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

• Published in: Cellular and molecular life sciences : CMLS 2013-06, Vol.70 (11), p.2015-2029
• Main Authors: Peserico, Alessia, Chiacchiera, Fulvio, Grossi, Valentina, Matrone, Antonio, Latorre, Dominga, Simonatto, Marta, Fusella, Aurora, Ryall, James G., Finley, Lydia W. S., Haigis, Marcia C., Villani, Gaetano, Puri, Pier Lorenzo, Sartorelli, Vittorio, Simone, Cristiano
• Format: Article
• Language: English
• Subjects: Adenylate Kinase - genetics; Adenylate Kinase - metabolism; Adenylate Kinase - physiology; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cells, Cultured; Cellular biology; Dietary restrictions; DNA, Mitochondrial - metabolism; Electron Transport; Energy Metabolism; Food Deprivation; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Forkhead Transcription Factors - physiology; Gene expression; Gene Expression Regulation; Genome, Mitochondrial; Glucose; Glucose - metabolism; Humans; Life Sciences; Male; Malnutrition; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; Mitochondrial DNA; Models, Biological; NIH 3T3 Cells; Nutrients; Proteins; Research Article; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Sirtuin 3 - physiology; Yeasts
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-012-1244-6

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.