{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:41:03Z","timestamp":1779208863020,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T00:00:00Z","timestamp":1744934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Heart, Lung, and Blood institute","award":["NIH R01HL132154"],"award-info":[{"award-number":["NIH R01HL132154"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Increased acetylation or \u201chyperacetylation\u201d of mitochondrial (MITO) proteins can lead to abnormalities of the electron transport chain (ETC) and oxidative phosphorylation. In this study we examined the levels of proteins that regulate acetylation. Studies were performed in isolated MITO fractions from left ventricular (LV) myocardium of seven healthy normal (NL) dogs and seven dogs with coronary microembolization-induced heart failure (HF, LV ejection fraction ~35%). Protein levels of drivers of hyperacetylation, namely sirtuin-3 (Sirt-3), a MITO deacetylase, and CD38, a regulator of nicotinamide adenine dinucleotide (NAD+), were measured by Western blotting, and the bands were quantified in densitometric units (du). To assess MITO function, MITO components directly influenced by a hyperacetylation state, namely the protein level of cytophillin-D (CyPD), a regulator of MITO permeability transition pore and MITO Complex-I activity, were also measured. Protein level of Sirt-3 and amount of NAD+ were decreased in HF compared to NL dogs. Protein levels of CD38 and CyPD were increased in HF compared to NL dogs. Complex-I activity was decreased in HF compared to NL dogs. The results support the existence of a protein hyperacetylation state in mitochondria of failing LV myocardium compared to NL. This abnormality can contribute to MITO dysfunction as evidenced by reduced Complex-I activity and opening of MITO permeability pores.<\/jats:p>","DOI":"10.3390\/ijms26083856","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T08:24:07Z","timestamp":1744964647000},"page":"3856","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evidence of Hyperacetylation of Mitochondrial Regulatory Proteins in Left Ventricular Myocardium of Dogs with Chronic Heart Failure"],"prefix":"10.3390","volume":"26","author":[{"given":"Ramesh C.","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Henry Ford Hospital, Detroit, MI 48202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Szekely","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Henry Ford Hospital, Detroit, MI 48202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4066-1877","authenticated-orcid":false,"given":"Kefei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Henry Ford Hospital, Detroit, MI 48202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6471-1483","authenticated-orcid":false,"given":"David E.","family":"Lanfear","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Henry Ford Hospital, Detroit, MI 48202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2850-6105","authenticated-orcid":false,"given":"Hani N.","family":"Sabbah","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Henry Ford Hospital, Detroit, MI 48202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1056\/NEJMoa1406656","article-title":"Demographic and Epidemiologic Drivers of Global Cardiovascular Mortality","volume":"372","author":"Roth","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.yjmcc.2012.09.002","article-title":"Mitochondria in Cardiac Hypertrophy and Heart Failure","volume":"55","author":"Rosca","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"326rv3","DOI":"10.1126\/scitranslmed.aac7410","article-title":"Novel Targets for Mitochondrial Medicine","volume":"8","author":"Wang","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1253\/circj.CJ-15-0742","article-title":"Mitochondrion as a Target for Heart Failure Therapy-Role of Protein Lysine Acetylation","volume":"79","author":"Lee","year":"2015","journal-title":"Circ. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.jacc.2012.08.1021","article-title":"Mitochondria as a Therapeutic Target in Heart Failure","volume":"61","author":"Bayeva","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/nrm3841","article-title":"The Growing Landscape of Lysine Acetylation Links Metabolism and Cell Signalling","volume":"15","author":"Choudhary","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev.biochem.74.082803.133500","article-title":"The Biochemistry of Sirtuins","volume":"75","author":"Sauve","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.cmet.2015.03.007","article-title":"SIRT3 Mediates Multi-Tissue Coupling for Metabolic Fuel Switching","volume":"21","author":"Richards","year":"2015","journal-title":"Cell Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1161\/CIRCHEARTFAILURE.114.001469","article-title":"Energy Metabolic Reprogramming in the Hypertrophied and Early Stage Failing Heart: A Multisystems Approach","volume":"7","author":"Lai","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1161\/CIRCULATIONAHA.115.017545","article-title":"Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure","volume":"133","author":"Bedi","year":"2016","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4008","DOI":"10.1021\/acs.biochem.5b00375","article-title":"Lysine Acetylation Activates Mitochondrial Aconitase in the Heart","volume":"54","author":"Fernandes","year":"2015","journal-title":"Biochemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1161\/CIRCRESAHA.113.301867","article-title":"Cyclophilin