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

Amanda R. Stram, Gregory R. Wagner, Brian D. Fogler, P. Melanie Pride, Matthew D. Hirschey, R. Payne

Research output: Contribution to journalArticle

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Abstract

Introduction: 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.

Original languageEnglish (US)
Article numbere0178354
JournalPLoS One
Volume12
Issue number5
DOIs
StatePublished - May 1 2017

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Friedreich Ataxia
Acetylation
Mitochondrial Proteins
cardiomyopathy
acetylation
heart failure
Cardiomyopathies
Lysine
lysine
Heart Failure
heart
proteins
Sirtuin 3
heart diseases
pathophysiology
hypertrophy
Metabolism
Heart Diseases
Proteins
Echocardiography

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's Ataxia cardiomyopathy. / Stram, Amanda R.; Wagner, Gregory R.; Fogler, Brian D.; Pride, P. Melanie; Hirschey, Matthew D.; Payne, R.

In: PLoS One, Vol. 12, No. 5, e0178354, 01.05.2017.

Research output: Contribution to journalArticle

Stram, Amanda R. ; Wagner, Gregory R. ; Fogler, Brian D. ; Pride, P. Melanie ; Hirschey, Matthew D. ; Payne, R. / Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich's Ataxia cardiomyopathy. In: PLoS One. 2017 ; Vol. 12, No. 5.
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