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

• Published in: Cell metabolism Vol. 28; no. 1; pp. 130 - 144.e7
• Main Authors: Wu, Zhihao, Wang, Yan, Lim, Junghyun, Liu, Boxiang, Li, Yanping, Vartak, Rasika, Stankiewicz, Trisha, Montgomery, Stephen, Lu, Bingwei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2018
• Subjects: ABCE1; Animals; ATP-Binding Cassette Transporters - metabolism; autophagy receptor recruitment; co-translational quality control; Drosophila; Drosophila Proteins - genetics; Endonucleases - metabolism; HeLa Cells; Humans; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; mitochondrial quality control; mitophagy; Mitophagy - genetics; Neurodegenerative Diseases - metabolism; NOT4; Nuclear Proteins - metabolism; PINK1; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Serine-Threonine Kinases - genetics; Ribonucleoproteins - metabolism; ribosome stalling; ribosome/mRNP remodeling; Ribosomes - metabolism; RNA, Messenger - metabolism; Transcription Factors - metabolism; Ubiquitination; mitochondrial quality control; mitophagy; PINK1; co-translational quality control; NOT4; ubiquitination; autophagy receptor recruitment; ribosome/mRNP remodeling; ribosome stalling; ABCE1
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2018.05.007

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. [Display omitted] •Enhanced translation of OXPHOS-related mRNAs on mitochondrial surface under stress•Severe mitochondrial damage induces translational stalling on mitochondrial surface•Stalled ribosomes recruit co-translational quality control machinery•Remodeling of stalled ribosome/mRNP generates signals that trigger mitophagy Removal of damaged mitochondria is essential for maintaining cellular vitality, but the earliest signal that initiates the mitophagy process is not well defined. Wu et al. show that mitochondrial damage causes stalled translation of OXPHOS-related mRNAs on the mitochondrial surface. Co-translational quality control of stalled ribosomes generates ubiquitin-containing signals that trigger mitophagy.