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Hypertension-associated mitochondrial DNA 4401A>G mutation caused the aberrant processing of tRNAMet, all 8 tRNAs and ND6 mRNA in the light-strand transcript

Zhao, Xiaoxu, Cui, Limei, Xiao, Yun, Mao, Qin, Aishanjiang, Maerhaba, Kong, Wanzhong, Liu, Yuqi, Chen, Hong, Hong, Fang, Jia, Zidong, Wang, Meng, Jiang, Pingping, Guan, Min-Xin·2019·Nucleic Acids Research
DOI 10.1093/nar/gkz742PMC PMC6821173
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Abstract

Mitochondrial tRNA processing defects were associated with human diseases but their pathophysiology remains elusively. The hypertension-associated m.4401A>G mutation resided at a spacer between mitochondrial tRNAMet and tRNAGln genes. An in vitro processing experiment revealed that the m.4401A>G mutation caused 59% and 69% decreases in the 5′ end processing efficiency of tRNAGln and tRNAMet precursors, catalyzed by RNase P, respectively. Using human umbilical vein endothelial cells-derived cybrids, we demonstrated that the m.4401A>G mutation caused the decreases of all 8 tRNAs and ND6 and increases of longer and uncleaved precursors from the Light-strand transcript. Conversely, the m.4401A>G mutation yielded the reduced levels of tRNAMet level but did not change the levels of other 13 tRNAs, 12 mRNAs including ND1, 12S rRNA and 16S rRNA from the Heavy-strand transcript. These implicated the asymmetrical processing mechanisms of H-strand and L-strand polycistronic transcripts. The tRNA processing defects play the determined roles in the impairing mitochondrial translation, respiratory deficiency, diminishing membrane potential, increasing production of reactive oxygen species and altering autophagy. Furthermore, the m.4401A>G mutation altered the angiogenesis, evidenced by aberrant wound regeneration and weaken tube formation in mutant cybrids. Our findings provide new insights into the pathophysiology of hypertension arising from mitochondrial tRNA processing defects.

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  • The AAV insert capacity limitation is more evident when the mutation affects mtDNA transcription or translation, such as mutations in the origin of replication for the light and heavy strands or in any of the tRNA genes that impact global protein translation in the mitochondrial matrix.

    “This is more evident when the mutation affects mtDNA transcription or translation, such as mutations in the origin of replication for the light and heavy strands [174], or in any of the tRNA genes that impact global protein translation in the mitochondrial matrix [175].”

    From The Mitochondrial Genome in Aging and Disease and the Future of Mitochondrial Therapeutics (2022) · cites this paper as [175]

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Authors
Zhao, X., Cui, L., Xiao, Y., Mao, Q., Aishanjiang, M., Kong, W., Liu, Y., Chen, H., Hong, F., Jia, Z., Wang, M., Jiang, P., & Guan, M.-X.
Affiliations
  • Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
  • Institute of Genetics, and Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
  • Department of Clinical Laboratory, Wenzhou Traditional Chinese Medicine Hospital, Wenzhou, Zhejiang 325000, China
  • Cardiac Department, Chinese PLA General Hospital, Beijing 100853, China
  • Emergy Medicine Department, Ningbo First Hospital, Zhejiang University School of Medicine, Ningbo, Zhejiang 315000, China
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2019-08-28
Volume
47
Issue
19
Pages
10340-10356
ISSN
  • 0305-1048
  • 1362-4962
DOI
10.1093/nar/gkz742
PMC
PMC6821173
Cited by
29
References
3
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Natural Science Foundation of China (81870314, 81330024, 31601025, 81500611, 81470542)
  • National Key Research and Development Program of China (2018YFC1004802)

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