{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:06:24Z","timestamp":1787162784252,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["016.176.147"],"award-info":[{"award-number":["016.176.147"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>ATPase inhibitory factor-1 (IF1) preserves cellular ATP under conditions of respiratory collapse, yet the function of IF1 under normal respiring conditions is unresolved. We tested the hypothesis that IF1 promotes mitochondrial dysfunction and pathological cardiomyocyte hypertrophy in the context of heart failure (HF). Methods and results: Cardiac expression of IF1 was increased in mice and in humans with HF, downstream of neurohumoral signaling pathways and in patterns that resembled the fetal-like gene program. Adenoviral expression of wild-type IF1 in primary cardiomyocytes resulted in pathological hypertrophy and metabolic remodeling as evidenced by enhanced mitochondrial oxidative stress, reduced mitochondrial respiratory capacity, and the augmentation of extramitochondrial glycolysis. Similar perturbations were observed with an IF1 mutant incapable of binding to ATP synthase (E55A mutation), an indication that these effects occurred independent of binding to ATP synthase. Instead, IF1 promoted mitochondrial fragmentation and compromised mitochondrial Ca2+ handling, which resulted in sarcoplasmic reticulum Ca2+ overloading. The effects of IF1 on Ca2+ handling were associated with the cytosolic activation of calcium\u2013calmodulin kinase II (CaMKII) and inhibition of CaMKII or co-expression of catalytically dead CaMKII\u03b4C was sufficient to prevent IF1 induced pathological hypertrophy. Conclusions: IF1 represents a novel member of the fetal-like gene program that contributes to mitochondrial dysfunction and pathological cardiac remodeling in HF. Furthermore, we present evidence for a novel, ATP-synthase-independent, role for IF1 in mitochondrial Ca2+ handling and mitochondrial-to-nuclear crosstalk involving CaMKII.<\/jats:p>","DOI":"10.3390\/ijms22094427","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T12:08:30Z","timestamp":1619179710000},"page":"4427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKII\u03b4"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3330-9384","authenticated-orcid":false,"given":"Mario G.","family":"Pavez-Giani","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-2500","authenticated-orcid":false,"given":"Pablo I.","family":"S\u00e1nchez-Aguilera","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5926-6960","authenticated-orcid":false,"given":"Nils","family":"Bomer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeki","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California San Diego, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harmen G.","family":"Booij","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Giraldo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke U.","family":"Oberdorf-Maass","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4979-5698","authenticated-orcid":false,"given":"Kirsten T.","family":"Nijholt","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9126-739X","authenticated-orcid":false,"given":"Salva R.","family":"Yurista","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Milting","sequence":"additional","affiliation":[{"name":"Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A. de","family":"Boer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Heller Brown","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California San Diego, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman W. H.","family":"Sillje","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1362-7019","authenticated-orcid":false,"given":"B. Daan","family":"Westenbrink","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nrcardio.2016.203","article-title":"Expert consensus document: Mitochondrial function as a therapeutic target in heart failure","volume":"14","author":"Perry","year":"2017","journal-title":"Nat. Rev. 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