NDP52 Interacts With Mitochondrial RNA poly(A) Polymerase to Promote Mitophagy

EMBO Rep. 2018 Dec;19(12):e46363. doi: 10.15252/embr.201846363. Epub 2018 Oct 11.

Abstract

Parkin-mediated mitophagy is a quality control pathway that selectively removes damaged mitochondria via the autophagic machinery. Autophagic receptors, which interact with ubiquitin and Atg8 family proteins, contribute to the recognition of damaged mitochondria by autophagosomes. NDP52, an autophagy receptor, is required for autophagic engulfment of damaged mitochondria during mitochondrial uncoupler treatment. The N-terminal SKICH domain and C-terminal zinc finger motif of NDP52 are both required for its function in mitophagy. While the zinc finger motif contributes to poly-ubiquitin binding, the function of the SKICH domain remains unclear. Here, we show that NDP52 interacts with mitochondrial RNA poly(A) polymerase (MTPAP) via the SKICH domain. During mitophagy, NDP52 invades depolarized mitochondria and interacts with MTPAP dependent on the proteasome but independent of ubiquitin binding. Loss of MTPAP reduces NDP52-mediated mitophagy, and the NDP52-MTPAP complex attracts more LC3 than NDP52 alone. These results indicate that NDP52 and MTPAP form an autophagy receptor complex, which enhances autophagic elimination of damaged mitochondria.

Keywords: MTPAP; NDP52; Parkin; SKICH domain; mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Directed RNA Polymerases / metabolism*
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Proteins / metabolism*
  • Mitophagy* / drug effects
  • Mutation / genetics
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Protein Binding / drug effects
  • Protein Domains
  • Protein-Serine-Threonine Kinases / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Valinomycin / pharmacology

Substances

  • CALCOCO2 protein, human
  • Mitochondrial Proteins
  • Nuclear Proteins
  • Ubiquitin
  • Valinomycin
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • DNA-Directed RNA Polymerases
  • MTPAP protein, human