Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Nat Chem Biol. 2014 Feb;10(2):133-40. doi: 10.1038/nchembio.1406. Epub 2013 Dec 8.


Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Humans
  • Ketones / chemistry*
  • Ketones / pharmacology
  • Melanoma / drug therapy
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / physiology*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Protein Conformation
  • Proto-Oncogene Proteins / metabolism
  • Pyrogallol / analogs & derivatives*
  • Pyrogallol / chemistry
  • Pyrogallol / pharmacology
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism


  • 1-(3,4,5-trihydroxyphenyl)nonan-1-one
  • BNIP3L protein, human
  • Ketones
  • Membrane Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Pyrogallol

Associated data

  • PDB/4JGV
  • PDB/4KZI
  • PDB/4KZJ
  • PDB/4KZM
  • PubChem-Substance/165230472
  • PubChem-Substance/165230473
  • PubChem-Substance/165230474
  • PubChem-Substance/165230475
  • PubChem-Substance/165230476
  • PubChem-Substance/165230477
  • PubChem-Substance/165230478
  • PubChem-Substance/165230479
  • PubChem-Substance/165230480
  • PubChem-Substance/165230481