GCN5L1-mediated acetylation prevents Rictor degradation in cardiac cells after hypoxic stress

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Ischemic heart disease causes significant mortality due to cardiomyocyte apoptosis and cardiac fibrosis.
• GCN5L1 (mitochondrial acetyltransferase) was previously shown to regulate cytoprotective signaling in heart injury.
• The Akt/mTORC2 pathway is critical for cardioprotection.

Purpose of the Study:

• To investigate the mechanism by which GCN5L1 regulates the Akt/mTORC2 cardioprotective signaling pathway.
• To determine the role of GCN5L1 in maintaining Rictor protein levels and acetylation.
• To elucidate the impact of GCN5L1 on Rictor stability and Akt/mTORC2 signaling in the context of cardiac injury.

Main Methods:

• Analysis of Rictor protein and mRNA levels in human cardiac tissues and AC16 cells under hypoxic stress.
• Investigating the effect of GCN5L1 knockdown and overexpression on Rictor levels and acetylation.
• Assessing Rictor degradation via proteasomal activity and the role of acetylation.
• Evaluating Akt signaling, mTORC2 abundance, and activity following GCN5L1 manipulation.

Main Results:

• Rictor protein levels were decreased in human ischemic heart disease tissues and hypoxic cardiac cells, while mRNA remained unchanged.
• GCN5L1 knockdown exacerbated Rictor reduction, whereas GCN5L1 overexpression prevented it.
• Rictor acetylation, mediated by GCN5L1, inhibited proteasomal degradation.
• GCN5L1 knockdown impaired Akt signaling and reduced mTORC2 abundance and activity.

Conclusions:

• GCN5L1 maintains Rictor protein stability through enhanced lysine acetylation.
• This acetylation process antagonizes Rictor proteasomal degradation.
• GCN5L1 promotes cardioprotective Akt/mTORC2 signaling by preserving Rictor levels, offering a therapeutic target for ischemic heart disease.