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A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan.
Chamoli, Manish; Rane, Anand; Foulger, Anna; Chinta, Shankar J; Shahmirzadi, Azar Asadi; Kumsta, Caroline; Nambiar, Dhanya K; Hall, David; Holcom, Angelina; Angeli, Suzanne; Schmidt, Minna; Pitteri, Sharon; Hansen, Malene; Lithgow, Gordon J; Andersen, Julie K.
Affiliation
  • Chamoli M; Buck Institute for Research on Aging, Novato, CA, USA. mchamoli@buckinstitute.org.
  • Rane A; Buck Institute for Research on Aging, Novato, CA, USA.
  • Foulger A; Buck Institute for Research on Aging, Novato, CA, USA.
  • Chinta SJ; Buck Institute for Research on Aging, Novato, CA, USA.
  • Shahmirzadi AA; Touro University California, Vallejo, CA, USA.
  • Kumsta C; Buck Institute for Research on Aging, Novato, CA, USA.
  • Nambiar DK; University of Southern California, Los Angeles, CA, USA.
  • Hall D; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • Holcom A; Stanford University, Stanford, CA, USA.
  • Angeli S; Buck Institute for Research on Aging, Novato, CA, USA.
  • Schmidt M; Buck Institute for Research on Aging, Novato, CA, USA.
  • Pitteri S; University of Southern California, Los Angeles, CA, USA.
  • Hansen M; Buck Institute for Research on Aging, Novato, CA, USA.
  • Lithgow GJ; Buck Institute for Research on Aging, Novato, CA, USA.
  • Andersen JK; University of Southern California, Los Angeles, CA, USA.
Nat Aging ; 3(12): 1529-1543, 2023 Dec.
Article in En | MEDLINE | ID: mdl-37957360
Autophagy-lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target. In this study, we screened a natural product library and discovered mitophagy-inducing coumarin (MIC), a benzocoumarin compound that enhances TFEB expression and lysosomal function. MIC robustly increases the lifespan of Caenorhabditis elegans in an HLH-30/TFEB-dependent and mitophagy-dependent manner involving DCT-1/BNIP3 while also preventing mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12/FXR, which, in turn, induces mitophagy and extends lifespan. In conclusion, our study uncovers MIC as a promising drug-like molecule that enhances mitochondrial function and extends lifespan by targeting DAF-12/FXR. Furthermore, we discovered DAF-12/FXR as a previously unknown upstream regulator of HLH-30/TFEB and mitophagy.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Caenorhabditis elegans Proteins / Mitophagy Limits: Animals Language: En Journal: Nat Aging Year: 2023 Type: Article Affiliation country: United States

Full text: 1 Database: MEDLINE Main subject: Caenorhabditis elegans Proteins / Mitophagy Limits: Animals Language: En Journal: Nat Aging Year: 2023 Type: Article Affiliation country: United States