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

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.

Late onset of type 2 diabetes is associated with mitochondrial tRNATrp A5514G and tRNASer(AGY) C12237T mutations

“…Based on these observations, we proposed that the possible molecular mechanisms underlying m.A5514G and m.C12237T mutations in the phenotypic expression of MIDD may be as follows: first, the mutations disrupted the secondary structures of tRNAs and subsequently resulted the failure in tRNAs metabolism, such as reducing tRNA steady‐state level, aminoacylation ability, affecting 3’ end processing, or its chemical modifications 58 …”

“…Based on these observations, we proposed that the possible molecular mechanisms underlying m.A5514G and m.C12237T mutations in the phenotypic expression of MIDD may be as follows: first, the mutations disrupted the secondary structures of tRNAs and subsequently resulted the failure in tRNAs metabolism, such as reducing tRNA steady‐state level, aminoacylation ability, affecting 3’ end processing, or its chemical modifications. 58 These biochemical processes will lead to the impairment of mitochondrial protein translation and influence the respiratory chain functions. As a result, these mutations led to mitochondrial dysfunctions which caused the pancreatic β‐cell apoptosis or necrosis, 59 , 60 and involved in the pathogenesis of MIDD in this pedigree.…”