RIPK1 Promotes Energy Sensing by the mTORC1 Pathway

Area of Science:

• Cellular Biology
• Molecular Mechanisms
• Metabolic Regulation

Background:

• Cellular energy homeostasis relies on intricate sensing pathways.
• AMP-activated protein kinase (AMPK) is a key regulator of cellular energy, often inhibiting mTORC1.
• The precise mechanisms linking energy status to mTORC1 inhibition remain incompletely understood.

Purpose of the Study:

• To elucidate the role of RIPK1 in cellular energy sensing and mTORC1 regulation.
• To investigate how RIPK1 influences the AMPK-mTORC1 signaling axis.
• To determine the physiological consequences of RIPK1 loss in response to energetic stress.

Main Methods:

• Investigated RIPK1's interaction with AMPK and TSC2.
• Assessed TSC2 phosphorylation at Ser1387.
• Utilized cell culture and mouse models with RIPK1 deficiency.
• Examined lysosomal function, cell death sensitivity, and metabolic stress responses.
• Evaluated the therapeutic potential of mTORC1 inhibition.

Main Results:

• RIPK1 mediates the interaction between AMPK and TSC2, facilitating TSC2 phosphorylation.
• RIPK1 loss leads to elevated basal mTORC1 activity, causing lysosomal defects.
• RIPK1-deficient cells exhibit impaired responses to energetic stress, including low glucose and metformin.
• RIPK1 deficiency sensitizes cells and neonatal mice to cell death.
• Inhibition of mTORC1 rescues lysosomal defects and improves survival in RIPK1-deficient models.

Conclusions:

• RIPK1 is a critical mediator of mTORC1 inhibition during energetic stress.
• RIPK1 plays a vital role in cellular adaptation to low energy levels.
• RIPK1 links energy sensing pathways to lysosomal function and cell survival.
• Targeting mTORC1 offers a potential therapeutic strategy for RIPK1-related metabolic disorders.