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

Cell Mol Life Sci. 2013 Jun;70(11):2015-29. doi: 10.1007/s00018-012-1244-6. Epub 2013 Jan 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / genetics
  • Adenylate Kinase / metabolism
  • Adenylate Kinase / physiology*
  • Animals
  • Cells, Cultured
  • 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 Regulation
  • Genome, Mitochondrial
  • Glucose / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Models, Biological
  • NIH 3T3 Cells
  • Sirtuin 3 / genetics
  • Sirtuin 3 / metabolism
  • Sirtuin 3 / physiology*

Substances

  • DNA, Mitochondrial
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • Sirt3 protein, mouse
  • Adenylate Kinase
  • Sirtuin 3
  • Glucose