An Alternative Mechanism of Subcellular Iron Uptake Deficiency in Cardiomyocytes.

Humans Myocytes, Cardiac / metabolism Mutation Cardiomyopathy, Dilated / genetics Induced Pluripotent Stem Cells / metabolism Iron Deficiencies Heart Failure / genetics Iron / metabolism Clathrin / genetics
cardiomyopathy, dilated cardiovascular disease heart failure iron deficiency sarcomere

Journal

Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103

Informations de publication

Date de publication:
07 07 2023
Historique:
medline: 10 7 2023
pubmed: 14 6 2023
entrez: 14 6 2023
Statut: ppublish

Résumé

Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis. We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell model of 2 inherited mutations ( We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell-derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure.

Sections du résumé

BACKGROUND
Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis.
METHODS
We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue. We used an integrated platform of DIA-MA (mass spectrometry data-independent acquisition)-based proteomics and signaling pathway interrogation. We employed a genetic induced pluripotent stem cell model of 2 inherited mutations (
RESULTS
We identified a druggable molecular pathomechanism of impaired subcellular iron deficiency that is independent of systemic iron metabolism. Clathrin-mediated endocytosis defects as well as impaired endosome distribution and cargo transfer were identified as a basis for subcellular iron deficiency in DCM-induced pluripotent stem cell-derived cardiomyocytes. The clathrin-mediated endocytosis defects were also confirmed in the hearts of patients with DCM with end-stage heart failure. Correction of the
CONCLUSIONS
Our findings suggest that impaired endocytosis and cargo transport resulting in subcellular iron deficiency could be a relevant pathomechanism for patients with DCM carrying inherited mutations. Insight into this molecular mechanism may contribute to the development of treatment strategies and risk management in heart failure.

Identifiants

DOI: 10.1161/CIRCRESAHA.122.321157 PMID: 37313752
pubmed: 37313752
doi: 10.1161/CIRCRESAHA.122.321157
doi:

Substances chimiques

Iron E1UOL152H7
Clathrin 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e19-e46

Auteurs

Yuanyuan Dai (Y)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).

Nadezda Ignatyeva (N)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).

Hang Xu (H)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).

Ruheen Wali (R)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).

Karl Toischer (K)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Heart Center, Clinic for Cardiology and Pneumology, University Medical Center Goettingen (K.T., S.B., S.S., G.H.), University of Goettingen, Germany.

Sören Brandenburg (S)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Heart Center, Clinic for Cardiology and Pneumology, University Medical Center Goettingen (K.T., S.B., S.S., G.H.), University of Goettingen, Germany.
ORCID: 0000-0001-5148-0997

Christof Lenz (C)

DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Department of Clinical Chemistry, University Medical Center Goettingen, (C.L., H.U.), University of Goettingen, Germany.
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC; C.L., F.E.F., N.V., S.E.L.), University of Goettingen, Germany.
Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Goettingen (C.L., H.U.).
ORCID: 0000-0002-0946-8166

Julius Pronto (J)

DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Institute of Pharmacology and Toxicology, University Medical Center Goettingen, (J.P., F.E.F., N.V.), University of Goettingen, Germany.
ORCID: 0000-0003-3556-5637

Funsho E Fakuade (FE)

DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Institute of Pharmacology and Toxicology, University Medical Center Goettingen, (J.P., F.E.F., N.V.), University of Goettingen, Germany.
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC; C.L., F.E.F., N.V., S.E.L.), University of Goettingen, Germany.
ORCID: 0000-0001-6683-6079

Samuel Sossalla (S)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
Heart Center, Clinic for Cardiology and Pneumology, University Medical Center Goettingen (K.T., S.B., S.S., G.H.), University of Goettingen, Germany.
Department for Internal Medicine II, University Medical Center Regensburg (S.S.).
ORCID: 0000-0001-8034-2673

Elisabeth M Zeisberg (EM)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).

Andreas Janshoff (A)

Institute for Physical Chemistry (A.J.), University of Goettingen, Germany.
ORCID: 0000-0002-0773-2963

Ingo Kutschka (I)

DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Department of Thoracic and Cardiovascular Surgery, University Medical Center Göttingen (I.K.).

Niels Voigt (N)

DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Institute of Pharmacology and Toxicology, University Medical Center Goettingen, (J.P., F.E.F., N.V.), University of Goettingen, Germany.
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC; C.L., F.E.F., N.V., S.E.L.), University of Goettingen, Germany.
ORCID: 0000-0001-8230-2341

Henning Urlaub (H)

Department of Clinical Chemistry, University Medical Center Goettingen, (C.L., H.U.), University of Goettingen, Germany.
Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Goettingen (C.L., H.U.).

Torsten Bloch Rasmussen (TB)

Department of Cardiology, Aarhus University Hospital, Denmark (T.B.R.).

Jens Mogensen (J)

Department of Cardiology, Aalborg University Hospital, Denmark (J.M.).
ORCID: 0000-0002-8813-573X

Stephan E Lehnart (SE)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC; C.L., F.E.F., N.V., S.E.L.), University of Goettingen, Germany.
ORCID: 0000-0002-8115-3513

Gerd Hasenfuss (G)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
Heart Center, Clinic for Cardiology and Pneumology, University Medical Center Goettingen (K.T., S.B., S.S., G.H.), University of Goettingen, Germany.

Antje Ebert (A)

Heart Research Center Goettingen, Clinic for Cardiology and Pneumology, University Medical Center Goettingen, Georg-August University of Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., S.S., E.M.Z., S.E.L., G.H., A.E.).
DZHK (German Center for Cardiovascular Research), partner site Goettingen, Germany (Y.D., N.I., H.X., R.W., K.T., S.B., C.L., J.P., F.E.F., E.M.Z., I.K., N.V., S.E.L., G.H., A.E.).
ORCID: 0000-0002-3642-242X

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes cardiaques › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Laminopathies › Cardiomyopathie dilatée › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles du métabolisme du fer › Carences en fer › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Défaillance cardiaque › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Produits chimiques inorganiques › Métaux › Métaux lourds › Fer › An Alternative Mechanism of Subcellular Iron...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Clathrine › An Alternative Mechanism of Subcellular Iron...