Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; Ramirez-Alvarado, Marina; Donohoe, Dallas; Williams, Angela; Macy, Sallie; Wooliver, Craig; Wortham, Dale; Morrell-Falvey, Jennifer; Foster, Carmen M.; Kennel, Stephen J.; Wall, Jonathan S.

doi:10.1371/journal.pone.0137716

Title: Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

Journal Article · Tue Sep 22 00:00:00 EDT 2015 · PLoS ONE

DOI: https://doi.org/10.1371/journal.pone.0137716 · OSTI ID:1260653

McWilliams-Koeppen, Helen P. ^[1]; Foster, James S. ^[1]; Hackenbrack, Nicole ^[1]; Ramirez-Alvarado, Marina ^[2]; Donohoe, Dallas ^[3]; Williams, Angela ^[1]; Macy, Sallie ^[1]; Wooliver, Craig ^[1]; Wortham, Dale ^[1]; Morrell-Falvey, Jennifer ^[4]; Foster, Carmen M. ^[4]; Kennel, Stephen J. ^[5]; Wall, Jonathan S. ^[5]

Univ. of Tennessee, Knoxville, TN (United States). Dept. of Medicine
Mayo Clinic, rochester, MN (United States)
Univ. of Tennessee, Knoxville, TN (United States). Dept. of Nutrition
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biosciences Division
Univ. of Tennessee, Knoxville, TN (United States). Dept. of Medicine; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Radiology

Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1260653

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 9 Vol. 10; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs Bourgault, Steve; Choi, Sungwook; Buxbaum, Joel N. Biochemical and Biophysical Research Communications, Vol. 410, Issue 4 https://doi.org/10.1016/j.bbrc.2011.04.133	journal	July 2011
What do I need to know about immunoglobulin light chain (AL) amyloidosis? Dispenzieri, Angela; Gertz, Morie A.; Buadi, Francis Blood Reviews, Vol. 26, Issue 4 https://doi.org/10.1016/j.blre.2012.03.001	journal	July 2012
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Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38 MAPK pathway Shi, J.; Guan, J.; Jiang, B. Proceedings of the National Academy of Sciences, Vol. 107, Issue 9 https://doi.org/10.1073/pnas.0912263107	journal	February 2010
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The Mitochondrial Uncoupling Agent 2,4-Dinitrophenol Improves Mitochondrial Function, Attenuates Oxidative Damage, and Increases White Matter Sparing in the Contused Spinal Cord Jin, Ying; McEwen, Melanie L.; Nottingham, Stephanie A. Journal of Neurotrauma, Vol. 21, Issue 10 https://doi.org/10.1089/neu.2004.21.1396	journal	October 2004
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Systemic Amyloidoses Blancas-Mejía, Luis M.; Ramirez-Alvarado, Marina Annual Review of Biochemistry, Vol. 82, Issue 1 https://doi.org/10.1146/annurev-biochem-072611-130030	journal	June 2013
Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells Wu, Min; Neilson, Andy; Swift, Amy L. American Journal of Physiology-Cell Physiology, Vol. 292, Issue 1 https://doi.org/10.1152/ajpcell.00247.2006	journal	January 2007
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Current perspectives on cardiac amyloidosis Guan, Jian; Mishra, Shikha; Falk, Rodney H. American Journal of Physiology-Heart and Circulatory Physiology, Vol. 302, Issue 3 https://doi.org/10.1152/ajpheart.00815.2011	journal	February 2012
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Diagnosis and Management of the Cardiac Amyloidoses Falk, Rodney H. Circulation, Vol. 112, Issue 13 https://doi.org/10.1161/CIRCULATIONAHA.104.489187	journal	September 2005
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Infusion of Light Chains From Patients With Cardiac Amyloidosis Causes Diastolic Dysfunction in Isolated Mouse Hearts Liao, Ronglih; Jain, Mohit; Teller, Paige Circulation, Vol. 104, Issue 14 https://doi.org/10.1161/circ.104.14.1594	journal	October 2001
Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL Palladini, Giovanni; Lavatelli, Francesca; Russo, Paola Blood, Vol. 107, Issue 10 https://doi.org/10.1182/blood-2005-11-4385	journal	May 2006
Radioimmunodetection of amyloid deposits in patients with AL amyloidosis Wall, Jonathan S.; Kennel, Stephen J.; Stuckey, Alan C. Blood, Vol. 116, Issue 13 https://doi.org/10.1182/blood-2010-03-273797	journal	September 2010
TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells Voigt, Susann; Philipp, Stephan; Davarnia, Parvin BMC Cancer, Vol. 14, Issue 1 https://doi.org/10.1186/1471-2407-14-74	journal	February 2014
Amyloidosis: Pathogenesis and New Therapeutic Options Merlini, Giampaolo; Seldin, David C.; Gertz, Morie A. Journal of Clinical Oncology, Vol. 29, Issue 14 https://doi.org/10.1200/JCO.2010.32.2271	journal	May 2011
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Amyloid heart disease Dubrey, Simon W.; Falk, Rodney H. British Journal of Hospital Medicine, Vol. 71, Issue 2 https://doi.org/10.12968/hmed.2010.71.2.46484	journal	February 2010
AL Amyloid Imaging and Therapy with a Monoclonal Antibody to a Cryptic Epitope on Amyloid Fibrils Wall, Jonathan S.; Kennel, Stephen J.; Williams, Angela PLoS ONE, Vol. 7, Issue 12 https://doi.org/10.1371/journal.pone.0052686	journal	December 2012
Amyloidogenesis: historical and modern observations point to heparan sulfate proteoglycans as a major culprit Ancsin, John B. Amyloid, Vol. 10, Issue 2 https://doi.org/10.3109/13506120309041728	journal	January 2003
The diagnosis and typing of cardiac amyloidosis O'Hara, Carl J.; Falk, Rodney H. Amyloid, Vol. 10, Issue 2 https://doi.org/10.3109/13506120309041735	journal	January 2003
Synaptotoxic Amyloid-β Oligomers: A Molecular Basis for the Cause, Diagnosis, and Treatment of Alzheimer's Disease? Klein, William L. Journal of Alzheimer's Disease, Vol. 33, Issue s1 https://doi.org/10.3233/JAD-2012-129039	journal	December 2012

