Taurine Hypomodification Underlies Mitochondrial TRNATrp-related Genetic Diseases

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2024 Oct 9

PMID 39380483

Authors

Jia-Li Lu

Yichen Dai

Kunqian Ji

Gui-Xin Peng

Hong Li

Chuanzhu Yan

Bin Shen

Xiao-Long Zhou

Affiliations

Soon will be listed here.

Abstract

Escherichia coli MnmE and MnmG form a complex (EcMnmEG), generating transfer RNA (tRNA) 5-carboxymethylaminomethyluridine (cmnm5U) modification. Both cmnm5U and equivalent 5-taurinomethyluridine (τm5U, catalyzed by homologous GTPBP3 and MTO1) are found at U34 in several human mitochondrial tRNAs (hmtRNAs). Certain mitochondrial DNA (mtDNA) mutations, including m.3243A > G in tRNALeu(UUR) and m.8344A > G in tRNALys, cause genetic diseases, partially due to τm5U hypomodification. However, whether other mtDNA variants in different tRNAs cause a defect in τm5U biogenesis remains unknown. Here, we purified naturally assembled EcMnmEG from E. coli. Notably, EcMnmEG was able to incorporate both cmnm5U and τm5U into hmtRNATrp (encoded by MT-TW), providing a valuable basis for directly monitoring the effects of mtDNA mutations on U34 modification. In vitro, several clinical hmtRNATrp pathogenic mutations caused U34 hypomodification. A patient harboring an m.5541C > T mutation exhibited hmtRNATrp τm5U hypomodification. Moreover, using mtDNA base editing, we constructed two cell lines carrying m.5532G > A or m.5545C > T mutations, both of which exhibited hmtRNATrp τm5U hypomodification. Taurine supplementation improved mitochondrial translation in patient cells. Our findings describe the third hmtRNA species with mutation-related τm5U-hypomodification and provide new insights into the pathogenesis and intervention strategy for hmtRNATrp-related genetic diseases.

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