{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T11:34:23Z","timestamp":1793100863867,"version":"4.5.0"},"reference-count":52,"publisher":"Canadian Science Publishing","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/deed.en_GB"}],"content-domain":{"domain":["cdnsciencepub.com"],"crossmark-restriction":false},"short-container-title":["Can. J. Physiol. Pharmacol."],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:p>Elevated bile acids, particularly hydrophobic secondary species, impair mitochondrial structure and function across multiple organs. In cardiomyocytes, pathologically elevated circulating bile acids impair mitochondrial biogenesis, diminish adenosine triphosphate generation, disrupt calcium homeostasis, and compromise myocardial energetics. These alterations promote oxidative stress and activate mitochondrial apoptotic pathways, culminating in systolic dysfunction, diastolic impairment, and heightened arrhythmogenic risk. Parallel mitochondrial injury in liver and skeletal muscle may contributes to liver fibrosis and sarcopenia. Accumulating evidence suggests that elevated circulating bile acids are not merely biochemical epiphenomena in Fontan circulation, where chronic hepatic congestion is intrinsic to the physiology. In metabolic-dysfunction associated steatotic liver disease (MASLD), the evidence is more nuanced: bile-acid metabolism and bile-acid pool composition may be altered, particularly in metabolic dysfunction-associated steatohepatitis (MASH) and with increasing fibrosis, but systemic bile-acid excess is not consistently demonstrated across uncomplicated steatosis. This review therefore emphasizes bile acids as systemic mitochondrial toxins in Fontan circulation and cholestatic\/cirrhotic disease states, while discussing MASLD\/heart failure with preserved ejection fraction as an emerging and hypothesis-generating context in which altered bile-acid signaling may contribute to cardiometabolic dysfunction. It also highlights emerging diagnostic opportunities and supports therapies aimed at reducing bile acid toxicity or improving mitochondrial resilience to enhance outcomes in these patients.<\/jats:p>","DOI":"10.1139\/cjpp-2026-0103","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T21:35:11Z","timestamp":1790976911000},"page":"1-9","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bile acids as mitochondrial toxins: emerging insights in fontan and heart failure with preserved ejection fraction"],"prefix":"10.1139","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9396-7178","authenticated-orcid":false,"given":"Ashish H.","family":"Shah","sequence":"first","affiliation":[{"name":"University of Manitoba","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moreshwar S.","family":"Desai","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine","place":["Houston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"155","reference":[{"key":"refg1\/ref1","first-page":"11","author":"Abrigo J.","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"refg2\/ref2","doi-asserted-by":"crossref","unstructured":"Alqabandi W., Alsaeid M., Dhaunsi G. 2025. l-carnitine protects against bile acid-induced mitochondrial dysfunction and IGF-1 impairment in hepatocyte cultures. 18: 100249.","DOI":"10.1016\/j.endmts.2025.100249"},{"key":"refg3\/ref3","doi-asserted-by":"publisher","DOI":"10.1038\/ng1147"},{"key":"refg4\/ref4","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.01.055"},{"key":"refg5\/ref5","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00805-x"},{"key":"refg6\/ref6","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840140609"},{"key":"refg7\/ref7","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R054114"},{"key":"refg8\/ref8","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28890"},{"key":"refg9\/ref9","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-023-10610-0"},{"key":"refg10\/ref10","doi-asserted-by":"publisher","DOI":"10.1385\/CT:5:1:063"},{"key":"refg11\/ref11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2022.09.013"},{"key":"refg12\/ref12","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706331"},{"key":"refg13\/ref13","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13796"},{"key":"refg14\/ref14","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01256-3"},{"key":"refg15\/ref15","doi-asserted-by":"publisher","DOI":"10.1042\/cs1030191"},{"key":"refg16\/ref16","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.08.018"},{"key":"refg17\/ref17","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)38331-0"},{"key":"refg18\/ref18","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.040030"},{"key":"refg19\/ref19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1978.tb00646.x"},{"key":"refg20\/ref20","doi-asserted-by":"publisher","DOI":"10.1111\/liv.14553"},{"key":"refg21\/ref21","doi-asserted-by":"publisher","DOI":"10.14309\/ctg.0000000000000503"},{"key":"refg22\/ref22","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-024-02168-x"},{"key":"refg23\/ref23","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(01)00092-7"},{"key":"refg24\/ref24","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(00)70180-6"},{"key":"refg25\/ref25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100911"},{"key":"refg26\/ref26","doi-asserted-by":"publisher","DOI":"10.3389\/fnetp.2022.849253"},{"key":"refg27\/ref27","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1996.v110.pm8613009"},{"key":"refg28\/ref28","doi-asserted-by":"publisher","DOI":"10.1136\/heart.87.1.9"},{"key":"refg29\/ref29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.01.006"},{"key":"refg30\/ref30","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2004.06.001"},{"key":"refg31\/ref31","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000057"},{"key":"refg32\/ref32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1325"},{"key":"refg33\/ref33","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401914"},{"key":"refg34\/ref34","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/57.1.177"},{"key":"refg35\/ref35","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000696"},{"key":"refg36\/ref36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2025.08.011"},{"key":"refg37\/ref37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2024.101563"},{"key":"refg38\/ref38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009689"},{"key":"refg39\/ref39","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200104000-00014"},{"key":"refg40\/ref40","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2017.00064"},{"key":"refg41\/ref41","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001032"},{"key":"refg42\/ref42","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-26163-3 10.1007\/978-3-031-26163-3_10"},{"key":"refg43\/ref43","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(22)00093-0"},{"key":"refg44\/ref44","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.11.038"},{"key":"refg45\/ref45","first-page":"7","author":"Virk M.K.","year":"2023","journal-title":"Hepatol Commun."},{"key":"refg46\/ref46","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000001043"},{"key":"refg47\/ref47","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(40)90880-8"},{"key":"refg48\/ref48","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.01084"},{"key":"refg49\/ref49","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.22702"},{"key":"refg50\/ref50","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v9.i2.308"},{"key":"refg51\/ref51","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116567"},{"key":"refg52\/ref52","doi-asserted-by":"publisher","DOI":"10.1111\/dom.15709"}],"container-title":["Canadian Journal of Physiology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdnsciencepub.com\/doi\/full-xml\/10.1139\/cjpp-2026-0103","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdnsciencepub.com\/doi\/pdf\/10.1139\/cjpp-2026-0103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T11:00:41Z","timestamp":1793098841000},"score":1,"resource":{"primary":{"URL":"https:\/\/cdnsciencepub.com\/doi\/10.1139\/cjpp-2026-0103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,1]]},"references-count":52,"alternative-id":["10.1139\/cjpp-2026-0103"],"URL":"https:\/\/doi.org\/10.1139\/cjpp-2026-0103","relation":{},"ISSN":["0008-4212","1205-7541"],"issn-type":[{"value":"0008-4212","type":"print"},{"value":"1205-7541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,1]]},"assertion":[{"value":"2026-10-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}