Elevated COMMD1 Contributes to Cardiomyocyte Copper Efflux in Chronic Myocardial Ischemia: Insights From Rhesus Monkey

Abstract

Copper deficiency, commonly observed in myocardial infarction, leads to cardiomyocyte loss and cardiac dysfunction, yet the mechanism driving copper efflux remains unclear. To further elucidate the relationship between copper transporters and cardiac copper efflux during chronic myocardial ischemia, a rhesus monkey model was established by performing the permanent ligation of the left anterior descending coronary artery. A dramatic decrease in copper concentration within ischemic cardiomyocytes was observed alongside declining cardiac function. Among major copper transporters, COMMD1 and ATP7B were significantly upregulated in the ischemic myocardium. COMMD1 was specifically localised in cardiomyocytes undergoing copper efflux, whereas increased ATP7B was restricted to cardiac fibroblasts. This indicates that elevated COMMD1 regulates copper efflux in cardiomyocytes during chronic myocardial ischemia, functioning independently of its interactions with P-type ATPase transporters. Given the discrepancy between RNA and protein levels of COMMD1 in ischemic myocardium, post-translational modification is likely responsible for regulating COMMD1 expression. We found that the copper-binding protein with E3 ubiquitin ligase activity, XIAP, augmented before the rise in COMMD1 expression within ischemic cardiomyocytes. Excessive XIAP specifically interacted with COMMD1 to enhance its protein levels under copper-deprivation conditions and vice versa. Overall, our findings reveal a positive feedback loop among XIAP, COMMD1 and copper, highlighting the intricate interplay between XIAP and COMMD1 in regulating copper efflux in cardiomyocytes. This loop sets the stage for further investigation into therapeutic strategies to manage copper homeostasis in chronic myocardial ischemia.

Keywords

chronic myocardial ischemia / COMMD1 / copper efflux / XIAP

References

[1] S. S. Martin, A. W. Aday, Z. I. Almarzooq, et al., “2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association,” Circulation 149, no. 8 (2024): e347-e913.

[2] K. Thygesen, J. S. Alpert, A. S. Jaffe, et al., “Fourth Universal Definition of Myocardial Infarction,” Journal of the American College of Cardiology 72, no. 18 (2018): 2231-2264.

[3] G. W. Reed, J. E. Rossi, and C. P. Cannon, “Acute Myocardial Infarction,” Lancet 389, no. 10065 (2017): 197-210.

[4] Y. Saito, K. Oyama, K. Tsujita, S. Yasuda, and Y. Kobayashi, “Treatment Strategies of Acute Myocardial Infarction: Updates on Revascularization, Pharmacological Therapy, and Beyond,” Journal of Cardiology 81, no. 2 (2023): 168-178.

[5] S. A. Dick and S. Epelman, “Chronic Heart Failure and Inflammation: What Do we Really Know?,” Circulation Research 119, no. 1 (2016): 159-176.

[6] M. Mazo, B. Pelacho, and F. Prósper, “Stem Cell Therapy for Chronic Myocardial Infarction,” Journal of Cardiovascular Translational Research 3, no. 2 (2010): 79-88.

[7] D. J. Hausenloy and D. M. Yellon, “Myocardial Ischemia-Reperfusion Injury: A Neglected Therapeutic Target,” Journal of Clinical Investigation 123, no. 1 (2013): 92-100.

[8] L. Chen, J. Min, and F. Wang, “Copper Homeostasis and Cuproptosis in Health and Disease,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 378.

[9] T. Tsang, C. I. Davis, and D. C. Brady, “Copper Biology,” Current Biology 31, no. 9 (2021): R421-R427.

[10] L. M. Klevay, “The Influence of Copper and Zinc on the Occurrence of Ischemic Heart Disease,” Journal of Environmental Pathology, Toxicology, and Oncology 4, no. 2-3 (1980): 281-287.

[11] X. Chen, Q. Cai, R. Liang, et al., “Copper Homeostasis and Copper-Induced Cell Death in the Pathogenesis of Cardiovascular Disease and Therapeutic Strategies,” Cell Death & Disease 14, no. 2 (2023): 105.

[12] K. Kitala, D. Tanski, J. Godlewski, M. Krajewska-Włodarczyk, L. Gromadziński, and M. Majewski, “Copper and Zinc Particles as Regulators of Cardiovascular System Function-A Review,” Nutrients 15, no. 13 (2023): 3040.

[13] L. Zheng, P. Han, J. Liu, et al., “Role of Copper in Regression of Cardiac Hypertrophy,” Pharmacology & Therapeutics 148 (2015): 66-84.

[14] L. Elsherif, R. V. Ortines, J. T. Saari, and Y. J. Kang, “Congestive Heart Failure in Copper-Deficient Mice,” Experimental Biology and Medicine (Maywood, N.J.) 228, no. 7 (2003): 811-817.

