Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux

FASEB J. 2015 Apr;29(4):1314-28. doi: 10.1096/fj.14-261503. Epub 2014 Dec 9.


Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPH-generating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stress-signaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.

Keywords: amino acid metabolism; metabolic reprogramming; mitochondrial myopathy; oxidative stress tolerance; polyamines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / physiology
  • Glycine / metabolism*
  • Hormesis
  • Humans
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Metabolic Networks and Pathways
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Muscle Fibers, Fast-Twitch / metabolism
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Proteins / metabolism
  • Oxidative Stress
  • Serine / metabolism*
  • Signal Transduction
  • Transcriptome
  • Uncoupling Protein 1


  • Ion Channels
  • Mitochondrial Proteins
  • Muscle Proteins
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Serine
  • Glycine

Associated data

  • GEO/GSE45991