4.7 Article

NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complexes in mice

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COMMUNICATIONS BIOLOGY
卷 6, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s42003-023-04680-x

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A study found that a mitochondrial tRNA modification enzyme, NSUN3, is crucial for embryonic development in mice. Whole-body knockout leads to embryonic death, while heart-specific knockout causes heart aberration in older mice. The research highlights the importance of mitochondrial tRNA anticodon modification for mammalian embryonic development and demonstrates that the loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens with age.
A mitochondrial tRNA modification enzyme, NSUN3, is found to be essential for embryonic development in mice, with whole-body knockout causing embryonic lethality and heart-specific Nsun3 knockout leading to heart aberration in older mice. In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f(5)C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3(HKO)) mice. Nsun3(HKO) heart mitochondria were enlarged and contained fragmented cristae. Nsun3(HKO) resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3(HKO) hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood.

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