Altered Functional Mitochondrial Protein Levels in Plasma Neuron-Derived Extracellular Vesicles of Patients With Gadolinium Deposition

Edward J Goetzl, Holden T Maecker, Yael Rosenberg-Hasson, Lorrin M Koran, Edward J Goetzl, Holden T Maecker, Yael Rosenberg-Hasson, Lorrin M Koran

Abstract

The retention of the heavy metal, gadolinium, after a Gadolinium-Based Contrast Agent-assisted MRI may lead to a symptom cluster termed Gadolinium Deposition Disease. Little is known of the disorder's underlying pathophysiology, but a recent study reported abnormally elevated serum levels of pro-inflammatory cytokines compared to normal controls. As a calcium channel blocker in cellular plasma and mitochondrial membranes, gadolinium also interferes with mitochondrial function. We applied to sera from nine Gadolinium Deposition Disease and two Gadolinium Storage Condition patients newly developed methods allowing isolation of plasma neuron-derived extracellular vesicles that contain reproducibly quantifiable levels of mitochondrial proteins of all major classes. Patients' levels of five mitochondrial functional proteins were statistically significantly lower and of two significantly higher than the levels in normal controls. The patterns of differences between study patients and controls for mitochondrial dynamics and mitochondrial proteins encompassing neuronal energy generation, metabolic regulation, ion fluxes, and survival differed from those seen for patients with first episode psychosis and those with Major Depressive Disorder compared to their controls. These findings suggest that mitochondrial dysfunction due to retained gadolinium may play a role in causing Gadolinium Deposition Disease. Larger samples of both GDD and GSC patients are needed to allow not only testing the repeatability of our findings, but also investigation of relationships of specific mitochondrial protein deficiencies or excesses and concurrent cytokine, genetic, or other factors to GDD's neurological and cognitive symptoms. Studies of neuronal mitochondrial proteins as diagnostic markers or indicators of treatment effectiveness are also warranted.

Keywords: GBCA; exosomes; gadolinium deposition disease; mitochondrial functions; toxic encephalopathy.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Goetzl, Maecker, Rosenberg-Hasson and Koran.

