Targeting intracellular cholesterol imbalance rescues sarcomere–ER contact site signaling and ER remodeling in dilated cardiomyopathy
Dysregulated intracellular lipid metabolism emerged as a driver of heart failure (HF), a leading cause of death worldwide that is frequently caused by dilated cardiomyopathy (DCM). Yet, how defective lipid signaling destabilizes failing cardiomyocytes (CMs) at the molecular level remains elusive. We utilized induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), patient-derived heart tissue, and living adult CMs to elucidate lipid-dependent endoplasmic reticulum (ER) dysregulation in DCM and HF and identify new therapeutic targets. Lipidomics revealed abnormal intracellular cholesterol in iPSC-CMs carrying DCM-causing mutations in sarcomere proteins (tropomyosin; troponin T). Elevated cholesterol in CMs was found linked to abnormal ER architecture and dysfunction. STED microscopy, electron tomography, and biochemical analyses demonstrated that pathological ER remodeling and abnormal curvature are triggered by loss of ER-sarcomere/cytoskeleton contacts due to sarcomere misalignment in DCM CMs. Mechanistically, this signaling axis levers ER membrane dysfunctions and abnormal cholesterol levels via ER-sarcomere contact sites and operates in a bidirectional manner. Restoring intracellular cholesterol balance rescued ER membrane remodeling, sarcomere-ER contact site signaling, and sarcomere disarray in DCM iPSC-CMs. This ultimately improved the defective contractility of DCM iPSC-CMs, a key feature of failing CMs that contain a misaligned, dysfunctional sarcomere cytoskeleton. We validated this pathomechanism in end-stage DCM hearts and living atrial cardiomyocytes. Our findings suggest that intracellular cholesterol functions as a conserved ER membrane modulator and structural determinant across human CMs. Taken together, we present the lipidomic landscape of DCM and identify defective ER/cholesterol signaling as a disease driver whose therapeutic targeting rescues key functions in failing CMs.
Authors
- Michael Gotthardt (ORCID: https://orcid.org/0000-0003-1788-3172)
- Volker Haucke (ORCID: https://orcid.org/0000-0003-3119-6993)
- Julius Ryan D. Pronto (ORCID: https://orcid.org/0000-0003-3556-5637)
- Samuel Tobias Sossalla (ORCID: https://orcid.org/0000-0001-8034-2673)
- Cleophas Cheruiyot
- Stephan E. Lehnart (ORCID: https://orcid.org/0000-0002-8115-3513)
- Niels Voigt (ORCID: https://orcid.org/0000-0001-8230-2341)
- Torben Ruhwedel (ORCID: https://orcid.org/0000-0002-9535-9395)
- Britta Brügger (ORCID: https://orcid.org/0000-0002-3477-8270)
- Soeren Brandenburg
- Jens Mogensen (ORCID: https://orcid.org/0000-0002-8813-573X)
- Antje Ebert (ORCID: https://orcid.org/0000-0002-3642-242X)
- Hafiza Nosheen Saleem
- Sophie Schön
- Zhengyi Yang (ORCID: https://orcid.org/0000-0001-7190-7505)
- Halyna R. Shcherbata (ORCID: https://orcid.org/0000-0002-3855-0345)
- Ruheen Wali
- Andreas Janshoff (ORCID: https://orcid.org/0000-0002-0773-2963)
- Anna M. Steyer (ORCID: https://orcid.org/0000-0002-4814-7517)
- Henning Urlaub (ORCID: https://orcid.org/0000-0003-1837-5233)
- Michaël Radkë (ORCID: https://orcid.org/0000-0003-0112-9917)
- Yannic Döring (ORCID: https://orcid.org/0000-0001-5060-8610)
- Wenjing Zhang (ORCID: https://orcid.org/0000-0002-0617-5886)
- Wiebke Möbius (ORCID: https://orcid.org/0000-0002-2902-7165)
- Daria Plota
- Torsten Rasmussen
- Nadezda Ignatyeva (ORCID: https://orcid.org/0009-0008-4421-0495)
- Karl Toischer
Institutions
- Trinity College Dublin (IE)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- Mount Desert Island Biological Laboratory (US)
- Aarhus University Hospital (DK)
- Medizinische Hochschule Hannover (DE)
- Max Planck Institute for Medical Research (DE)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Nephrologisches Zentrum Goettingen (DE)
- German Centre for Cardiovascular Research (DE)
- Max Planck Institute for Biophysical Chemistry (DE)
- European Molecular Biology Laboratory (DE)
- Max Planck Research Unit for Neurogenetics (DE)
- St. James's Hospital (IE)
- University of Göttingen (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2026-06-16
- DOI
- https://doi.org/10.1038/s41392-026-02731-3
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Zentrum für Herz-Kreislaufforschung
- Deutsche Forschungsgemeinschaft
- China Scholarship Council
- Deutsche Herzstiftung