A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model

Piyush M. Vyas, Wendy J. Tomamichel, P. Melanie Pride, Clifford M. Babbey, Qiujuan Wang, Jennifer Mercier, Elizabeth M. Martin, R. Mark Payne

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Friedreich's ataxia (FRDA) is the most common inherited human ataxia and results from a deficiency of the mitochondrial protein, frataxin (FXN), which is encoded in the nucleus. This deficiency is associated with an iron-sulfur (Fe-S) cluster enzyme deficit leading to progressive ataxia and a frequently fatal cardiomyopathy. There is no cure. To determine whether exogenous replacement of the missing FXN protein in mitochondria would repair the defect, we used the transactivator of transcription (TAT) protein transduction domain to deliver human FXN protein to mitochondria in both cultured patient cells and a severe mouse model of FRDA. A TAT-FXN fusion protein bound iron in vitro, transduced into mitochondria of FRDA deficient fibroblasts and reduced caspase-3 activation in response to an exogenous iron-oxidant stress. Injection of TAT-FXN protein into mice with a conditional loss of FXN increased their growth velocity and mean lifespan by 53% increased their mean heart rate and cardiac output, increased activity of aconitase and reversed abnormal mitochondrial proliferation and ultrastructure in heart. These results show that a cell-penetrant peptide is capable of delivering a functional mitochondrial protein in vivo to rescue a very severe disease phenotype, and present the possibility of TAT-FXN as a protein replacement therapy.

Original languageEnglish (US)
Article numberddr554
Pages (from-to)1230-1247
Number of pages18
JournalHuman molecular genetics
Volume21
Issue number6
DOIs
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model'. Together they form a unique fingerprint.

  • Cite this

    Vyas, P. M., Tomamichel, W. J., Pride, P. M., Babbey, C. M., Wang, Q., Mercier, J., Martin, E. M., & Payne, R. M. (2012). A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model. Human molecular genetics, 21(6), 1230-1247. [ddr554]. https://doi.org/10.1093/hmg/ddr554