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

• DOI: 10.1007/s00018-012-1244-6
• Publication Date: 2013-01-02T06:29:27Z
• Authors: 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
• Keywords: SIRT3; Calorie Restriction; AMP-Activated Protein Kinase; Nutrient Sensing

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.