A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels

Alessia Peserico, Fulvio Chiacchiera, Valentina Grossi, Antonio Matrone, Dominga Latorre, Marta Simonatto, Aurora Fusella, James G. Ryall, Lydia W S Finley, Marcia C. Haigis, Gaetano Villani, Pier Lorenzo Puri, Vittorio Sartorelli, Cristiano Simone

Research output: Contribution to journalArticlepeer-review


Reduction of nutrient intake without malnutrition positively influences lifespan and healthspan from yeast to mice and exerts some beneficial effects also in humans. The AMPK-FoxO axis is one of the evolutionarily conserved nutrient-sensing pathways, and the FOXO3A locus is associated with human longevity. Interestingly, FoxO3A has been reported to be also a mitochondrial protein in mammalian cells and tissues. Here we report that glucose restriction triggers FoxO3A accumulation into mitochondria of fibroblasts and skeletal myotubes in an AMPK-dependent manner. A low-glucose regimen induces the formation of a protein complex containing FoxO3A, SIRT3, and mitochondrial RNA polymerase (mtRNAPol) at mitochondrial DNA-regulatory regions causing activation of the mitochondrial genome and a subsequent increase in mitochondrial respiration. Consistently, mitochondrial transcription increases in skeletal muscle of fasted mice, with a mitochondrial DNA-bound FoxO3A/SIRT3/mtRNAPol complex detectable also in vivo. Our results unveil a mitochondrial arm of the AMPK-FoxO3A axis acting as a recovery mechanism to sustain energy metabolism upon nutrient restriction.

Original languageEnglish
Pages (from-to)2015-2029
Number of pages15
JournalCellular and Molecular Life Sciences
Issue number11
Publication statusPublished - Jun 2013


  • AMPK
  • FoxO3A
  • Glucose restriction
  • SIRT3

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Molecular Medicine
  • Pharmacology
  • Cellular and Molecular Neuroscience


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