Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells

Nat Cell Biol. 2012 Jan 22;14(2):177-85. doi: 10.1038/ncb2422.

Abstract

Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy*
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cells, Cultured
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Microscopy, Immunoelectron
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Protein Binding
  • RNA Interference
  • Sequence Homology, Amino Acid

Substances

  • FUNDC1 protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • light chain 3, human
  • Green Fluorescent Proteins