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- Title
A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels.
- Authors
Peserico, Alessia; Chiacchiera, Fulvio; Grossi, Valentina; Matrone, Antonio; Latorre, Dominga; Simonatto, Marta; Fusella, Aurora; Ryall, James; Finley, Lydia; Haigis, Marcia; Villani, Gaetano; Puri, Pier; Sartorelli, Vittorio; Simone, Cristiano
- Abstract
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.
- Subjects
CYCLIC-AMP-dependent protein kinase; FORKHEAD transcription factors; SIRTUINS; MITOCHONDRIAL proteins; NUTRITION; BLOOD sugar analysis; LIFE spans
- Publication
Cellular & Molecular Life Sciences, 2013, Vol 70, Issue 11, p2015
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-012-1244-6