{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T01:54:03Z","timestamp":1768701243865,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T00:00:00Z","timestamp":1575590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["Transregio 19, C7"],"award-info":[{"award-number":["Transregio 19, C7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (\u2206\u03c8m) and increased caspase 3\/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.<\/jats:p>","DOI":"10.3390\/cells8121588","type":"journal-article","created":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T10:41:44Z","timestamp":1575628904000},"page":"1588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Adenine Nucleotide Translocase 1 Expression Is Coupled to the HSP27-Mediated TLR4 Signaling in Cardiomyocytes"],"prefix":"10.3390","volume":"8","author":[{"given":"Julia","family":"Winter","sequence":"first","affiliation":[{"name":"Department of Cardiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, 12200 Berlin, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research, partner site Berlin), 10785 Berlin, Germany"},{"name":"Institute of Chemistry and Biochemistry, Structural Biochemistry, Free University Berlin, 14195 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1507-0402","authenticated-orcid":false,"given":"Elke","family":"Hammer","sequence":"additional","affiliation":[{"name":"Interfaculty Institute of Genetics and Functional Genomics, Ernst-Moritz-Arndt-University, 17475 Greifswald, Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Heger","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Justus-Liebig-University, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinz-Peter","family":"Schultheiss","sequence":"additional","affiliation":[{"name":"Institute of Cardiac Diagnostics and Therapy (IKDT), 12203 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"Rauch","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, 12200 Berlin, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research, partner site Berlin), 10785 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulf","family":"Landmesser","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, 12200 Berlin, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research, partner site Berlin), 10785 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1398-1779","authenticated-orcid":false,"given":"Andrea","family":"D\u00f6rner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, 12200 Berlin, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research, partner site Berlin), 10785 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1016\/j.bbamem.2008.04.011","article-title":"The ADP and ATP transport in mitochondria and its carrier","volume":"1778","author":"Klingenberg","year":"2008","journal-title":"Biochim. 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