Lipidated COVID-19 Localizes into Mitochondria and Causes Oxidative Damage to Mitochondrial DNA–Pathophysiology of long COVID
Main Article Content
Abstract
Protein lipidation modifies proteins in eukaryotic cells, including cysteine prenylation, and N-terminal glycine myristoylation, and regulates many biological pathways. We summarize the history of lipidation and the roles of prenylation, myristoylation, and palmitoylation. Lipidation modifies other molecules and takes them to the cellular membrane. Lipidized proteins also go to mitochondria. Prenylation links protein C end motif, and myristoylation links protein N end motif. Palmitoylation links protein C or N motif. It is possible to take both prenylation and myristoylation. Previously, we showed that HSP47 interacts with prenylated and myristoylated proteins, goes to mitochondria, and generates reactive oxygen species (ROS) from mitochondria. It is known that mitochondrial ROS (mtROS) further causes apoptosis and intra-mitochondrial damage to lipids, proteins, and mtDNA. Viral proteins are lipid-modified by infected cells and go to mitochondria, and the electron transport chain (ETC) generates further reactive oxygen species (ROS). The excess ROS may cause lipid peroxidation and damage to mitochondrial DNA (mtDNA). COVID-19, also prenylated and myristoylated, goes to mitochondria, generates mtROS, and damages mtDNA. It is the pathophysiology of long COVID.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Joseph R. Climate Change: The First Four Billion Years. The Biological Cosmology of Global Warming and Global Freezing. J Cosmol. 2010;8:2000–2020.
3. Stein WD. Transport and diffusion across cell membranes. Academic Press, Devon, UK, 1986. doi:10.1016/B978-0-12-664660-3.X5001-7
4. Möller MN, Cuevasanta E, Orrico F, Lopez AC, Thomson L, Denicola A. Diffusion and transport of Reactive Species Across Cell Membranes. Adv Exp Med Biol. 2019;1127:3–19. doi:10.1007/978-3-030-11488-6_1
5. Indo HP, Masuda D, Sriburee S, Ito H, Nakanishi I, Matsumoto KI, Mankhetkorn S, Chatatikun M, Surinkaew S, Udomwech L, Kawakami F, Ichikawa T, Matsui H, Tang-pong J, Majima HJ. Evidence of Nrf2/Keap1 Signaling Regulation by Mitochondria-Generated Reactive Oxygen Species in RGK1 Cells. Biomolecules. 2023;13:445. doi:10.3390/biom13030445
6. Masuda D, Nakanishi I, Ohkubo K, Ito H, Matsumoto KI, Ichikawa H, Chatatikun M, Klangbud WK, Kotepui M, Imai M, Kawakami F, Kubo M, Matsui H, Tangpong J, Ichikawa T, Ozawa T, Yen HC, St Clair DK, Indo HP, Majima HJ. Mitochondria Play Essential Roles in Intracellular Protection against Oxidative Stress–Which Molecules among the ROS Generated in the Mitochondria Can Escape the Mitochondria and Contribute to Signal Activation in Cytosol? Biomolecules. 2024;14:128. doi:10.3390/biom14010128
7. Indo HP, Chatatikun M, Nakanishi I, Matsumoto K, Imai M, Kawakami F, Kubo M, Abe, H, Ichikawa H, Yonei Y, Beppu HJ, Minamiyama Y, Kanekura T, Ichikawa T, Phongphithakchai A, Udomwech L, Sukati S, Charong N, Somsak V, Tangpong J, Nomura S, Majima HJ. The roles of mitochondria in human being’s life and aging. biomolecules. 2024;14:1317. doi:10.3390/biom14101317
