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

Lingdi Wang, Iain Scott, Lu Zhu, Kaiyuan Wu, Kim Han, Yong Chen, Marjan Gucek and Michael N. Sack ()
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Lingdi Wang: Lung and Blood Institute, NIH
Iain Scott: University of Pittsburgh Medical Center
Lu Zhu: National Institute of Diabetes and Digestive and Kidney Diseases
Kaiyuan Wu: Lung and Blood Institute, NIH
Kim Han: Lung and Blood Institute, NIH
Yong Chen: Lung and Blood Institute, NIH
Marjan Gucek: Lung and Blood Institute, NIH
Michael N. Sack: Lung and Blood Institute, NIH

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00521-8

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