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

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.

Mitochondrial General Control of Amino Acid Synthesis 5 Like 1 Regulates Glutaminolysis, Mammalian Target of Rapamycin Complex 1 Activity, and Murine Liver Regeneration

“…The major differences noted were a marked reduction in glycolytic intermediates, increased lactate levels, and accumulation of tricarboxylic acid cycle (TCA) intermediates. This evidence suggested that increased glycolysis was compatible with our earlier finding of reduced flux through the counter‐regulatory gluconeogenesis pathway, although we did not pursue this further . The increase in TCA cycle intermediates suggested that there was either impaired TCA flux or that excess anaplerosis was saturating the pathway (Fig.…”

“…Our laboratory has focused on the study of the general control of amino acid synthesis 5 like 1 (GCN5L1) protein, which modulates hepatic mitochondrial protein acetylation . In hepatocyte‐specific Gcn5l1 knockout mice (LKO), we have found that hepatic lipid accumulation was diminished in response to high‐fat feeding and that these mice showed increased hepatocyte mitochondrial protein acetylation and fatty acid oxidation, as well as reduced gluconeogenesis . Given these phenotypes, we proposed that this model may uncover insights into the role of mitochondrial biology and acetylation‐mediated remodeling during hepatoxic stress‐induced hepatic regeneration.…”

“…In contrast, the cytosolic GCN5L1 has been found to bind to a canonical acetyltransferase and modulate microtubular acetylation . The mitochondrial phenotype following the disruption of GCN5L1 suggests that this protein plays an integral role in fatty acid and glucose metabolism, mitochondrial turnover, and retrograde signaling from the mitochondria to nucleus for regulation of gluconeogenesis …”

“…To better explore the mitochondrial‐regulatory effects of GCN5L1 and its effect on hepatic regeneration, we initially utilized an unbiased metabolomics approach to uncover the metabolic signatures linked to GCN5L1 depletion in primary hepatocytes extracted from littermate‐control compared to LKO mice . The metabolomic data implicated that the glutaminolysis pathway was induced in LKO liver.…”

Mitochondrial DNA: Epigenetics and environment

“…These modifications include lysine methylation, phosphorylation, acetylation, ubiquitylation, sumoylation, and PARylation (reviewed in Bannister and Kouzarides, 2011). The enzymatic acetylation inside mitochondria has been recently acknowledged as four acetyl transferases ACAT1, MOF, GCN5L1, and PCAF have been identified in the mitochondria and are responsible for regulation of acetylation levels of mitochondrial proteins (Fan et al, 2014;Chatterjee et al, 2016;Wang et al, 2017;Savoia et al, 2019). It is estimated that approximately 63% of proteins that are localized within the mitochondrion contain lysine acetylation sites, and in one study conducted in 2011, 216 phosphopeptides were identified from mitochondrial preparations (Zhao et al, 2011).…”