Electron microscopy evidence of gadolinium toxicity being mediated through cytoplasmic membrane dysregulation

Arino, Trevor; Faulkner, David; Bustillo, Karen C.; An, Dahlia D.; Jorgens, Danielle; Hébert, Solène; McKinley, Carla; Proctor, Michael; Loguinov, Alex; Vulpe, Christopher; Abergel, Rebecca J.

doi:10.1093/mtomcs/mfae042

Title: Electron microscopy evidence of gadolinium toxicity being mediated through cytoplasmic membrane dysregulation

Journal Article · 23 September 2024 · Metallomics (Online)

DOI: https://doi.org/10.1093/mtomcs/mfae042 · OSTI ID:2473159

;

; Hébert, Solène;

; Proctor, Michael;

;

Abstract Past functional toxicogenomic studies have indicated that genes relevant to membrane lipid synthesis are important for tolerance to the lanthanides. Moreover, previously reported imaging of patient's brains following administration of gadolinium-based contrast agents shows gadolinium lining the vessels of the brain. Taken together, these findings suggest the disruption of cytoplasmic membrane integrity as a mechanism by which lanthanides induce cytotoxicity. In the presented work we used scanning transmission electron microscopy and spatially resolved elemental spectroscopy to image the morphology and composition of gadolinium, europium, and samarium precipitates that formed on the outside of yeast cell membranes. In no sample did we find that the lanthanide contaminant had crossed the cell membrane, even in experiments using yeast mutants with disrupted genes for sphingolipid synthesis—the primary lipids found in yeast cytoplasmic membranes. Rather, we have evidence that lanthanides are co-located with phosphorus outside the yeast cells. These results lead us to hypothesize that the lanthanides scavenge or otherwise form complexes with phosphorus from the sphingophospholipid head groups in the cellular membrane, thereby compromising the structure or function of the membrane, and gaining the ability to disrupt membrane function without entering the cell.

View Journal Article

Cite

Export

Save

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2473159

Journal Information:: Metallomics (Online), Journal Name: Metallomics (Online) Journal Issue: 10 Vol. 16; ISSN 1756-591X

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

References (47)

