Leber's Hereditary Optic Neuropathy: the roles of mitochondrial transfer RNA variants

Yu Ding; Guangchao Zhuo; Qinxian Guo; Meiya Li

doi:10.7717/peerj.10651

Leber's Hereditary Optic Neuropathy: the roles of mitochondrial transfer RNA variants

PeerJ. 2021 Jan 18:9:e10651. doi: 10.7717/peerj.10651. eCollection 2021.

Authors

Yu Ding¹, Guangchao Zhuo¹, Qinxian Guo¹, Meiya Li²

Affiliations

¹ Central laboratory, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China.
² Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.

Abstract

Leber's Hereditary Optic Neuropathy (LHON) was a common maternally inherited disease causing severe and permanent visual loss which mostly affects males. Three primary mitochondrial DNA (mtDNA) mutations, ND1 3460G>A, ND4 11778G>A and ND6 14484T>C, which affect genes encoding respiratory chain complex I subunit, are responsible for >90% of LHON cases worldwide. Families with maternally transmitted LHON show incomplete penetrance with a male preponderance for visual loss, suggesting the involvement of secondary mtDNA variants and other modifying factors. In particular, variants in mitochondrial tRNA (mt-tRNA) are important risk factors for LHON. These variants decreased the tRNA stability, prevent tRNA aminoacylation, influence the post-transcriptionalmodification and affect tRNA maturation. Failure of mt-tRNA metabolism subsequently impairs protein synthesis and expression, folding, and function of oxidative phosphorylation (OXPHOS) enzymes, which aggravates mitochondrial dysfunction that is involved in the progression and pathogenesis of LHON. This review summarizes the recent advances in our understanding of mt-tRNA biology and function, as well as the reported LHON-related mt-tRNA second variants; it also discusses the molecular mechanism behind the involvement of these variants in LHON.

Keywords: tRNA metabolism; LHON; OXPHOS; Variants; mt-tRNA.

Grants and funding

This work was supported by grants from Ministry of Public Health from Zhejiang Province (no. 2018ZH019 and 2021RC022), and the Zhejiang Provincial Administration of Traditional Chinese Medicine (no. 2018ZB082). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.