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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\u2010TG) mice as model of muscle\u2010specific 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\u2010carbon\/glycine pathway and the longevity\u2010promoting polyamine spermidine as well as the trans\u2010sulfuration pathway. This is related to an induction of NADPH\u2010generating 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\u2010signaling 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.\u2014Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K.\u2010J., Jove, M., Pamplona, R., Portero\u2010Otin, M., Keijer, J., Klaus, S. Muscle mitohormesis promotes cellular survival via serine\/glycine pathway flux.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    29, 1314\u20101328 (2015).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.14-261503","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T22:22:56Z","timestamp":1418163776000},"page":"1314-1328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Muscle mitohormesis promotes cellular survival via serine\/glycine pathway flux"],"prefix":"10.1096","volume":"29","author":[{"given":"Mario","family":"Ost","sequence":"first","affiliation":[{"name":"German Institute of Human Nutrition Potsdam\u2010Rehbruecke 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