Lanthanide Chelates as Bilayer Alignment Tools in NMR Studies of Membrane-Associated Peptides Prosser, R. S.; Bryant, H.; Bryant, R. G. Journal of Magnetic Resonance, Vol. 141, Issue 2 https://doi.org/10.1006/jmre.1999.1855	journal	December 1999
Lanthanide Ions Bind Specifically to an Added “EF-Hand” and Orient a Membrane Protein in Micelles for Solution NMR Spectroscopy Ma, Che; Opella, Stanley J. Journal of Magnetic Resonance, Vol. 146, Issue 2 https://doi.org/10.1006/jmre.2000.2172	journal	October 2000
Enhancement of cisplatin cytotoxicity by terbium in cisplatin-resistant MDA/CH human breast cancer cells Fuller, Teresa L.; Canada, Robert G. Cancer Chemotherapy and Pharmacology, Vol. 44, Issue 3 https://doi.org/10.1007/s002800050974	journal	July 1999
Gadolinium-based contrast agents induce gadolinium deposits in cerebral vessel walls, while the neuropil is not affected: an autopsy study Fingerhut, Stefanie; Sperling, Michael; Holling, Markus Acta Neuropathologica, Vol. 136, Issue 1 https://doi.org/10.1007/s00401-018-1857-4	journal	May 2018
SUR1 (CSG1 / BCL21), a gene necessary for growth of Saccharomyces cerevisiae in the presence of high Ca2+ concentrations at 37° C, is required for mannosylation of inositolphosphorylceramide Beeler, T. J.; Fu, D.; Rivera, J. Molecular and General Genetics MGG, Vol. 255, Issue 6 https://doi.org/10.1007/s004380050530	journal	August 1997
Gadolinium induces domain and pore formation of human erythrocyte membrane: an atomic force microscopic study Cheng, Yi; Liu, Maozi; Li, Rongchang Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1421, Issue 2 https://doi.org/10.1016/S0005-2736(99)00125-X	journal	October 1999
Dipole Potentials Indicate Restructuring of the Membrane Interface Induced by Gadolinium and Beryllium Ions Ermakov, Yuri A.; Averbakh, Alexander Z.; Yusipovich, Alexander I. Biophysical Journal, Vol. 80, Issue 4 https://doi.org/10.1016/S0006-3495(01)76155-3	journal	April 2001
SANS Study on the Effect of Lanthanide Ions and Charged Lipids on the Morphology of Phospholipid Mixtures Nieh, Mu-Ping; Glinka, Charles J.; Krueger, Susan Biophysical Journal, Vol. 82, Issue 5 https://doi.org/10.1016/S0006-3495(02)75591-4	journal	May 2002
Lanthanides—the future drugs? Wang, Kui; Li, Rongchang; Cheng, Yi Coordination Chemistry Reviews, Vol. 190-192 https://doi.org/10.1016/S0010-8545(99)00072-7	journal	September 1999
Multi-metallic modelling for biosorption of binary systems Pagnanelli, Francesca; Esposito, Antonio; Vegliò, Francesco Water Research, Vol. 36, Issue 16 https://doi.org/10.1016/S0043-1354(02)00112-4	journal	September 2002
Biosorption of heavy metals by Saccharomyces cerevisiae: A review Wang, Jianlong; Chen, Can Biotechnology Advances, Vol. 24, Issue 5 https://doi.org/10.1016/j.biotechadv.2006.03.001	journal	September 2006
Gadolinium Ions Block Mechanosensitive Channels by Altering the Packing and Lateral Pressure of Anionic Lipids Ermakov, Yury A.; Kamaraju, Kishore; Sengupta, Krishnendu Biophysical Journal, Vol. 98, Issue 6 https://doi.org/10.1016/j.bpj.2009.11.044	journal	March 2010
Simulating calcium influx and free calcium concentrations in yeast Cui, Jiangjun; Kaandorp, Jaap A.; Ositelu, Olufisayo O. Cell Calcium, Vol. 45, Issue 2 https://doi.org/10.1016/j.ceca.2008.07.005	journal	February 2009
Gadolinium deposition in nephrogenic fibrosing dermopathy Boyd, Alan S.; Zic, John A.; Abraham, Jerrold L. Journal of the American Academy of Dermatology, Vol. 56, Issue 1 https://doi.org/10.1016/j.jaad.2006.10.048	journal	January 2007
Gadolinium deposition in nephrogenic systemic fibrosis: An examination of tissue using synchrotron x-ray fluorescence spectroscopy High, Whitney A.; Ranville, James F.; Brown, Mariah Journal of the American Academy of Dermatology, Vol. 62, Issue 1 https://doi.org/10.1016/j.jaad.2009.07.018	journal	January 2010
Spatially resolved quantification of gadolinium deposited in the brain of a patient treated with gadolinium-based contrast agents Fingerhut, Stefanie; Niehoff, Ann-Christin; Sperling, Michael Journal of Trace Elements in Medicine and Biology, Vol. 45 https://doi.org/10.1016/j.jtemb.2017.10.004	journal	January 2018