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Immunoglobulin Light Chains Form an Extensive and Highly Ordered Fibril Involving the N- and C-Termini Piehl, Dennis W.; Blancas-Mejía, Luis M.; Wall, Jonathan S. ACS Omega, Vol. 2, Issue 2 https://doi.org/10.1021/acsomega.6b00494	journal	February 2017
Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers Young, Lydia M.; Tu, Ling-Hsien; Raleigh, Daniel P. Chemical Science, Vol. 8, Issue 7 https://doi.org/10.1039/c7sc00620a	journal	January 2017
2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis Renz, Mark; Torres, Ronald; Dolan, Philip J. Amyloid, Vol. 23, Issue 3 https://doi.org/10.1080/13506129.2016.1205974	journal	July 2016
Differential recruitment efficacy of patient-derived amyloidogenic and myeloma light chain proteins by synthetic fibrils—A metric for predicting amyloid propensity Martin, Emily B.; Williams, Angela; Wooliver, Craig PLOS ONE, Vol. 12, Issue 3 https://doi.org/10.1371/journal.pone.0174152	journal	March 2017
Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells Jordan, Torri L.; Maar, Khansaa; Redhage, Keely R. Leukemia, Vol. 34, Issue 5 https://doi.org/10.1038/s41375-019-0640-4	journal	December 2019
Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis Radamaker, Lynn; Lin, Yin-Hsi; Annamalai, Karthikeyan Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-09032-0	journal	March 2019
Immunoglobulin light chain amyloid aggregation Blancas-Mejia, Luis M.; Misra, Pinaki; Dick, Christopher J. Chemical Communications, Vol. 54, Issue 76 https://doi.org/10.1039/c8cc04396e	journal	January 2018
Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy Wall, Jonathan S.; Williams, Angela D.; Foster, James S. Proceedings of the National Academy of Sciences, Vol. 115, Issue 46 https://doi.org/10.1073/pnas.1805515115	journal	October 2018
Inter-assay variability in automated serum free light chain assays and their use in the clinical laboratory Caponi, Laura; Romiti, Nadia; Koni, Elona Critical Reviews in Clinical Laboratory Sciences, Vol. 57, Issue 2 https://doi.org/10.1080/10408363.2019.1670133	journal	October 2019
2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis Renz, Mark; Torres, Ronald; Dolan, Philip J. Amyloid, Vol. 23, Issue 3 https://doi.org/10.1080/13506129.2016.1205974	journal	July 2016
A functional assay to identify amyloidogenic light chains Martin, Emily B.; Williams, Angela D.; Heidel, R. Eric Amyloid, Vol. 25, Issue 2 https://doi.org/10.1080/13506129.2018.1456425	journal	March 2018
What is new in diagnosis and management of light chain amyloidosis? Palladini, Giovanni; Merlini, Giampaolo Blood, Vol. 128, Issue 2 https://doi.org/10.1182/blood-2016-01-629790	journal	July 2016

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Title: Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

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