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.
Original language | English |
---|---|
Pages (from-to) | 2015-2029 |
Number of pages | 15 |
Journal | Cellular and Molecular Life Sciences |
Volume | 70 |
Issue number | 11 |
DOIs | |
Publication status | Published - Jun 2013 |
Keywords
- AMPK
- FoxO3A
- Glucose restriction
- OXPHOS
- SIRT3
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
- Molecular Medicine
- Pharmacology
- Cellular and Molecular Neuroscience