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Mol. Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC-5) is a fully penetrant form of ARVC caused by the missense mutation in the gene\n                    <jats:italic>TMEM43<\/jats:italic>\n                    p.S358L. Despite extensive research, the molecular basis underlying the detrimental effects of\n                    <jats:italic>TMEM43<\/jats:italic>\n                    p.S358L still needs to be discovered. TMEM43 is a phylogenetically conserved protein. We previously analysed the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    homologue (CG8111 or Dmel\\Tmem43) to understand the protein's physiological relevance and the mutation p.S358L.\n                    <jats:italic>Drosophila<\/jats:italic>\n                    Tmem43 is localised at the ER\/SR membrane and interacts with the outer mitochondrial membrane protein Porin\/VDAC. This interaction is lost in a Tmem43p.S333L mutant that resembles the human p.S358L mutation. In addition, Tmem43p.S333L caused a breakdown in mitochondrial membrane potential and increased cellular reactive oxygen species, suggesting impaired mitochondrial function as a major pathomechanism. Complementary ultrastructural analyses revealed severe structural defects in the affected mitochondria, including degeneration of the organelles. Highly similar ultrastructural defects were observed in the human right ventricular myocardium of a TMEM43p.S358L trait carrier, suggesting a common molecular basis for the detrimental effects of the mutation in flies and humans. We propose that both the p.S358L mutation in humans and the p.S333L mutation in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    impair TMEM43\/VDAC interaction, which affects the stability of ER\/SR-mitochondrial contact sites and, thus, proper mitochondrial function and oxidative phosphorylation rates. The consequential undersupply of ATP likely results in cardiac cell death and, ultimately, heart failure.\n                  <\/jats:p>","DOI":"10.1007\/s00018-025-05942-z","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T15:15:39Z","timestamp":1763133339000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The ARVC-5-associated protein TMEM43 controls mitochondrial energy metabolism by stabilising ER-mitochondrial contact sites"],"prefix":"10.1007","volume":"82","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0491-8877","authenticated-orcid":false,"given":"Kai","family":"J\u00fcrgens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1481-7834","authenticated-orcid":false,"given":"Lena","family":"Menzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-5567","authenticated-orcid":false,"given":"Nora","family":"Klinke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Sch\u00e4per","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9880-5939","authenticated-orcid":false,"given":"Leonhard","family":"Breitsprecher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2396-2627","authenticated-orcid":false,"given":"Michael","family":"Holtmannsp\u00f6tter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4035-6840","authenticated-orcid":false,"given":"Olympia-Ekaterini","family":"Psathaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8797-3184","authenticated-orcid":false,"given":"Stefan","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4856-5767","authenticated-orcid":false,"given":"Sandra","family":"Ratnavadivel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-9717","authenticated-orcid":false,"given":"Anders","family":"Malmendal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3304-4523","authenticated-orcid":false,"given":"Heiko","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9722-0007","authenticated-orcid":false,"given":"Hendrik","family":"Milting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8845-6859","authenticated-orcid":false,"given":"Achim","family":"Paululat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"5942_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04458-0","volume":"79","author":"N Klinke","year":"2022","unstructured":"Klinke N, Meyer H, Ratnavadivel S, Reinhardt M, Heinisch JJ, Malmendal A, Milting H, Paululat A (2022) A dr\u2044osophila melanogaster model for TMEM43 related arrhythmogenic right ventricular cardiomyopathy type 5. 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