GCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis

Nat Commun. 2017 Sep 12;8(1):523. doi: 10.1038/s41467-017-00521-8.

Abstract

The mitochondrial enriched GCN5-like 1 (GCN5L1) protein has been shown to modulate mitochondrial protein acetylation, mitochondrial content and mitochondrial retrograde signaling. Here we show that hepatic GCN5L1 ablation reduces fasting glucose levels and blunts hepatic gluconeogenesis without affecting systemic glucose tolerance. PEPCK and G6Pase transcript levels are downregulated in hepatocytes from GCN5L1 liver specific knockout mice and their upstream regulator, FoxO1 protein levels are decreased via proteasome-dependent degradation and via reactive oxygen species mediated ERK-1/2 phosphorylation. ERK inhibition restores FoxO1, gluconeogenic enzyme expression and glucose production. Reconstitution of mitochondrial-targeted GCN5L1 blunts mitochondrial ROS, ERK activation and increases FoxO1, gluconeogenic enzyme expression and hepatocyte glucose production. We suggest that mitochondrial GCN5L1 modulates post-translational control of FoxO1, regulates gluconeogenesis and controls metabolic pathways via mitochondrial ROS mediated ERK activation. Exploring mechanisms underpinning GCN5L1 mediated ROS signaling may expand our understanding of the role of mitochondria in gluconeogenesis control.Hepatic gluconeogenesis is tightly regulated at transcriptional level and is essential for survival during prolonged fasting. Here Wang et al. show that the mitochondrial enriched GCN5-like 1 protein controls hepatic glucose production by regulating FoxO1 protein levels via proteasome-dependent degradation and, in turn, gluconeogenic gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Gene Expression
  • Gluconeogenesis*
  • Glucose / metabolism
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / metabolism
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism*
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Liver / metabolism*
  • Mitochondrial Proteins
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Signal Transduction*

Substances

  • BLOC1S1 protein, mouse
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Mitochondrial Proteins
  • Nerve Tissue Proteins
  • Glucose-6-Phosphatase
  • Proteasome Endopeptidase Complex
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Glucose