NIPSNAP1 and NIPSNAP2 Act as "Eat Me" Signals for Mitophagy

Dev Cell. 2019 May 20;49(4):509-525.e12. doi: 10.1016/j.devcel.2019.03.013. Epub 2019 Apr 11.


The clearance of damaged or dysfunctional mitochondria by selective autophagy (mitophagy) is important for cellular homeostasis and prevention of disease. Our understanding of the mitochondrial signals that trigger their recognition and targeting by mitophagy is limited. Here, we show that the mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) and NIPSNAP2 accumulate on the mitochondria surface upon mitochondrial depolarization. There, they recruit proteins involved in selective autophagy, including autophagy receptors and ATG8 proteins, thereby functioning as an "eat me" signal for mitophagy. NIPSNAP1 and NIPSNAP2 have a redundant function in mitophagy and are predominantly expressed in different tissues. Zebrafish lacking a functional Nipsnap1 display reduced mitophagy in the brain and parkinsonian phenotypes, including loss of tyrosine hydroxylase (Th1)-positive dopaminergic (DA) neurons, reduced motor activity, and increased oxidative stress.

Keywords: ALFY; NDP52; NIPSNAP1; NIPSNAP2; Parkin; TAX1BP1; autophagy; mitophagy; optineurin; p62/SQSTM1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Autophagy / physiology
  • Autophagy-Related Protein 8 Family / metabolism
  • Autophagy-Related Proteins
  • Carrier Proteins / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Mitophagy / physiology*
  • Neurons / metabolism
  • Protein Binding
  • RNA-Binding Proteins / metabolism
  • Sequestosome-1 Protein / metabolism
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Zebrafish
  • Zebrafish Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Protein 8 Family
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • NIPSNAP1 protein, human
  • NIPSNAP2 protein, human
  • P62 protein, human
  • RNA-Binding Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transcription Factors
  • WDFY3 protein, human
  • Zebrafish Proteins
  • Ubiquitin-Protein Ligases