AMPK phosphorylates NAMPT to regulate NAD⁺ homeostasis under ionizing radiation

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Biology

Background:

• Head and neck radiotherapy often causes oral mucositis.
• Nicotinamide adenine dinucleotide (NAD+) is essential for DNA repair following ionizing radiation exposure.
• Cellular NAD+ levels are depleted during DNA repair processes.

Purpose of the Study:

• To investigate the role of nicotinamide phosphoribosyltransferase (NAMPT) in maintaining NAD+ homeostasis after ionizing radiation.
• To elucidate the mechanism by which NAMPT activity is regulated under ionizing radiation.
• To explore NAMPT as a potential therapeutic target for radiation-induced injuries.

Main Methods:

• Analysis of NAMPT activation and protein expression following ionizing radiation.
• Investigation of AMPK-mediated phosphorylation of NAMPT at serine 314 (S314).
• Assessment of NAD+ levels, DNA repair efficiency, and cell viability in irradiated cells.

Main Results:

• Ionizing radiation rapidly activates NAMPT without altering its protein levels.
• AMP-activated protein kinase (AMPK) phosphorylates NAMPT at S314, enhancing its enzymatic activity.
• AMPK-mediated NAMPT phosphorylation restores NAD+ levels, promotes DNA repair, and improves cell viability in irradiated cells.

Conclusions:

• A novel signaling pathway involving post-translational modification of NAMPT regulates NAD+ metabolism for DNA repair.
• AMPK-mediated NAMPT S314 phosphorylation is a rapid response to ionizing radiation.
• Targeting NAMPT may offer a strategy for preventing radiation-induced damage.