D Modulates the Mitochondrial Acetylome","volume":"113","author":"Nguyen","year":"2013","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1016\/j.bbrc.2006.05.042","article-title":"Regulation of Intracellular Levels of NAD: A Novel Role for CD38","volume":"345","author":"Aksoy","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.1096\/fj.07-8290com","article-title":"The Enzyme CD38 (a NAD Glycohydrolase, EC 3.2.2.5) is Necessary for the Development of Diet-Induced Obesity","volume":"21","author":"Barbosa","year":"2007","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e002206","DOI":"10.1161\/CIRCHEARTFAILURE.115.002206","article-title":"Chronic Therapy with Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs with Advanced Heart Failure","volume":"9","author":"Sabbah","year":"2016","journal-title":"Circ. Heart Fail."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1006\/jmcc.2000.1266","article-title":"Abnormal Mitochondrial Respiration in Failed Human Myocardium","volume":"32","author":"Sharov","year":"2000","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1006\/jmcc.1998.0739","article-title":"Abnormal Mitochondrial Function in Myocardium of Dogs with Chronic Heart Failure","volume":"30","author":"Sharov","year":"1998","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_18","first-page":"88","article-title":"Targeting the Mitochondria in Heart Failure: A Translational Perspective","volume":"5","author":"Sabbah","year":"2020","journal-title":"J. Am. Coll. Cardiol. Basic. Trans. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.2337\/db12-1139","article-title":"Flavonoid Apigenin is an Inhibitor of the NAD+ ase CD38: Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome","volume":"62","author":"Escande","year":"2013","journal-title":"Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cell.2008.06.016","article-title":"A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology","volume":"134","author":"Pagliarini","year":"2008","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.cmet.2013.07.002","article-title":"Mitochondrial Complex I Deficiency Increases Protein Acetylation and Accelerates Heart Failure","volume":"18","author":"Karamanlidis","year":"2013","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/nature03434","article-title":"Loss of Cyclophilin D Reveals a Critical Role for Mitochondrial Permeability Transition in Cell Death","volume":"434","author":"Baines","year":"2005","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"465","DOI":"10.33594\/000000151","article-title":"Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore","volume":"53","author":"Castillo","year":"2019","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"914","DOI":"10.18632\/aging.100252","article-title":"Regulation of the mPTP by SIRT3-Mediated Deacetylation of CypD at Lysine 166 Suppresses Age-Related Cardiac Hypertrophy","volume":"2","author":"Hafner","year":"2010","journal-title":"Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.molcel.2011.07.019","article-title":"SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome","volume":"44","author":"Hirschey","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5887","DOI":"10.1073\/pnas.1217823110","article-title":"Dimers of Mitochondrial ATP Synthase Form the Permeability Transition Pore","volume":"110","author":"Giorgio","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100486","DOI":"10.1016\/j.cophys.2022.100486","article-title":"Cyclophilin D regulation of the mitochondrial permeability transition pore","volume":"25","author":"Murphy","year":"2022","journal-title":"Curr. Opin. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/nature19095","article-title":"Structure of Mammalian Respiratory Complex I","volume":"536","author":"Zhu","year":"2016","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1093\/cvr\/cvw176","article-title":"Mitochondrial Complex I Dysfunction and Altered NAD(P)H Kinetics in Rat Myocardium in Cardiac Right Ventricular Hypertrophy and Failure","volume":"111","author":"Wust","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_30","first-page":"1379","article-title":"A canine Model of Chronic Heart Failure Produced by Multiple Sequential Coronary Microembolizations","volume":"260","author":"Sabbah","year":"1991","journal-title":"Am. J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1093\/cvr\/cvn184","article-title":"Cardiac Mitochondria in Heart Failure: Decrease in Respirasomes and Oxidative Phosphorylation","volume":"80","author":"Rosca","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s11010-005-2538-x","article-title":"Reduced Inhibitor 1 and 2 Activity is Associated with Increased Protein Phosphatase Type 1 Activity in Left Ventricular Myocardium of One-Kidney, One-Clip Hypertensive Rats","volume":"269","author":"Gupta","year":"2005","journal-title":"Mol. Cell. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3856\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:17:27Z","timestamp":1760030247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3856"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,18]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083856"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083856","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,18]]}}}