8. Majima HJ, Oberley TD, Furukawa K, Mattson MP, Yen H-C, Szweda LI, St Clair DK. Prevention of mitochondrial injury by manganese superoxide dismutase reveals a primary mechanism for alkaline-induced cell death. J Biol Chem. 1998;273:8217–8224. doi:10.1074/jbc.273.14.8217
9. Indo HP, Hawkins CL, Nakanishi I, Matsumoto K, Matsui H, Suenaga S. Davies MJ, St Clair DK, Ozawa T, Majima HJ. Role of mitochondrial reactive oxygen species in the activation of cellular signals, molecules, and function. Handb Exp Pharmacol. 2017;240:439–456. doi:10.1007/164_2016_117
10. Ito S, Nagata K. Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone. Semin Cell Dev Biol. 2017;62:142–151. doi:10.1016/j.semcdb.2016.11.005
11. Miyamura T, Sakamoto N, Kakugawa T, Taniguchi H, Akiyama Y, Okuno D, Moriyama S, Hara A, Kido T, Ishimoto H, Yamaguchi H, Miyazaki T, Obase Y, Ishimatsu Y, Tanaka Y, Mukae H. Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro. Biochem Biophys Res Commun. 2020;530:561–565. doi:10.1016/j.bbrc.2020.07.085
12. Ramazi S, Zahiri J. Posttranslational modifications in proteins: resources, tools and prediction methods. Database (Oxford). 2021;2021:baab012. doi:10.1093/database/baab012
13. Indo, H. P., Ito, H., Nakagawa, K., Chaiswing, L., & Majima, H. J. (2021). Translocation of HSP47 and generation of mitochondrial reactive oxygen species in human neuroblastoma SK-N-SH cells following electron and X-ray irradiation. Archives of biochemistry and biophysics, 703, 108853. https://doi.org/10.1016/j.abb.2021.108853
14. Resh MD. Fatty acylation of proteins: The long and the short of it. Prog Lipid Res. 2016;63:120–131. doi:10.1016/j.plipres.2016.05.002
15. S Mesquita F, Abrami L, Linder ME, Bamji SX, Dickinson BC, van der Goot FG. Mechanisms and functions of protein S-acylation. Nat Rev Mol Cell Biol. 2024;25:488–509. doi:10.1038/s41580-024-00700-8
16. Pisanti S, Rimondi E, Pozza E, Melloni E, Zauli E, Bifulco M, Martinelli R, Marcuzzi A. Prenylation defects and oxidative stress trigger the main consequences of neuroinflammation linked to mevalonate pathway deregulation. Int J Environ Res Public Health. 2022;19:9061. doi:10.3390/ijerph19159061
17. Wang M, Casey PJ. Protein prenylation: unique fats make their mark on biology. Nat Rev Mol Cell Biol. 2016;17:110–122. doi:10.1038/nrm.2015.11
18. Jiang H, Zhang X, Chen X, Aramsangtienchai P, Tong Z, Lin, H. Protein lipidation: occurrence, mechanisms, biological functions, and enabling technologies. Chem Rev. 2018;118:919–988. doi:10.1021/acs.chemrev.6b00750
19. Chen B, Sun Y, Niu J, Jarugumilli GK, Wu X. Protein lipidation in cell signaling and diseases: function, regulation, and therapeutic opportunities. Cell Chem Biol. 2018;25:817–831. doi:10.1016/j.chembiol.2018.05.003
20. Yuan Y, Li P, Li J, Zhao Q, Chang Y, He X. Protein lipidation in health and disease: molecular basis, physiological function and pathological implication. Signal Transduct Target Ther. 2024;9:60. doi:10.1038/s41392-024-01759-7
21. Wang R, Chen YQ. Protein lipidation types: current strategies for enrichment and characterization. Int J Mol Sci. 2022;23:2365. doi:10.3390/ijms23042365
22. Palsuledesai CC, Distefano MD. Protein prenylation: enzymes, therapeutics, and biotechnology applications. ACS Chem Biol. 2015;10:51–62. doi:10.1021/cb500791f
