Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's ataxia cardiomyopathy

dc.contributor.authorStram, Amanda R.
dc.contributor.authorWagner, Gregory R.
dc.contributor.authorFogler, Brian D.
dc.contributor.authorPride, P. Melanie
dc.contributor.authorHirschey, Matthew D.
dc.contributor.authorPayne, R. Mark
dc.contributor.departmentSurgery, School of Medicineen_US
dc.date.accessioned2017-12-15T19:44:27Z
dc.date.available2017-12-15T19:44:27Z
dc.date.issued2017-05-25
dc.description.abstractINTRODUCTION: The childhood heart disease of Friedreich's Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and loss of SIRT3 increases susceptibility of the heart to stress-induced cardiac hypertrophy and ischemic injury. The underlying pathophysiology of heart failure in FRDA is unclear. The purpose of this study was to examine in detail the physiologic and acetylation changes of the heart that occur over time in a model of FRDA heart failure. We predicted that increased mitochondrial protein acetylation would be associated with a decrease in heart function in a model of FRDA. METHODS: A conditional mouse model of FRDA cardiomyopathy with ablation of FXN (FXN KO) in the heart was compared to healthy controls at postnatal days 30, 45 and 65. We evaluated hearts using echocardiography, cardiac catheterization, histology, protein acetylation and expression. RESULTS: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function. CONCLUSION: These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationStram, A. R., Wagner, G. R., Fogler, B. D., Pride, P. M., Hirschey, M. D., & Payne, R. M. (2017). Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich’s ataxia cardiomyopathy. PLoS ONE, 12(5), e0178354. http://doi.org/10.1371/journal.pone.0178354en_US
dc.identifier.urihttps://hdl.handle.net/1805/14834
dc.language.isoen_USen_US
dc.publisherPLoSen_US
dc.relation.isversionof10.1371/journal.pone.0178354en_US
dc.relation.journalPLoS ONEen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/us
dc.sourcePMCen_US
dc.subjectHeart failureen_US
dc.subjectHeart -- Hypertrophyen_US
dc.subjectAcetylationen_US
dc.subjectFriedreich's ataxiaen_US
dc.subjectMitochondrial pathologyen_US
dc.subjectProteomicsen_US
dc.titleProgressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's ataxia cardiomyopathyen_US
dc.typeArticleen_US
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