{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:45:04Z","timestamp":1776797104424,"version":"3.51.2"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      TMEM43 (transmembrane protein 43) is a ubiquitously expressed 4-transmembrane-protein localized in the endoplasmic reticulum and nuclear lamina. The missense mutation\n                      <jats:italic toggle=\"yes\">TMEM43<\/jats:italic>\n                      -p.S358L causes fully penetrant ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5) especially in males. The TMEM43 function of the protein and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. Here we provide evidence for a novel pathomechanism contributing to the onset of ARVC5.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Microsomes of human wild-type myocardium were separated by sucrose-gradient ultracentrifugation and characterized by mass-spectrometry to identify potential interacting proteins. Proteome and metabolome analyses of a\n                      <jats:italic toggle=\"yes\">TMEM43<\/jats:italic>\n                      -p.S358L explanted human myocardium were performed. hiPSC-derived cardiomyocytes of\n                      <jats:italic toggle=\"yes\">TMEM43<\/jats:italic>\n                      -p.S358L carrier and a corresponding isogenic control were generated. A 3\u2019-end HA-Tag was introduced in\n                      <jats:italic toggle=\"yes\">TMEM43<\/jats:italic>\n                      for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Pull-down analyses of TMEM43-WT and mutant showed altered interacting proteins involved in metabolic pathways. Lipidomics revealed the accumulation of lipids and decreased lipid metabolism capacity in mutant hiPSC-CMs. The ATP to ADP ratio was lower in mutant hiPSC-CMs and could be associated with diminished contraction frequency. The human\n                      <jats:italic toggle=\"yes\">TMEM43<\/jats:italic>\n                      -p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      We suggest differential interaction of mutant TMEM43 with proteins of mitochondria and endoplasmic reticulum influences endoplasmic reticulum-mitochondrial contact sites.\n                      <jats:italic toggle=\"yes\">TMEM43<\/jats:italic>\n                      -p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005171","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T09:00:11Z","timestamp":1775034011000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Newfoundland Mutation\n                    <i>TMEM43<\/i>\n                    -p.S358L Causes Impaired Cardiac Energy Metabolism and Mitochondrial Function Through Altered Protein Interaction"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4856-5767","authenticated-orcid":true,"given":"Sandra","family":"Ratnavadivel","sequence":"first","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. Milting)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0491-8877","authenticated-orcid":true,"given":"Kai","family":"J\u00fcrgens","sequence":"additional","affiliation":[{"name":"Faculty of Biology &amp; Chemistry, Zoology &amp; Developmental Biology, Osnabr\u00fcck University, Germany (K.J., N.K., S.W., H. Meyer, A.P.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora","family":"Klinke","sequence":"additional","affiliation":[{"name":"Faculty of Biology &amp; Chemistry, Zoology &amp; Developmental Biology, Osnabr\u00fcck University, Germany (K.J., N.K., S.W., H. Meyer, A.P.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-7693","authenticated-orcid":true,"given":"Anna","family":"G\u00e4rtner","sequence":"additional","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. Milting)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3347-9888","authenticated-orcid":true,"given":"Joline","family":"Gro\u00df","sequence":"additional","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. Milting)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-2498","authenticated-orcid":true,"given":"Karin","family":"Klingel","sequence":"additional","affiliation":[{"name":"Department of Cardiopathology, Institute for Pathology &amp; Molecular Pathology, Eberhard Karls University of T\u00fcbingen, Germany (K.K.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-9717","authenticated-orcid":true,"given":"Anders","family":"Malmendal","sequence":"additional","affiliation":[{"name":"Department of Science and Environment, Roskilde University, Denmark (A.M.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8797-3184","authenticated-orcid":true,"given":"Stefan","family":"Walter","sequence":"additional","affiliation":[{"name":"Faculty of Biology &amp; Chemistry, Zoology &amp; Developmental Biology, Osnabr\u00fcck University, Germany (K.J., N.K., S.W., H. Meyer, A.P.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7135-3178","authenticated-orcid":true,"given":"Hanne","family":"Boen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Antwerp University Hospital, Belgium (H.B., E.V.C.)."},{"name":"Research group Cardiovascular Diseases, GENCOR, University of Antwerp, Belgium (H.B., E.V.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7686-2668","authenticated-orcid":true,"given":"Emeline","family":"Van Craenenbroeck","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Antwerp University Hospital, Belgium (H.B., E.V.C.)."},{"name":"Research group Cardiovascular Diseases, GENCOR, University of Antwerp, Belgium (H.B., E.V.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9","family":"Schramm","sequence":"additional","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. Milting)."},{"name":"Now with Department of Medicine, University of California San Diego, La Jolla (R.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9349-6257","authenticated-orcid":true,"given":"Anna","family":"Kostareva","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology &amp; Genetics, Almazov National Medical Research Centre, Saint Petersburg, Russia (A. Kostareva)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-9110","authenticated-orcid":true,"given":"Jan","family":"Gummert","sequence":"additional","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. Milting)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Kassner","sequence":"additional","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. Milting)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3304-4523","authenticated-orcid":true,"given":"Heiko","family":"Meyer","sequence":"additional","affiliation":[{"name":"Faculty of Biology &amp; Chemistry, Zoology &amp; Developmental Biology, Osnabr\u00fcck University, Germany (K.J., N.K., S.W., H. Meyer, A.P.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8845-6859","authenticated-orcid":true,"given":"Achim","family":"Paululat","sequence":"additional","affiliation":[{"name":"Faculty of Biology &amp; Chemistry, Zoology &amp; Developmental Biology, Osnabr\u00fcck University, Germany (K.J., N.K., S.W., H. Meyer, A.P.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9722-0007","authenticated-orcid":true,"given":"Hendrik","family":"Milting","sequence":"additional","affiliation":[{"name":"Ruhr-University Bochum, Heart &amp; Diabetescenter NRW, Clinic for Thoracic and Cardiovascular Surgery, Erich &amp; Hanna Klessmann Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany (S.R., A.G., J. Gro\u00df, R.S., J. Gummert, A. Kassner, H. 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