23. Swahari V, Nakamura A. Speeding up the clock: The past, present and future of progeria. Dev Growth Differ. 2016;58:116–130. doi:10.1111/dgd.12251
24. Capell BC, Erdos MR, Madigan JP, Fiordalisi JJ, Varga R, Conneely KN, Gordon LB, Der CJ, Cox AD, Collins FS. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2005;102:12879–12884. doi:10.1073/pnas.0506001102
25. Fong LG, Frost D, Meta M, Qiao X, Yang SH, Coffinier C, Young SG. A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006;311:1621–1623. doi:10.1126/science.1124875
26. Yang SH, Chang SY, Ren S, Wang Y, Andres DA, Spielmann HP, Fong LG, Young SG. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin. Hum Mol Genet. 2011;20:436–444. doi:10.1093/hmg/ddq490
27 Capell BC, Erdos MR, Madigan JP, Fiordalisi JJ. Varga R, Conneely KN. Gordon LB, Der CJ, Cox AD, Collins FS. Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2005;102:12879–12884. doi:10.1073/pnas.0506001102
28. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–269. doi:10.1146/annurev.bi.65.070196.001325,
29. Yuan M, Song ZH, Ying MD, Zhu H, He QJ, Yang B, Cao J.. N-myristoylation: from cell biology to translational medicine. Acta Pharmacol Sin. 2020;41:1005–1015. doi:10.1038/s41401-020-0388-4
30. Gelb MH, Brunsveld L, Hrycyna CA, Michaelis S, Tamanoi F, Van Voorhis WC, Waldmann H. Therapeutic intervention based on protein prenylation and associated modifications. Nat Chem Biol. 2006;2:518–528. doi:10.1038/nchembio818
31. Tsuchiya E, Fukui, S, Kamiya Y, Sakagami Y, Fujino M. Requirements of chemical structure for hormonal activity of lipo-peptidyl factors inducing sexual differentiation in vegetative cells of heterobasidiomycetous yeasts. Biochem Biophys Res Commun. 1978;85:459–463. [PubMed:743289]
32. Sakagami Y, Isogai A, Suzuki A, Tamura S, Tsuchiya E, Fukui S. Isolation of a novel sex hormone, tremerogen A-10, controlling conjugation tube formation in Tremella mesenterica fries. Agric Biol Chem. 1978;42:1093–1094. doi:10.1080/00021369.1978.10863118
33. Sakagami Y, Yoshida M, Isogai A, Suzuki A. Peptidal sex hormones inducing conjugation tube formation in compatible mating-type cells of Tremella mesenterica. Science. 1981;212:1525–1527. doi:10.1126/science.212.4502.1525
34. Kamiya Y, Sakurai A, Tamura S, Takahashi N. Structure of rhodotorucine A, a novel lipopeptide, inducing mating tube formation in Rhodosporidium toruloides. Biochem Biophys Res Commun. 1978;83:1077–1083. doi:10.1016/0006-291x(78)91505-x
35. Ishibashi Y, Sakagami Y, Isogai A, Suzuki,A. Structures of tremerogens A-9291-I and A-9291-VIII: peptidal sex hormones of Tremella brasiliensis. Biochemistry. 1984;23:1399–1404. doi:10.1021/BI00302A010
36. Casey PJ. Mechanisms of protein prenylation and role in G protein function. Biochem Soc Trans. 1995;23:161–166. doi:10.1042/bst0230161
37. Del Villar K, Dorin D, Sattler I, Urano J, Poullet P.; Robinson N, Mitsuzawa H, Tamanoi F. C-terminal motifs found in Ras-superfamily G-proteins: CAAX and C-seven motifs. Biochem Soc Trans. 1996;24:709–713. doi:10.1042/bst0240709
38. Marshall CJ. Protein prenylation: a mediator of protein-protein interactions. Science. 1993;259:1865–1866. doi:10.1126/science.8456312