[15] L. Elsherif, L. Wang, J. T. Saari, and Y. J. Kang, “Regression of Dietary Copper Restriction-Induced Cardiomyopathy by Copper Repletion in Mice,” Journal of Nutrition 134, no. 4 (2004): 855-860.

[16] Y. Jiang, C. Reynolds, C. Xiao, et al., “Dietary Copper Supplementation Reverses Hypertrophic Cardiomyopathy Induced by Chronic Pressure Overload in Mice,” Journal of Experimental Medicine 204, no. 3 (2007): 657-666.

[17] N. M. Garza, A. B. Swaminathan, K. P. Maremanda, M. Zulkifli, and V. M. Gohil, “Mitochondrial Copper in Human Genetic Disorders,” Trends in Endocrinology and Metabolism: TEM 34, no. 1 (2023): 21-33.

[18] H. Uehara, S. Luo, B. Aryal, R. L. Levine, and V. A. Rao, “Distinct Oxidative Cleavage and Modification of Bovine [Cu- Zn]-SOD by an Ascorbic Acid/Cu(II) System: Identification of Novel Copper Binding Site on SOD Molecule,” Free Radical Biology & Medicine 94 (2016): 161-173.

[19] B. Wen, L. Y. Xu, and E. M. Li, “LOXL2 in Cancer: Regulation, Downstream Effectors and Novel Roles,” Biochimica Et Biophysica Acta. Reviews on Cancer 1874, no. 2 (2020): 188435.

[20] W. He and Y. James Kang, “Ischemia-Induced Copper Loss and Suppression of Angiogenesis in the Pathogenesis of Myocardial Infarction,” Cardiovascular Toxicology 13, no. 1 (2013): 1-8.

[21] P. O. Wester, “Trace Elements in Human Myocardial Infarction Determined by Neutron Activation Analysis,” Acta Medica Scandinavica 178, no. 6 (1965): 765-788.

[22] B. E. Kim, T. Nevitt, and D. J. Thiele, “Mechanisms for Copper Acquisition, Distribution and Regulation,” Nature Chemical Biology 4, no. 3 (2008): 176-185.

[23] S. G. Kaler, “ATP7A-Related Copper Transport Diseases-Emerging Concepts and Future Trends,” Nature Reviews. Neurology 7, no. 1 (2011): 15-29.

[24] A. Członkowska, T. Litwin, P. Dusek, et al., “Wilson Disease,” Nature Reviews. Disease Primers 4, no. 1 (2018): 21.

[25] A. Fedoseienko, P. Bartuzi, and B. van de Sluis, “Functional Understanding of the Versatile Protein Copper Metabolism MURR1 Domain 1 (COMMD1) in Copper Homeostasis,” Annals of the New York Academy of Sciences 1314 (2014): 6-14.

[26] W. I. M. Vonk, P. Bartuzi, P. de Bie, et al., “Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation,” PLoS One 6, no. 12 (2011): e29183.

[27] K. Li, C. Li, Y. Xiao, T. Wang, and Y. James Kang, “The Loss of Copper Is Associated With the Increase in Copper Metabolism MURR Domain 1 in Ischemic Hearts of Mice,” Experimental Biology and Medicine 243, no. 9 (2018): 780-785.

[28] C. Li, T. Wang, Y. Xiao, K. Li, X. Meng, and Y. James Kang, “COMMD1 Upregulation Is Involved in Copper Efflux From Ischemic Hearts,” Experimental Biology and Medicine 246, no. 5 (2021): 607-616.

[29] W. Zhang, X. Zhao, Y. Xiao, et al., “The Association of Depressed Angiogenic Factors With Reduced Capillary Density in the Rhesus Monkey Model of Myocardial Ischemia,” Metallomics: Integrated Biometal Science 8, no. 7 (2016): 654-662.

[30] C. Jopling, E. Sleep, M. Raya, M. Martí, A. Raya, and J. C. Izpisúa Belmonte, “Zebrafish Heart Regeneration Occurs by Cardiomyocyte Dedifferentiation and Proliferation,” Nature 464, no. 7288 (2010): 606-609.

[31] B. Hu, S. Lelek, B. Spanjaard, et al., “Origin and Function of Activated Fibroblast States During Zebrafish Heart Regeneration,” Nature Genetics 54, no. 8 (2022): 1227-1237.

[32] T. Dolejsi, M. Delgobo, T. Schuetz, et al., “Adult T-Cells Impair Neonatal Cardiac Regeneration,” European Heart Journal 43, no. 28 (2022): 2698-2709.

[33] C. J. Charles, M. T. Rademaker, N. J. A. Scott, and A. M. Richards, “Large Animal Models of Heart Failure: Reduced vs. Preserved Ejection Fraction,” Animals 10, no. 10 (2020): 1906.

[34] A. Spannbauer, J. Mester-Tonczar, D. Traxler, et al., “Large Animal Models of Cell-Free Cardiac Regeneration,” Biomolecules 10, no. 10 (2020): 1392.

