title: Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes.
abstract: 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.
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Helen P
authors.initials: HP
authors.lastname: McWilliams-Koeppen
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Foster
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hackenbrack
authors.affiliation: Department of Biochemistry/Mol. Biol. and Immunology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
authors.affiliation: Department of Nutrition, University of Tennessee Knoxville, TN, United States of America.
authors.forename: Dallas
authors.initials: D
authors.lastname: Donohoe
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Sallie
authors.initials: S
authors.lastname: Macy
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Wooliver
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Dale
authors.initials: D
authors.lastname: Wortham
authors.affiliation: Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morrell-Falvey
authors.affiliation: Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States of America.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Foster
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America; Department of Radiology, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America; Department of Radiology, University of Tennessee Graduate School of Medicine, Knoxville, TN United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000682:Amyloid; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D009252:NADPH Dehydrogenase; D010100:Oxygen