39. Vandermoten S, Haubruge É, Cusson M. New insights into short-chain prenyltransferases: structural features, evolutionary history and potential for selective inhibition. Cell Mol Life Sci. 2009;66:3685–3695. doi:10.1007/s00018-009-0100-9
40. Boutin JA. Myristoylation. Cell Signal. 1997;9:15–35. doi:10.1016/s0898-6568(96)00100-3
41. Ochoa-Solano A, Romero G, Gitler C. Catalysis of ester hydrolysis by mixed micelles containing N-alpha-myristoyl-L-histidine. Science. 1967;156:1243–1244. doi:10.1126/science.156.3779.1243
42. Boveris A, Navarro A. Brain mitochondrial dysfunction in aging. IUBMB Life. 2008;60:308–314. doi: 10.1002/iub.46
43. Baker ZN, Forny P, Pagliarini DJ. Mitochondrial proteome research: the road ahead. Nat Rev Mol Cell Biol. 2024;25:65–82. doi:10.1038/s41580-023-00650-7
44. Wiedemann N, Pfanner N. Mitochondrial machineries for Protein and assembly. Annu Rev Biochem. 2017;86:685–714. doi:10.1146/annurev-biochem-060815-014352
45. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91–123. doi:10.1146/annurev.neuro.30.051606.094302
46. Pfanner N, Warscheid, B, Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol. 2019;20:267–284. doi:10.1038/s41580-018-0092-0
47. Böttinger L, Ellenrieder L, Becker T. How lipids modulate mitochondrial protein import. J Bioenerg Biomembr. 2016;48:125–135. doi:10.1007/s10863-015-9599-7
48. Gebert N, Ryan MT, Pfanner, N, Wiedemann N, Stojanovski D. Mitochondrial protein import machineries and lipids: functional connection. Biochim Biophys Acta. 2011;1808:1002–1011. doi:10.1016/j.bbamem.2010.08.003
49. Lübben M, Morand K. Novel prenylated hemes as cofactors of cytochrome oxidases. Archae have modified hemes A and O. J Biol Chem. 1994;269:21473–21479. PMID:8063781
50. Frohlich M, Dejanovic B, Kashkar H, Schwarz G, Nussberger S. S-palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiating apoptosis. Cell Death Dis. 2014;5:e1057. doi:10.1038/cddis.2014.17
51. Liang J, Xu ZX, Ding Z, Lu Y, Yu Q, Werle KD, ZhouG, Park YY, Peng G, Gambello MJ, Mills GB. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat Commun. 2015;6:7926. doi:10.1038/ncomms8926
52. Kostiuk MA, Corvi MM, Keller BO, Plummer G, Prescher JA, Hangauer MJ, Bertozzi CR, Rajaiah G, Falck JR, Berthiaume LG. Identification of palmitoylated mitochondrial proteins using a bio-orthogonal azido-palmitate analog. FASEB J. 2008;22:721–732. doi:10.1096/fj.07-9199com
53. Blanco-Colio LM, Justo P, Daehn I, Lorz C, Ortiz A, Egido J. Bcl-xL overexpression protects from apoptosis induced by HMG-CoA reductase inhibitors in murine tubular cells. Kidney Int. 2003;64:181–191. doi:10.1046/j.1523-1755.2003.00080.x
54. Zha J, Weiler, S, Oh KJ, Wei MC, Korsmeyer SJ. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science. 2000;290: 1761–1765. doi:10.1126/science.290.5497.1761
55. Utsumi T, Sakurai N, Nakano K, Ishisaka R. C-terminal 15 kDa fragment of cytoskeletal actin is posttranslationally N-myristoylated upon caspase-mediated cleavage and targeted to mitochondria. FEBS Lett. 2003;539:37–44. doi:10.1016/s0014-5793(03)00180-7
56. Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, Miura J, Wiener HH, Wright L, Saba SG, Yim D, Fein A, Pérez de Castro I, Li C, Thompson CB, Cox AD, Philips MR. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol . 2006;21:481-493. doi:10.1016/j.molcel.2006.01.012
