, Y., Long, M., Chen, Z., Huang, J. W., Qin, Z., Li, L. (2021) Downregulation of miR-181a-5p alleviates oxidative stress and inflammation in coronary microembolization-induced myocardial damage by directly targeting XIAP. Journal of Geriatric Cardiology: JGC, 18(6), 426.
[20] McClintock, D. S., Santore, M. T., Lee, V. Y., Brunelle, J., Budinger, G. S., Zong, W. X., Chandel, N. S. (2002) Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death. Molecular and Cellular Biology, 22(1), 94-104.
[21] Gross, A., McDonnell, J. M., Korsmeyer, S. J. (1999) BCL-2 family members and the mitochondria in apoptosis. Genes & Development, 13(15), 1899-1911.
[22] Wang, H. T., Tong, X., Zhang, Z. X., Sun, Y. Y., Yan, W., Xu, Z. M., Fu, W. N. (2019) MYCT 1 represses apoptosis of laryngeal cancerous cells through the MAX/miR-181a/NPM 1 pathway. The FEBS Journal, 286(19), 3892-3908.
[23] Hayashi, H., Nakagami, H., Takeichi, M., Shimamura, M., Koibuchi, N., Oiki, E., Sato, N., Koriyama, H., Mori, M., Araujo, R. G., Maeda, A., Morishita, R., Tamai, K., Kaneda, Y. (2012) HIG1, a novel regulator of mitochondrial γ-secretase, maintains normal mitochondrial function. The FASEB Journal, 26(6), 2306-2317.
[24] Mears, J. A., Lackner, L. L. Fang, S., Ingerman, E., Nunnari, J., Hinshaw, J. E. (2011) Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nature Structural & Molecular Biology, 18(1), 20-26.

Share and Cite
Pang, Y., Lu, J., Lu, J., Pan, C., Wen, Z., Zhu, Z., Xiang, Q., Lin, H., Tang, M. (2024) MiR-181a promotes hypoxia-induced apoptosis and mitochondrial damage through regulating Higd-1a. Scientific Research Bulletin, 1(4), 35-44. https://doi.org/10.71052/srb2024/XBRB3109

Published

29/10/2024