Unveiling a common mechanism of apoptosis in β-cells and neurons in Friedreich's ataxia

Hum Mol Genet. 2015 Apr 15;24(8):2274-86. doi: 10.1093/hmg/ddu745. Epub 2014 Dec 30.


Friedreich's ataxia (FRDA) is a neurodegenerative disorder associated with cardiomyopathy and diabetes. Effective therapies for FRDA are an urgent unmet need; there are currently no options to prevent or treat this orphan disease. FRDA is caused by reduced expression of the mitochondrial protein frataxin. We have previously demonstrated that pancreatic β-cell dysfunction and death cause diabetes in FRDA. This is secondary to mitochondrial dysfunction and apoptosis but the underlying molecular mechanisms are not known. Here we show that β-cell demise in frataxin deficiency is the consequence of oxidative stress-mediated activation of the intrinsic pathway of apoptosis. The pro-apoptotic Bcl-2 family members Bad, DP5 and Bim are the key mediators of frataxin deficiency-induced β-cell death. Importantly, the intrinsic pathway of apoptosis is also activated in FRDA patients' induced pluripotent stem cell-derived neurons. Interestingly, cAMP induction normalizes mitochondrial oxidative status and fully prevents activation of the intrinsic pathway of apoptosis in frataxin-deficient β-cells and neurons. This preclinical study suggests that incretin analogs hold potential to prevent/delay both diabetes and neurodegeneration in FRDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • Diabetes Mellitus / etiology
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / physiopathology
  • Female
  • Friedreich Ataxia / complications
  • Friedreich Ataxia / genetics
  • Friedreich Ataxia / metabolism
  • Friedreich Ataxia / physiopathology*
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / metabolism
  • Iron-Binding Proteins / genetics
  • Iron-Binding Proteins / metabolism
  • Male
  • Middle Aged
  • Neurons / cytology*
  • Neurons / metabolism
  • Oxidative Stress
  • Rats
  • Rats, Wistar


  • Iron-Binding Proteins
  • frataxin