References

    1. Alkhunizi S. M., Fakhoury M., Abou-Kheir W., Lawand N. (2020). Gadolinium Retention in the central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis. Radiology 297 (2), 407–416. 10.1148/radiol.2020192645
    1. Bower D. V., Richter J. K., von Tengg-Kobligk H., Heverhagen J. T., Runge V. M. (2019). Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases with Reduced Kinetic Stability of the Agent. Invest. Radiol. 54 (8), 453–463. 10.1097/RLI.0000000000000567
    1. Devine M. J., Kittler J. T. (2018). Mitochondria at the Neuronal Presynapse in Health and Disease. Nat. Rev. Neurosci. 19 (2), 63–80. 10.1038/nm.2017.17010.1038/nrn.2017.170
    1. Escala-Garcia M., Morra A., Canisius S., Chang-Claude J., Kar S., Zheng W., et al. (2020). Breast Cancer Risk Factors and Their Effects on Survival: a Mendelian Randomisation Study. BMC Med. 18 (1), 327. 10.1186/s12916-020-01797-2
    1. Eshima H., Poole D. C., Kano Y. (2014). In Vivo calcium Regulation in Diabetic Skeletal Muscle. Cell Calcium 56 (5), 381–389. 10.1016/j.ceca.2014.08.008
    1. Feng X., Xia Q., Yuan L., Yang X., Wang K. (2010). Impaired Mitochondrial Function and Oxidative Stress in Rat Cortical Neurons: Implications for Gadolinium-Induced Neurotoxicity. NeuroToxicology 31 (4), 391–398. 10.1016/j.neuro.2010.04.003
    1. Goetzl E. J., Srihari V. H., Guloksuz S., Ferrara M., Tek C., Heninger G. R. (2020). Decreased Mitochondrial Electron Transport Proteins and Increased Complement Mediators in Plasma Neural-Derived Exosomes of Early Psychosis. Transl Psychiatry 10, 361. 10.1038/s41398-020-01046-3
    1. Goetzl E. J., Wolkowitz O. M., Srihari V. H., Reus V. I., Goetzl L., Kapogiannis D., et al. (2021). Abnormal Levels of Mitochondrial Proteins in Plasma Neuronal Extracellular Vesicles in Major Depressive Disorder. Mol. Psychiatry. Online ahead of print. 10.1038/s41380-021-01268-x
    1. Gureev A. P., Shaforostova E. A., Popov V. N. (2019). Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction between the Nrf2 and PGC-1α Signaling Pathways. Front. Genet. 10, 435. 10.3389/fgene.2019.00435
    1. Han B., Jiang W., Liu H., Wang J., Zheng K., Cui P., et al. (2020). Upregulation of Neuronal PGC-1α Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion. Theranostics 10 (6), 2832–2848. 10.7150/thno.37119
    1. Kelly D. P., Scarpulla R. C. (2004). Transcriptional Regulatory Circuits Controlling Mitochondrial Biogenesis and Function. Genes Dev. 18, 357–368. 10.1101/gad.1177604
    1. Lancelot E. (2016). Revisiting the Pharmacokinetic Profiles of Gadolinium-Based Contrast Agents. Invest. Radiol. 51 (11), 691–700. 10.1097/RLI.0000000000000280
    1. Levine D., McDonald R. J., Kressel H. Y. (2018). Gadolinium Retention after Contrast-Enhanced MRI. JAMA 320 (18), 1853. 10.1001/jama.2018.13362
    1. Liu H., Yuan L., Yang X., Wang K. (2003). La3+, Gd3+ and Yb3+ Induced Changes in Mitochondrial Structure, Membrane Permeability, Cytochrome C Release and Intracellular ROS Level. Chemico-Biological Interactions 146 (1), 27–37. 10.1016/S0009-2797(03)00072-3
    1. Maecker H. T., Siebert J. C., Rosenberg-Hasson Y., Koran L. M., Ramalho M., Semelka R. C. (2021). Acute Chelation Therapy‐Associated Changes in Urine Gadolinium, Self-Reported Flare Severity, and Serum Cytokines in Gadolinium Deposition Disease. Invest. Radiol. 56 (6), 374–384. 10.1097/RLI.0000000000000752
    1. Maecker H. T., Wang W., Rosenberg-Hasson Y., Semelka R. C., Hickey J., Koran L. M. (2020). An Initial Investigation of Serum Cytokine Levels in Patients with Gadolinium Retention. Radiol. Bras. 53 (5), 306–313. 10.1590/0100-3984.2019.0075
    1. Mistry S., Harrison J. R., Smith D. J., Escott-Price V., Zammit S. (2018). The Use of Polygenic Risk Scores to Identify Phenotypes Associated with Genetic Risk of Bipolar Disorder and Depression: A Systematic Review. J. Affective Disord. 234, 148–155. 10.1016/j.jad.2018.02.005
    1. Natarajan G. K., Mishra J., Camara A. K. S., Kwok W.-M. (2021). LETM1: A Single Entity with Diverse Impact on Mitochondrial Metabolism and Cellular Signaling. Front. Physiol. 12, 637852. 10.3389/fphys.2021.637852
    1. Radbruch A., Richter H., Bücker P., Berlandi J., Schänzer A., Deike-Hofmann K., et al. (2020). Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents? Invest. Radiol. 55, 473–480. Publish Ahead of Print. 10.1097/RLI.0000000000000677
    1. Ramalho J., Semelka R. C., Ramalho M., Nunes R. H., AlObaidy M., Castillo M. (2016). Gadolinium-based Contrast Agent Accumulation and Toxicity: An Update. Am. J. Neuroradiology 37 (7), 1192–1198. 10.3174/ajnr.A4615
    1. Ramalho M., Ramalho J., Burke L. M., Semelka R. C. (2017). Gadolinium Retention and Toxicity-An Update. Adv. Chronic Kidney Dis. 24 (3), 138–146. 10.1053/j.ackd.2017.03.004
    1. Rogosnitzky M., Branch S. (2016). Gadolinium-based Contrast Agent Toxicity: a Review of Known and Proposed Mechanisms. Biometals 29, 365–376. 10.1007/s10534-016-9931-7
    1. Semelka R. C., Ramalho J., Vakharia A., AlObaidy M., Burke L. M., Jay M., et al. (2016a). Gadolinium Deposition Disease: Initial Description of a Disease that Has Been Around for a while. Magn. Reson. Imaging 34, 1383–1390. 10.1016/j.mri.2016.07.016
    1. Semelka R. C., Ramalho M., AlObaidy M., Ramalho J. (2016b). Gadolinium in Humans: A Family of Disorders. Am. J. Roentgenology 207, 229–233. 10.2214/AJR.15.15842
    1. Stein L. R., Imai S.-i. (2012). The Dynamic Regulation of NAD Metabolism in Mitochondria. Trends Endocrinol. Metab. 23 (9), 420–428. 10.1016/j.tem.2012.06.005
    1. Sui B.-d., Xu T.-q., Liu J.-w., Wei W., Zheng C.-x., Guo B.-l., et al. (2013). Understanding the Role of Mitochondria in the Pathogenesis of Chronic Pain. Postgrad. Med. J. 89 (1058), 709–714. 10.1136/postgradmedj-2012-131068
    1. Wise A. L., Manolio T. A., Mensah G. A., Peterson J. F., Roden D. M., Tamburro C., et al. (2019). Genomic Medicine for Undiagnosed Diseases. The Lancet 394 (10197), 533–540. 10.1016/s0140-6736(19)31274-7
    1. Zhao J., Zhou Z.-Q., Jin J.-C., Yuan L., He H., Jiang F.-L., et al. (2014). Mitochondrial Dysfunction Induced by Different Concentrations of Gadolinium Ion. Chemosphere 100, 194–199. 10.1016/j.chemosphere.2013.11.031
    1. Zolkipli-Cunningham Z., Xiao R., Stoddart A., McCormick E. M., Holberts A., Burrill N., et al. (2018). Mitochondrial Disease Patient Motivations and Barriers to Participate in Clinical Trials. PLoS One 13 (5), e0197513. 10.1371/journal.pone.0197513

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren