2. Academic Validation
  3. Ubiquitination of ABCE1 by NOT4 in Response to Mitochondrial Damage Links Co-translational Quality Control to PINK1-Directed Mitophagy

Ubiquitination of ABCE1 by NOT4 in Response to Mitochondrial Damage Links Co-translational Quality Control to PINK1-Directed Mitophagy

  • Cell Metab. 2018 Jul 3;28(1):130-144.e7. doi: 10.1016/j.cmet.2018.05.007.
Zhihao Wu 1,  Yan Wang 2,  Junghyun Lim 1,  Boxiang Liu 3,  Yanping Li 1,  Rasika Vartak 1,  Trisha Stankiewicz 1,  Stephen Montgomery 3,  Bingwei Lu 4
Affiliations

Affiliations

  • 1 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, China.
  • 3 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Programs in Neuroscience and Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 29861391 DOI: 10.1016/j.cmet.2018.05.007
Abstract

Translation of mRNAs is tightly regulated and constantly surveyed for errors. Aberrant translation can trigger co-translational protein and RNA quality control processes, impairments of which cause neurodegeneration by still poorly understood mechanism(s). Here we show that quality control of translation of mitochondrial outer membrane (MOM)-localized mRNA intersects with the turnover of damaged mitochondria, both orchestrated by the mitochondrial kinase PINK1. Mitochondrial damage causes stalled translation of complex-I 30 kDa subunit (C-I30) mRNA on MOM, triggering the recruitment of co-translational quality control factors Pelo, ABCE1, and NOT4 to the ribosome/mRNA-ribonucleoprotein complex. Damage-induced ubiquitination of ABCE1 by NOT4 generates poly-ubiquitin signals that attract Autophagy receptors to MOM to initiate Mitophagy. In the Drosophila PINK1 model, these factors act synergistically to restore Mitophagy and neuromuscular tissue integrity. Thus ribosome-associated co-translational quality control generates an early signal to trigger Mitophagy. Our results have broad therapeutic implications for the understanding and treatment of neurodegenerative diseases.

Keywords

ABCE1; NOT4; PINK1; autophagy receptor recruitment; co-translational quality control; mitochondrial quality control; mitophagy; ribosome stalling; ribosome/mRNP remodeling; ubiquitination.

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