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. ^[6]

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
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 Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725; R01DK079984

OSTI ID:: 1260653

Alternate ID(s):: OSTI ID: 1265825

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

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 40 works

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