title: A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels.
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.
authors.affiliation: Laboratory of Signal-dependent Transcription, Department of Translational Pharmacology DTP, Consorzio Mario Negri Sud, 66030, Santa Maria Imbaro Ch, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Peserico
authors.forename: Fulvio
authors.initials: F
authors.lastname: Chiacchiera
authors.forename: Valentina
authors.initials: V
authors.lastname: Grossi
authors.forename: Antonio
authors.initials: A
authors.lastname: Matrone
authors.forename: Dominga
authors.initials: D
authors.lastname: Latorre
authors.forename: Marta
authors.initials: M
authors.lastname: Simonatto
authors.forename: Aurora
authors.initials: A
authors.lastname: Fusella
authors.forename: James G
authors.initials: JG
authors.lastname: Ryall
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Gaetano
authors.initials: G
authors.lastname: Villani
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D004579:Electron Transport; D004734:Energy Metabolism; D005508:Food Deprivation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D054629:Genome, Mitochondrial; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D041681:NIH 3T3 Cells; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D004272:DNA, Mitochondrial; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525046:Sirt3 protein, mouse; D000263:Adenylate Kinase; D056566:Sirtuin 3; D005947:Glucose