OR2H2 Activates CAMKKβ-AMPK-Autophagy Signaling Axis and Suppresses Senescence in VK2/E6E7 Cells

Area of Science:

• Cellular Biology
• Molecular Biology
• Geroscience

Background:

• Olfactory receptors (ORs) are found in various extra-nasal tissues, mediating specific cellular functions.
• Ectopic ORs in genital tissues are of interest due to constant odorant exposure.
• The functionality of OR2H2 in human vaginal epithelial cells (VK2/E6E7) was explored.

Purpose of the Study:

• To investigate the function of ectopic olfactory receptor OR2H2 in human vaginal epithelial cells.
• To determine the signaling pathways activated by OR2H2.
• To assess the impact of OR2H2 activation on cellular senescence and aging.

Main Methods:

• VK2/E6E7 cells were used to study OR2H2 expression and function.
• Activation of OR2H2 with aldehyde 13-13 and subsequent measurement of intracellular calcium and cAMP.
• Immunoblotting to analyze the CAMKKβ-AMPK-mTORC1-autophagy signaling axis.
• OR2H2 knockdown to confirm pathway specificity.
• Assessment of proliferation, senescence markers (P16, P19), and apoptosis in H2O2-induced senescent cells.
• Lifespan studies in Caenorhabditis elegans and budding yeast.

Main Results:

• OR2H2 was the most highly expressed OR in VK2/E6E7 cells.
• Aldehyde 13-13 activated OR2H2, increasing intracellular calcium and cAMP.
• OR2H2 activation stimulated the CAMKKβ-AMPK-mTORC1-autophagy axis, effects reversed by OR2H2 knockdown.
• Aldehyde 13-13 restored proliferation and reduced senescence markers in senescent cells.
• Aldehyde 13-13 induced apoptosis in senescent cells.
• Aldehyde 13-13 extended lifespan in C. elegans and yeast.

Conclusions:

• OR2H2 is a functional receptor in human vaginal epithelial cells.
• Activation of OR2H2 by aldehyde 13-13 stimulates the AMPK-autophagy pathway.
• OR2H2 activation suppresses cellular aging and senescence, promoting cellular health.
• These findings suggest a role for OR2H2 in modulating cellular physiology and potentially lifespan.