Friedreich's ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase

Gregory R. Wagner, P. Melanie Pride, Clifford M. Babbey, R. Mark Payne

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Friedreich's ataxia (FRDA) is the most common inherited human ataxia and is caused by a deficiency in the mitochondrial protein frataxin. Clinically, patients suffer from progressive spinocerebellar degeneration, diabetes and a fatal cardiomyopathy, associated with mitochondrial respiratory chain defects. Recent findings have shown that lysine acetylation regulates mitochondrial function and intermediary metabolism. However, little is known about lysine acetylation in the setting of pathologic energy stress and mitochondrial dysfunction. We tested the hypothesis that the respiratory chain defects in frataxin deficiency alter mitochondrial protein acetylation. Using two conditional mouse models of FRDA, we demonstrate marked hyperacetylation of numerous cardiac mitochondrial proteins. Importantly, this biochemical phenotype develops concurrently with cardiac hypertrophy and is caused by inhibition of the NAD+-dependent SIRT3 deacetylase. This inhibition is caused by an 85-fold decrease in mitochondrial NAD+/NADH and direct carbonyl group modification of SIRT3, and is reversed with excess SIRT3 and NAD+ in vitro. We further demonstrate that protein hyperacetylation may be a common feature of mitochondrial disorders caused by respiratory chain defects, notably, cytochrome oxidase I (COI) deficiency. These findings suggest that SIRT3 inhibition and consequent protein hyperacetylation represents a negative feedback mechanism limiting mitochondrial oxidative pathways when respiratory metabolism is compromised, and thus, may contribute to the lethal cardiomyopathy in FRDA.

Original languageEnglish (US)
Article numberdds095
Pages (from-to)2688-2697
Number of pages10
JournalHuman molecular genetics
Issue number12
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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