期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.71634
关键词
mitochondria; mitochondrial unfolded protein response; ELAC2; HOE-1; tRNAs; C; elegans
类别
资金
- NIH Office of Research Infrastructure Programs [P40 OD010440, R01 GM123260, R35 GM145378, R00 AG052666, R35GM145378]
- NIH [R01GM123260, R00AG052666, T32ES007028]
- National Institute of General Medical Sciences [P40 OD010440, R00 AG052666]
- National Institute on Aging [R35 GM145378]
- National Institute of Environmental Health Sciences [R01 GM123260]
Researchers have discovered a new RNA-based cellular pathway, mediated by the enzyme HOE-1, that activates the mitochondrial unfolded protein response (UPRmt) by regulating the transcription factors ATFS-1 and DVE-1. This pathway does not rely on the integrated stress response and is likely mediated by tRNAs. The subcellular localization of HOE-1 is responsive to mitochondrial stress and is negatively regulated by ATFS-1.
The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing toward its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.
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