Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes
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,...
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| creator | 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 |
| description | 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. 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. |
| doi_str_mv | 10.1371/journal.pone.0137716 |
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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. 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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0137716</identifier><identifier>PMID: 26393799</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine Triphosphate - metabolism ; Alzheimer's disease ; Alzheimers disease ; Amyloid ; Amyloid - chemistry ; Amyloid - genetics ; Amyloid - metabolism ; Amyloidosis ; BASIC BIOLOGICAL SCIENCES ; Cardiomyocytes ; Cardiomyopathy ; Cell death ; Cell Line ; Cell surface ; Cell Survival ; Chains ; Cytotoxicity ; Enzymatic activity ; Enzymes ; Extreme values ; Fibrils ; Fluorescence ; Fluorescence microscopy ; Heart ; Heart cells ; Heparan sulfate ; Humans ; Internalization ; Kidneys ; Laboratories ; Light ; Light chains ; Liver ; Medicine ; Metabolism ; Microscopy, Confocal ; Microscopy, Fluorescence ; Molecular structure ; Mutation ; Myocytes, Cardiac - enzymology ; Myocytes, Cardiac - metabolism ; NAD ; NADPH Dehydrogenase - metabolism ; Oxidative stress ; Oxidoreductase ; Oxygen ; Oxygen - metabolism ; Oxygen consumption ; Physiology ; Prognosis ; Proteins ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Spinal cord ; Type 2 diabetes</subject><ispartof>PloS one, 2015-09, Vol.10 (9), p.e0137716-e0137716</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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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. 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.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Alzheimer's disease</subject><subject>Alzheimers disease</subject><subject>Amyloid</subject><subject>Amyloid - chemistry</subject><subject>Amyloid - genetics</subject><subject>Amyloid - metabolism</subject><subject>Amyloidosis</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cell death</subject><subject>Cell Line</subject><subject>Cell surface</subject><subject>Cell Survival</subject><subject>Chains</subject><subject>Cytotoxicity</subject><subject>Enzymatic activity</subject><subject>Enzymes</subject><subject>Extreme values</subject><subject>Fibrils</subject><subject>Fluorescence</subject><subject>Fluorescence microscopy</subject><subject>Heart</subject><subject>Heart cells</subject><subject>Heparan sulfate</subject><subject>Humans</subject><subject>Internalization</subject><subject>Kidneys</subject><subject>Laboratories</subject><subject>Light</subject><subject>Light chains</subject><subject>Liver</subject><subject>Medicine</subject><subject>Metabolism</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Fluorescence</subject><subject>Molecular structure</subject><subject>Mutation</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>NAD</subject><subject>NADPH Dehydrogenase - metabolism</subject><subject>Oxidative stress</subject><subject>Oxidoreductase</subject><subject>Oxygen</subject><subject>Oxygen - metabolism</subject><subject>Oxygen consumption</subject><subject>Physiology</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Spinal cord</subject><subject>Type 2 diabetes</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk02P0zAQhiMEYpeFf4AgAgnBoSV2Eju-IFWFZSsVVeLrajnOpHHl2CV2EP33OG121aA9IB9sjZ95ZzyeiaLnKJmjlKL3O9t3Ruj53hqYJ8FEEXkQXSKW4hnBSfrw7HwRPXFulyR5WhDyOLrAJGUpZewy2qzVtvHxshHKxIv2oK2q4mtVdkq7eCl6B_EX8KK0Wsn448HVvZFeWRMH_KZvhQlQVynbHqw8eHBPo0e10A6ejftV9OP60_flzWy9-bxaLtYzSRHzM8gwrjCwqpBYSlrkdZmIiuSyKmvIioIgKoGIAueYJQIKyMtaJlnFEKWsEDS9il6edPfaOj7WwnEU1DHDKRuI1YmorNjxfada0R24FYofDbbbctF5JTVwigpcJ6TGWOYZqZmQaUYJwlSKusIlBK0PY7S-bKGSYHwn9ER0emNUw7f2N89yyhI6JPPqJGCdV9xJ5UE20hoD0nOESULyNEBvxyid_dWD87xVToLWwoDtj4-jGU1DYgF9_Q96fwlGaivCK5WpbUhODqJ8kVEU2iM_UvN7qLAqaFXIEWoV7BOHdxOHwHj447ehWxxfffv6_-zm55R9c8Y2ILRvnNX90G9uCmYnUHbWuQ7qu59ACR-G47YafBgOPg5HcHtx_ot3TrfTkP4FsukI8A</recordid><startdate>20150922</startdate><enddate>20150922</enddate><creator>McWilliams-Koeppen, Helen P</creator><creator>Foster, James S</creator><creator>Hackenbrack, Nicole</creator><creator>Ramirez-Alvarado, Marina</creator><creator>Donohoe, Dallas</creator><creator>Williams, Angela</creator><creator>Macy, Sallie</creator><creator>Wooliver, Craig</creator><creator>Wortham, Dale</creator><creator>Morrell-Falvey, Jennifer</creator><creator>Foster, Carmen M</creator><creator>Kennel, Stephen J</creator><creator>Wall, Jonathan S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150922</creationdate><title>Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c719t-e422d2e9d8c2cc785fb0ad65cdbfe488617ce6a825290ae8e5bfc04d917798a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenosine Triphosphate - 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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. 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26393799</pmid><doi>10.1371/journal.pone.0137716</doi><tpages>e0137716</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2015-09, Vol.10 (9), p.e0137716-e0137716 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenosine Triphosphate - metabolism Alzheimer's disease Alzheimers disease Amyloid Amyloid - chemistry Amyloid - genetics Amyloid - metabolism Amyloidosis BASIC BIOLOGICAL SCIENCES Cardiomyocytes Cardiomyopathy Cell death Cell Line Cell surface Cell Survival Chains Cytotoxicity Enzymatic activity Enzymes Extreme values Fibrils Fluorescence Fluorescence microscopy Heart Heart cells Heparan sulfate Humans Internalization Kidneys Laboratories Light Light chains Liver Medicine Metabolism Microscopy, Confocal Microscopy, Fluorescence Molecular structure Mutation Myocytes, Cardiac - enzymology Myocytes, Cardiac - metabolism NAD NADPH Dehydrogenase - metabolism Oxidative stress Oxidoreductase Oxygen Oxygen - metabolism Oxygen consumption Physiology Prognosis Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Spinal cord Type 2 diabetes |
| title | Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T06%3A15%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Light%20Chain%20Amyloid%20Fibrils%20Cause%20Metabolic%20Dysfunction%20in%20Human%20Cardiomyocytes&rft.jtitle=PloS%20one&rft.au=McWilliams-Koeppen,%20Helen%20P&rft.aucorp=Oak%20Ridge%20National%20Laboratory%20(ORNL),%20Oak%20Ridge,%20TN%20(United%20States)&rft.date=2015-09-22&rft.volume=10&rft.issue=9&rft.spage=e0137716&rft.epage=e0137716&rft.pages=e0137716-e0137716&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0137716&rft_dat=%3Cgale_plos_%3EA471193597%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1719292397&rft_id=info:pmid/26393799&rft_galeid=A471193597&rft_doaj_id=oai_doaj_org_article_7182f06f22c546f9ac3476127cafd2be&rfr_iscdi=true |