{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T20:55:53Z","timestamp":1793307353240,"version":"4.5.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"vor","delay-in-days":39,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Care Research Netherlands Medical Sciences","award":["04510012010041"],"award-info":[{"award-number":["04510012010041"]}]},{"name":"Care Research Netherlands Medical Sciences","award":["09032232310042"],"award-info":[{"award-number":["09032232310042"]}]},{"name":"Care Research Netherlands Medical Sciences","award":["10250022110004"],"award-info":[{"award-number":["10250022110004"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["101115536"],"award-info":[{"award-number":["101115536"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["101080204"],"award-info":[{"award-number":["101080204"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["801540"],"award-info":[{"award-number":["801540"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["09150181910020"],"award-info":[{"award-number":["09150181910020"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease in which most patients carry (likely) pathogenic variants in desmosomal genes, most commonly in plakophilin-2 (PKP2). While the genetic causes are well described, the molecular mechanisms driving disease progression\u2014particularly in response to exercise\u2014remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>To investigate disease-driving pathways in ACM, we used PKP2 mutant human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from ACM patients. Transcriptomic profiling revealed consistent downregulation of oxidative phosphorylation (OXPHOS) genes in PKP2 mutant hiPSC-CMs, which was confirmed in explanted ACM hearts carrying PKP2 variants. Reduced expression of OXPHOS-related genes was associated with lower PPARGC1A expression and decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. The reduction in PPARGC1A expression appeared to result, at least in part, from decreased AMPK\u03b1 protein levels, a known activator of PPARGC1A previously shown to localize at the intercalated disc, as PKP2 mutant cells failed to increase PPARGC1A expression following treatment with AICAR, an AMPK activator. To directly assess whether increasing PPARGC1A expression could compensate for this defect, we overexpressed PPARGC1A, which partially restored OXPHOS gene expression and improved contractility in PKP2 mutant cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study identifies a novel transcriptional mechanism linking PKP2 loss to reduced mitochondrial function via decreased PGC1\u03b1 signaling, partially through reduced AMPK\u03b1 levels. Disruption of this axis reduces OXPHOS gene expression and mitochondrial function in PKP2 mutant hiPSC-CMs, potentially impairing the heart\u2019s ability to meet increased energy demands during stress, and offering a mechanistic explanation for the detrimental effects of exercise in ACM. Furthermore, these findings highlight PGC1\u03b1 induction as a potential therapeutic strategy to restore OXPHOS gene expression and mitochondrial adaptability in ACM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag141","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T11:21:58Z","timestamp":1783336918000},"page":"2024-2038","source":"Crossref","is-referenced-by-count":1,"title":["PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1\u03b1-dependent mechanism"],"prefix":"10.1093","volume":"122","author":[{"given":"Su Ji","family":"Han","sequence":"first","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesther","family":"de Ruiter","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoyee","family":"Tsui","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Kyriakopoulou","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Koopmans","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Perini","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jantine","family":"Monshouwer-Kloots","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan J","family":"van Kampen","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 CT ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneline S J M","family":"te Riele","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht 3584 CX ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse R","family":"Kelters","sequence":"additional","affiliation":[{"name":"Experimental Cardiology Laboratory, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht 3584 CX ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8835-2339","authenticated-orcid":false,"given":"Monica","family":"Gianoli","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht 3584 CX ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boudewijn M T","family":"Burgering","sequence":"additional","affiliation":[{"name":"Molecular Cancer Research, University Medical Center Utrecht , Utrecht 3584 CX ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2026-9408","authenticated-orcid":false,"given":"Eva","family":"van Rooij","sequence":"additional","affiliation":[{"name":"Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Uppsalalaan 8, Utrecht 3584 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