Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51

Cell Rep. 2023 Apr 25;42(4):112336. doi: 10.1016/j.celrep.2023.112336. Epub 2023 Mar 31.


The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function.

Keywords: CP: Metabolism; Mss51; TGF-β; metabolism; mitochondria; muscle mass; respiration; site-1 protease; skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Respiration* / genetics
  • Cell Respiration* / physiology
  • Mice
  • Mitochondria* / metabolism
  • Muscle, Skeletal / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta* / genetics
  • Transforming Growth Factor beta* / metabolism


  • membrane-bound transcription factor peptidase, site 1
  • Mss51 protein, mouse
  • Transforming Growth Factor beta