Regulation of TSC2 lysosome translocation and mitochondrial turnover by TSC2 acetylation status

Sci Rep. 2024 May 31;14(1):12521. doi: 10.1038/s41598-024-63525-7.


Sirtuin1 (SIRT1) activity decreases the tuberous sclerosis complex 2 (TSC2) lysine acetylation status, inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) signalling and concomitantly, activating autophagy. This study analyzes the role of TSC2 acetylation levels in its translocation to the lysosome and the mitochondrial turnover in both mouse embryonic fibroblast (MEF) and in mouse insulinoma cells (MIN6) as a model of pancreatic β cells. Resveratrol (RESV), an activator of SIRT1 activity, promotes TSC2 deacetylation and its translocation to the lysosome, inhibiting mTORC1 activity. An improvement in mitochondrial turnover was also observed in cells treated with RESV, associated with an increase in the fissioned mitochondria, positive autophagic and mitophagic fluxes and an enhancement of mitochondrial biogenesis. This study proves that TSC2 in its deacetylated form is essential for regulating mTORC1 signalling and the maintenance of the mitochondrial quality control, which is involved in the homeostasis of pancreatic beta cells and prevents from several metabolic disorders such as Type 2 Diabetes Mellitus.

Keywords: Acetylation; Lysosome; Mitophagy; Pancreatic β cells; TSC2; mTORC1.

MeSH terms

  • Acetylation
  • Animals
  • Autophagy
  • Cell Line, Tumor
  • Fibroblasts / metabolism
  • Insulin-Secreting Cells / metabolism
  • Lysosomes* / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mitochondria* / metabolism
  • Protein Transport
  • Resveratrol / pharmacology
  • Signal Transduction
  • Sirtuin 1 / metabolism
  • Tuberous Sclerosis Complex 2 Protein* / genetics
  • Tuberous Sclerosis Complex 2 Protein* / metabolism


  • Mechanistic Target of Rapamycin Complex 1
  • Resveratrol
  • Sirtuin 1
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein