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Dev Cell. 2019 Apr 3. pii: S1534-5807(19)30224-2. doi: 10.1016/j.devcel.2019.03.013. [Epub ahead of print]

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

Author information

1
Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø 9037, Norway.
2
Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 1112 Blindern, Oslo 0317, Norway.
3
Section for Biochemistry and Molecular Biology, University of Oslo, 1066 Blindern, Oslo 0316, Norway.
4
Department of Neurology, Pathology and Cell Biology, Columbia University, New York, NY 10032-3784, USA.
5
Centre for Molecular Medicine Norway, University of Oslo, 1137 Blindern, Oslo 0318, Norway.
6
Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø 9037, Norway. Electronic address: terje.johansen@uit.no.
7
Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 1112 Blindern, Oslo 0317, Norway. Electronic address: anne.simonsen@medisin.uio.no.

Abstract

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

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