57. Beauchamp E, Tekpli X, Marteil, G, Lagadic-Gossmann D, Legrand P, Rioux V. N-myristoylation targets dihydroceramide Delta4-desaturase 1 to mitochondria: partial involvement in the apoptotic effect of myristic acid. Biochimie. 2009;91:1411–1419. doi:10.1016/j.biochi.2009.07.014
58. Lynes EM, Raturi A, Shenkman M, Ortiz Sandoval C, Yap MC, Wu J, Janowicz A, Myhill N, Benson MD, Campbell RE, Berthiaume LG, Lederkremer GZ, Simmen T. Palmitoylation is the switch that assigns calnexin to quality control or ER Ca2+ signaling. J Cell Sci. 2013;126:3893–3903. doi:10.1242/jcs.125856
59. Bhat SA, Vasi Z, Jiang L, Selvaraj S, Ferguson R, Salarvand S, Gudur A, Adhikari R, Castillo V, Ismail H, Dhabaria A, Ueberheide B, Kuchay S. Geranylgeranylated-SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function. Cell Rep. 2024;43:114783. doi:10.1016/j.celrep.2024.114783
60. Ducluzeau AL, Wamboldt Y, Elowsky CG, Mackenzie SA, Schuurink RC, Basset GJ. Gene network reconstruction identifies the authentic trans-prenyl diphosphate synthase that makes the solanesyl moiety of ubiquinone-9 in Arabidopsis. Plant J. 2012;69:366–375. doi:10.1111/j.1365-313X.2011.04796.x
61. Grant J, Saldanha JW, Gould AP. A Drosophila model for primary coenzyme Q deficiency and dietary rescue in the developing nervous system. Dis Model Mech. 2010;3:799–806. doi:10.1242/dmm.005579
62. Artuch R, Brea-Calvo G, Briones P, Aracil A, Galván M, Espinós C, Corral J, Volpini V, Ribes A, Andreu AL, Palau F, Sánchez-Alcázar JA, Navas P, Pineda M. Cerebellar ataxia with coenzyme Q10 deficiency: diagnosis and follow-up after coenzyme Q10 supplementation. J Neurol Sci. 2006;246:153–158. doi:10.1016/j.jns.2006.01.021
63. Saiki R, Lunceford, A.L, Shi Y, Marbois B, King R, Pachuski J, Kawamukai M, Gasser DL, Clarke CF. Coenzyme Q10 supplementation rescues renal disease in Pdss2kd/kd mice with mutations in prenyl diphosphate synthase subunit 2. Am J Physiol Renal Physiol. 2008;295:F1535–F1544. doi:10.1152/ajprenal.90445.2008
64. Marakasova, E.S.; Eisenhaber, B.; Maurer-Stroh, S.; Eisenhaber, F.; Baranova, A. Prenylation of viral proteins by enzymes of the host: Virus-driven rationale for therapy with statins and FT/GGT1 inhibitors. Bioessay. 2017;39:10. doi:10.1002/bies.201700014
65. Einav S, Glenn JS. Prenylation inhibitors: a novel class of antiviral agents. J Antimicrob Chemother. 2003;52:883–886. doi:10.1093/jac/dkg490
6466. Glenn JS, Watson JA, Havel CM, White JM. Identification of a prenylation site in delta virus large antigen. Science. 1992;256:1331–1333. doi:10.1126/science.1598578
67. Bordier BB, Marion PL, Ohashi K, Kay MA, Greenberg HB, Casey JL, Glenn JS. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J Virol. 2002;76:10465–10472. doi:10.1128/jvi.76.20.10465-10472.2002
68. V'kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 2021;19:155–170. doi:10.1038/s41579-020-00468-6
69. Zhou Y, Liu Y, Gupta S, Paramo MI, Hou Y, Mao C, Luo Y, Judd J, Wierbowski S, Bertolotti M, Nerkar M, Jehi L, Drayman N, Nicolaescu, V, Gula H, Tay S, Randall G, Wang P, Lis JT, Feschotte C, Erzurum SC, Cheng F, Yu H. A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nat Biotechnol. 2023;41:128–139. doi:10.1038/s41587-022-01474-0