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Updated: May 14, 2026

Live-Cell Förster Resonance Energy Transfer Imaging of Metabolically Regulated Akt Activation Dynamics in HepG2 Cells
08:03

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Published on: May 23, 2025

PI3K/AKT signaling regulates bioenergetics in immortalized hepatocytes

Chen Li1, Yang Li, Lina He

  • 1Pharmacology and Pharmaceutical Sciences, School of Pharmacy, Los Angeles, CA 90089 United States.

Free Radical Biology & Medicine
|February 5, 2013
PubMed

Insights

The PI3K/AKT pathway regulates cellular energy by enhancing glycolysis and mitochondrial respiration. Activated AKT moves to mitochondria, boosting ATP synthase and Complex I activity for increased energy production.

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Metabolic Regulation

Background:

  • The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a crucial role in cellular metabolism.
  • PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a key negative regulator of PI3K/AKT signaling.
  • Understanding how this pathway influences cellular bioenergetics, particularly in liver cells, is vital.

Purpose of the Study:

  • To investigate the role of PI3K/AKT signaling in regulating cellular bioenergetics in hepatocytes.
  • To elucidate the mitochondrial mechanisms by which PI3K/AKT signaling controls energy production.

Main Methods:

  • Utilized isogenic hepatocyte cell lines lacking PTEN.
  • Manipulated PI3K/AKT signaling using insulin-like growth factor 1 (IGF-1) and LY 294002.
  • Assessed changes in anaerobic glycolysis, mitochondrial respiration, protein phosphorylation, and enzyme/complex activity.

Main Results:

  • Activation of PI3K/AKT signaling increased both anaerobic glycolysis and mitochondrial respiration.
  • Phosphorylated AKT translocated to mitochondria, phosphorylating ATP synthase subunits α and β, enhancing its activity.
  • Inhibition of GSK3β led to pyruvate dehydrogenase activation, and AKT translocation increased mitochondrial Complex I expression and activity.

Conclusions:

  • The mitochondrial AKT/GSK3β/PDH pathway is critical for regulating cellular bioenergetics.
  • AKT-dependent phosphorylation of ATP synthase and upregulation of Complex I contribute to enhanced mitochondrial energy production.
  • These findings highlight a novel signaling axis controlling cellular energy metabolism through mitochondrial regulation.

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