Structural, surface morphological and low temperature studies on gadolinium tri chloride (GdCl3) Ariponnammal, S.; Shalini, S.; Devi, S. Nishanthini Materials Today: Proceedings, Vol. 35 https://doi.org/10.1016/j.matpr.2019.05.406	journal	January 2021
Electrochemical Stability of Metastable Materials Singh, Arunima K.; Zhou, Lan; Shinde, Aniketa Chemistry of Materials, Vol. 29, Issue 23 https://doi.org/10.1021/acs.chemmater.7b03980	journal	November 2017
Increases in Anthropogenic Gadolinium Anomalies and Rare Earth Element Concentrations in San Francisco Bay over a 20 Year Record Hatje, Vanessa; Bruland, Kenneth W.; Flegal, A. Russell Environmental Science & Technology, Vol. 50, Issue 8 https://doi.org/10.1021/acs.est.5b04322	journal	January 2016
Evaluation of thermodynamic equations of state across chemistry and structure in the materials project Latimer, Katherine; Dwaraknath, Shyam; Mathew, Kiran npj Computational Materials, Vol. 4, Issue 1 https://doi.org/10.1038/s41524-018-0091-x	journal	July 2018
Gene products and processes contributing to lanthanide homeostasis and methanol metabolism in Methylorubrum extorquens AM1 Roszczenko-Jasińska, Paula; Vu, Huong N.; Subuyuj, Gabriel A. Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-69401-4	journal	July 2020
Charting the complete elastic properties of inorganic crystalline compounds de Jong, Maarten; Chen, Wei; Angsten, Thomas Scientific Data, Vol. 2, Issue 1 https://doi.org/10.1038/sdata.2015.9	journal	March 2015
Surface energies of elemental crystals Tran, Richard; Xu, Zihan; Radhakrishnan, Balachandran Scientific Data, Vol. 3, Issue 1 https://doi.org/10.1038/sdata.2016.80	journal	September 2016
Delineating toxicity mechanisms associated with MRI contrast enhancement through a multidimensional toxicogenomic profiling of gadolinium Pallares, Roger M.; An, Dahlia D.; Hébert, Solène Molecular Omics, Vol. 18, Issue 3 https://doi.org/10.1039/D1MO00267H	journal	January 2022
Evidence that lanthanum ions stimulate calcium inflow to isolated hepatocytes Parker, J. C.; Barritt, G. J. Biochemical Journal, Vol. 200, Issue 1 https://doi.org/10.1042/bj2000109	journal	October 1981
Atomic Radii in Crystals Slater, J. C. The Journal of Chemical Physics, Vol. 41, Issue 10 https://doi.org/10.1063/1.1725697	journal	November 1964
Commentary: The Materials Project: A materials genome approach to accelerating materials innovation Jain, Anubhav; Ong, Shyue Ping; Hautier, Geoffroy APL Materials, Vol. 1, Issue 1 https://doi.org/10.1063/1.4812323	journal	July 2013
Genome-wide toxicogenomic study of the lanthanides sheds light on the selective toxicity mechanisms associated with critical materials Pallares, Roger M.; Faulkner, David; An, Dahlia D. Proceedings of the National Academy of Sciences, Vol. 118, Issue 18 https://doi.org/10.1073/pnas.2025952118	journal	April 2021
The Saccharomyces cerevisiae TSC10/YBR265w Gene Encoding 3-Ketosphinganine Reductase Is Identified in a Screen for Temperature-sensitive Suppressors of the Ca2+-sensitive csg2Δ Mutant Beeler, Troy; Bacikova, Dagmar; Gable, Ken Journal of Biological Chemistry, Vol. 273, Issue 46 https://doi.org/10.1074/jbc.273.46.30688	journal	November 1998
The Active Transport of Phosphate into the Yeast cell Goodman, Joan; Rothstein, Aser The Journal of General Physiology, Vol. 40, Issue 6 https://doi.org/10.1085/jgp.40.6.915	journal	July 1957
Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Grobner, Thomas Nephrology Dialysis Transplantation, Vol. 21, Issue 4 https://doi.org/10.1093/ndt/gfk062	journal	January 2006
Freeze substitution in 3 hours or less: FREEZE SUBSTIUTION IN 3 HOURS OR LESS McDONALD, K. L.; Webb, R. I. Journal of Microscopy, Vol. 243, Issue 3 https://doi.org/10.1111/j.1365-2818.2011.03526.x	journal	August 2011
Thermodynamic limit for synthesis of metastable inorganic materials Aykol, Muratahan; Dwaraknath, Shyam S.; Sun, Wenhao Science Advances, Vol. 4, Issue 4 https://doi.org/10.1126/sciadv.aaq0148	journal	April 2018
