{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:39:46Z","timestamp":1791549586183,"version":"4.3.4"},"reference-count":48,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08 HL145138"],"award-info":[{"award-number":["K08 HL145138"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL147545"],"award-info":[{"award-number":["R01 HL147545"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). The metabolic derangement and underlying mechanisms of cardio\u2010encephalomyopathy in LS remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed echocardiography, electrophysiology, confocal microscopy, metabolic and molecular\/morphometric analysis of the mice lacking Ndufs4. HEK293 cells, human iPS cells\u2010derived cardiomyocytes and neurons were used to determine the mechanistic role of mitochondrial complex I deficiency.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LS mice develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes (iPS\u2010CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular (nicotinamide adenine dinucleotide) NAD\n                      <jats:sup>+<\/jats:sup>\n                      \/NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD\n                      <jats:sup>+<\/jats:sup>\n                      \u2010dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD\n                      <jats:sup>+<\/jats:sup>\n                      \/ NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD\n                      <jats:sup>+<\/jats:sup>\n                      \u2010dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of Na\n                      <jats:sub>V<\/jats:sub>\n                      1.5 current and SERCA2a function measured by Ca2\n                      <jats:sup>+<\/jats:sup>\n                      \u2010transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS\u2010derived neurons with Ndufs4 deletion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of LS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.954","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T03:16:20Z","timestamp":1658718980000},"source":"Crossref","is-referenced-by-count":36,"title":["Metabolic rescue ameliorates mitochondrial encephalo\u2010cardiomyopathy in murine and human iPSC models of Leigh syndrome"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5707-3636","authenticated-orcid":false,"given":"Jin\u2010Young","family":"Yoon","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City Iowa USA"},{"name":"Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nastaran","family":"Daneshgar","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City Iowa USA"},{"name":"Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Hefti","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine University of Iowa  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-3842","authenticated-orcid":false,"given":"Ajit","family":"Vikram","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaikobad","family":"Irani","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City Iowa USA"},{"name":"Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long\u2010Sheng","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine University of Iowa Carver College of Medicine  Iowa City Iowa USA"},{"name":"Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Diabetes &amp; Cancer Metabolism City of Hope National Medical Center  Duarte California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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