Targeting intracellular cholesterol imbalance rescues sarcomere–ER contact site signaling and ER remodeling in dilated cardiomyopathy
Year: 2026
Type: article
Abstract: 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: Nadezda Ignatyeva, Cleophas Cheruiyot, Hafiza Nosheen Saleem, Ruheen Wali, Daria Plota, Wenjing Zhang, Sophie Schön, Soeren Brandenburg, Zhengyi Yang, Anna Steyer, Henning Urlaub, Torsten Rasmussen, Jens Mogensen, Julius Ryan D. Pronto, Yannic Döring, Michael H. Radke, Halyna Shcherbata, Stephan E. Lehnart, Andreas Janshoff, Samuel Sossalla, Torben Ruhwedel, Wiebke Moebius, Karl Toischer, Britta Brügger, Volker Haucke, Michael Gotthardt, Niels Voigt, Antje Ebert
Institutions: Universitätsmedizin Göttingen, German Centre for Cardiovascular Research, University of Göttingen, European Molecular Biology Laboratory, European Molecular Biology Laboratory, Max Planck Institute for Multidisciplinary Sciences, Aarhus University Hospital, Trinity College Dublin, St. James's Hospital, Max Delbrück Center, Mount Desert Island Biological Laboratory, Medizinische Hochschule Hannover, Multiscale Bioimaging, Max Planck Institute for Medical Research, Max Planck School Matter to Life, University Hospital Regensburg, University of Regensburg, Heidelberg University, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Freie Universität Berlin, Charité - Universitätsmedizin Berlin
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,790
OpenAlex ID: W7164899327