Functional Characterization of the S. cerevisiae Genome by Gene Deletion and Parallel Analysis Winzeler, E. A. Science, Vol. 285, Issue 5429 https://doi.org/10.1126/science.285.5429.901	journal	August 1999
Extracellular and Intracellular Lanthanide Accumulation in the Methylotrophic Beijerinckiaceae Bacterium RH AL1 Wegner, Carl-Eric; Westermann, Martin; Steiniger, Frank Applied and Environmental Microbiology, Vol. 87, Issue 13 https://doi.org/10.1128/AEM.03144-20	journal	June 2021
Long-Term Preservation of Fungal Isolates in Commercially Prepared Cryogenic Microbank Vials Espinel-Ingroff, A.; Montero, D.; Martin-Mazuelos, E. Journal of Clinical Microbiology, Vol. 42, Issue 3 https://doi.org/10.1128/JCM.42.3.1257-1259.2004	journal	March 2004
Microbial Cells as Biosorbents for Heavy Metals: Accumulation of Uranium by Saccharomyces cerevisiae and Pseudomonas aeruginosa Strandberg, Gerald W.; Shumate, Starling E.; Parrott, John R. Applied and Environmental Microbiology, Vol. 41, Issue 1 https://doi.org/10.1128/aem.41.1.237-245.1981	journal	January 1981
Different lanthanide elements induce strong gene expression changes in a lanthanide-accumulating methylotroph Gorniak, Linda; Bechwar, Julia; Westermann, Martin Microbiology Spectrum, Vol. 11, Issue 6 https://doi.org/10.1128/spectrum.00867-23	journal	December 2023
High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material Kanda, Tomonori; Ishii, Kazunari; Kawaguchi, Hiroki Radiology, Vol. 270, Issue 3 https://doi.org/10.1148/radiol.13131669	journal	March 2014
Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging McDonald, Robert J.; McDonald, Jennifer S.; Kallmes, David F. Radiology, Vol. 275, Issue 3 https://doi.org/10.1148/radiol.15150025	journal	June 2015
Symptoms Associated with Gadolinium Exposure (SAGE): A Suggested Term McDonald, Robert J.; Weinreb, Jeffrey C.; Davenport, Matthew S. Radiology, Vol. 302, Issue 2 https://doi.org/10.1148/radiol.2021211349	journal	January 2022
Biological and Clinical Aspects of Lanthanide Coordination Compounds Misra, Sudhindra N.; Gagnani, Minaz A.; M., Indira Devi Bioinorganic Chemistry and Applications, Vol. 2, Issue 3-4 https://doi.org/10.1155/S1565363304000111	journal	January 2004
Regulation of Cation Balance in Saccharomyces cerevisiae Cyert, Martha S.; Philpott, Caroline C. Genetics, Vol. 193, Issue 3 https://doi.org/10.1534/genetics.112.147207	journal	March 2013
Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging Marckmann, Peter; Skov, Lone; Rossen, Kristian Journal of the American Society of Nephrology, Vol. 17, Issue 9 https://doi.org/10.1681/ASN.2006060601	journal	August 2006
Toxicological and cytophysiological aspects of lanthanides action. Pałasz, A.; Czekaj, P. Acta Biochimica Polonica, Vol. 47, Issue 4 https://doi.org/10.18388/abp.2000_3963	journal	December 2000
Hyperaccumulation of Gadolinium by Methylorubrum extorquens AM1 Reveals Impacts of Lanthanides on Cellular Processes Beyond Methylotrophy Good, Nathan M.; Lee, Harvey D.; Hawker, Emily R. Frontiers in Microbiology, Vol. 13 https://doi.org/10.3389/fmicb.2022.820327	journal	March 2022
Nephrogenic systemic fibrosis Braverman, Irwin M.; Cowper, Shawn F1000 Medicine Reports, Vol. 2 https://doi.org/10.3410/M2-84	journal	November 2010

Similar Records

Multidimensional genome-wide screening in yeast provides mechanistic insights into europium toxicity

Journal Article · 2021 · Metallomics (Online) · OSTI ID:1834258

Pallares, Roger M.; An, Dahlia D.; Hébert, Solène; +8 more

Production of high-purity gadolinium-153. 2. Removal of samarium, terbium, and microamounts of europium from gadolinium by extraction chromatography

Journal Article · 1995 · Radiochemistry · OSTI ID:136349

Mel`nik, M I; Karelin, E A; Filimonov, V T

Metabolic and functional connections between cytoplasmic and chloroplast triacylglycerol storage

Journal Article · 2020 · Progress in Lipid Research · OSTI ID:1706607

Xu, Changcheng; Fan, Jilian; Shanklin, John

Title: Electron microscopy evidence of gadolinium toxicity being mediated through cytoplasmic membrane dysregulation

Citation Formats

References (47)

Similar Records

Related Subjects