[35] Y. W. Liu, B. Chen, X. Yang, et al., “Human Embryonic Stem Cell-Derived Cardiomyocytes Restore Function in Infarcted Hearts of Non-Human Primates,” Nature Biotechnology 36, no. 7 (2018): 597-605.

[36] P. de Bie, B. van de Sluis, E. Burstein, et al., “Distinct Wilson's Disease Mutations in ATP7B Are Associated With Enhanced Binding to COMMD1 and Reduced Stability of ATP7B,” Gastroenterology 133, no. 4 (2007): 1316-1326.

[37] C. A. Phillips-Krawczak, A. Singla, P. Starokadomskyy, et al., “COMMD1 Is Linked to the WASH Complex and Regulates Endosomal Trafficking of the Copper Transporter ATP7A,” Molecular Biology of the Cell 26, no. 1 (2015): 91-103.

[38] E. Burstein, L. Ganesh, R. D. Dick, et al., “A Novel Role for XIAP in Copper Homeostasis Through Regulation of MURR1,” EMBO Journal 23, no. 1 (2004): 244-254.

[39] A. O'Hara, J. Simpson, P. Morin, et al., “p300-Mediated Acetylation of COMMD1 Regulates Its Stability, and the Ubiquitylation and Nucleolar Translocation of the RelA NF-κB Subunit,” Journal of Cell Science 127, no. Pt 17 (2014): 3659-3665.

[40] J. Kalita, V. Kumar, and U. K. Misra, “A Study on Apoptosis and Anti-Apoptotic Status in Wilson Disease,” Molecular Neurobiology 53, no. 10 (2016): 6659-6667.

[41] Q. Xue, R. Kang, D. J. Klionsky, D. Tang, J. Liu, and X. Chen, “Copper Metabolism in Cell Death and Autophagy,” Autophagy 19, no. 8 (2023): 2175-2195.

[42] K. Chen, L. Wu, Q. Liu, et al., “Glutathione Improves Testicular Spermatogenesis Through Inhibiting Oxidative Stress, Mitochondrial Damage, and Apoptosis Induced by Copper Deposition in Mice With Wilson Disease,” Biomedicine & Pharmacotherapy 158 (2023): 114107.

[43] E. Pizzo, S. Berrettoni, R. Kaul, et al., “Heart Rate Variability Reveals Altered Autonomic Regulation in Response to Myocardial Infarction in Experimental Animals,” Frontiers in Cardiovascular Medicine 9 (2022): 843144.

[44] S. Gent, P. Kleinbongard, P. Dammann, M. Neuhäuser, and G. Heusch, “Heart Rate Reduction and Longevity in Mice,” Basic Research in Cardiology 110, no. 2 (2015): 2.

[45] J. R. Prohaska, “Role of Copper Transporters in Copper Homeostasis,” American Journal of Clinical Nutrition 88, no. 3 (2008): 826S-829S.

[46] J. R. Prohaska, “Copper,” in Present Knowledge in Nutrition, ed. B. A. Bowman and R. M. Russell (International Life Sciences Institute, 2006), 458-470.

[47] E. C. West and J. R. Prohaska, “Cu,Zn-Superoxide Dismutase Is Lower and Copper Chaperone CCS Is Higher in Erythrocytes of Copper-Deficient Rats and Mice,” Experimental Biology and Medicine (Maywood, N.J.) 229, no. 8 (2004): 756-764.

[48] G. F. Brady, S. Galbán, X. Liu, et al., “Regulation of the Copper Chaperone CCS by XIAP-Mediated Ubiquitination,” Molecular and Cellular Biology 30, no. 8 (2010): 1923-1936.

[49] Z. N. Baker, K. Jett, A. Boulet, et al., “The Mitochondrial Metallochaperone SCO1 Maintains CTR1 at the Plasma Membrane to Preserve Copper Homeostasis in the Murine Heart,” Human Molecular Genetics 26, no. 23 (2017): 4617-4628.

[50] Y. Xiao, Q. Feng, L. Huang, et al., “Copper Promotes Cardiac Functional Recovery via Suppressing the Transformation of Fibroblasts to Myofibroblasts in Ischemia-Infarcted Monkey Hearts,” Journal of Nutritional Biochemistry 111 (2023): 109180.

[51] A. R. Mufti, E. Burstein, R. A. Csomos, et al., “XIAP Is a Copper Binding Protein Deregulated in Wilson's Disease and Other Copper Toxicosis Disorders,” Molecular Cell 21, no. 6 (2006): 775-785.

[52] M. M. Hou, P. Polykretis, E. Luchinat, et al., “Solution Structure and Interaction With Copper In Vitro and in Living Cells of the First BIR Domain of XIAP,” Scientific Reports 7, no. 1 (2017): 16630.

[53] G. N. Maine, X. Mao, P. A. Muller, C. M. Komarck, L. W. Klomp, and E. Burstein, “COMMD1 Expression Is Controlled by Critical Residues That Determine XIAP Binding,” Biochemical Journal 417, no. 2 (2009): 601-609.

RIGHTS & PERMISSIONS

2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.