A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan

Area of Science:

• Cellular Biology
• Aging Research
• Pharmacology

Background:

• Autophagy-lysosomal function is vital for healthy aging and disease prevention.
• The transcription factor TFEB regulates this pathway, and its decline is linked to age-related disorders.
• Targeting TFEB offers a potential therapeutic avenue for age-related conditions.

Purpose of the Study:

• To identify natural compounds that enhance TFEB expression and autophagy-lysosomal function.
• To investigate the therapeutic potential of such compounds in extending lifespan and preventing age-related diseases.
• To elucidate the molecular mechanisms underlying the action of identified compounds.

Main Methods:

• Screening of a natural product library to identify mitophagy-inducing compounds.
• Utilizing Caenorhabditis elegans to assess lifespan extension and dependence on specific genetic pathways (HLH-30/TFEB, DCT-1/BNIP3).
• Employing mammalian cell models to evaluate the compound's effects on mitochondrial function.
• Investigating the molecular mechanism involving the nuclear hormone receptor DAF-12/FXR.

Main Results:

• Discovery of mitophagy-inducing coumarin (MIC), a benzocoumarin that enhances TFEB expression and lysosomal function.
• MIC significantly increases lifespan in C. elegans via HLH-30/TFEB and mitophagy (involving DCT-1/BNIP3).
• MIC prevents mitochondrial dysfunction in mammalian cells and extends lifespan by inhibiting DAF-12/FXR activation, thereby inducing mitophagy.

Conclusions:

• MIC is a promising drug-like molecule that enhances mitochondrial function and extends lifespan.
• MIC acts by inhibiting DAF-12/FXR, leading to mitophagy and lifespan extension.
• DAF-12/FXR is identified as a novel upstream regulator of HLH-30/TFEB and mitophagy.