Concurrent activation of growth factor and nutrient arms of mTORC1 induces oxidative liver injury

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism, influenced by growth factor and nutrient signaling pathways.
• These pathways are mediated by Rheb and Rag GTPases, respectively, and their dysregulation is implicated in various diseases.

Purpose of the Study:

• To develop and characterize the first animal model with concurrently upregulated growth factor and nutrient signaling pathways affecting mTORC1.
• To investigate the role of hyperactive mTORC1 in liver damage and identify the underlying molecular mechanisms.

Main Methods:

• Generation of a dual knockout (DKO) mouse model with concurrent mutations in Tsc1 and Depdc5, key GTPase-activating proteins.
• Analysis of liver pathology, transcriptome profiling, and molecular stress markers (ER stress, oxidative stress, DNA damage, inflammation).
• Assessment of the effects of mTORC1 inhibition and oxidative stress suppressors (NAC, Tempol) on DKO liver phenotypes.

Main Results:

• DKO mice exhibited strong, synergistic mTORC1 activation and severe hepatocyte damage, leading to liver failure phenotypes.
• Transcriptome profiles of DKO livers resembled human hepatitis and chemically induced oxidative stress models.
• DKO livers showed significant ER stress, oxidative stress, DNA damage, and inflammation; however, oxidative stress reduction, not ER stress suppression, ameliorated pathologies.

Conclusions:

• Concurrent upregulation of growth factor and nutrient signaling pathways leads to unregulated mTORC1 activation and significant liver injury.
• Hyperactive mTORC1 induces liver damage predominantly via oxidative stress pathways.
• This DKO model provides a valuable tool for studying mTORC1-driven pathologies and potential therapeutic interventions.