Leber’s hereditary optic neuropathy (LHON) is the most common mitochondrial disease. Mitochondrial modifiers are proposed to modify the phenotypic expression of primary LHON-associated mitochondrial DNA (mtDNA) mutations. In this study, we demonstrated that the LHON susceptibility allele (m.14502T > C, p. 58I > V) in the ND6 gene modulated the phenotypic expression of primary LHON-associated m.11778G > A mutation. Twenty-two Han Chinese pedigrees carrying m.14502T > C and m.11778G > A mutations exhibited significantly higher penetrance of optic neuropathy than those carrying only m.11778G > A mutation. We performed functional assays using the cybrid cell models, generated by fusing mtDNA-less ρo cells with enucleated cells from LHON patients carrying both m.11778G > A and m.14502T > C mutations, only m.14502T > C or m.11778G > A mutation and a control belonging to the same mtDNA haplogroup. These cybrids cell lines bearing m.14502T > C mutation exhibited mild effects on mitochondrial functions compared with those carrying only m.11778G > A mutation. However, more severe mitochondrial dysfunctions were observed in cell lines bearing both m.14502T > C and m.11778G > A mutations than those carrying only m.11778G > A or m.14502T > C mutation. In particular, the m.14502T > C mutation altered assemble of complex I, thereby aggravating the respiratory phenotypes associated with m.11778G > A mutation, resulted in a more defective complex I. Furthermore, more reductions in the levels of mitochondrial ATP and increasing production of reactive oxygen species were also observed in mutant cells bearing both m.14502T > C and m.11778G > A mutation than those carrying only 11778G > A mutation. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between primary and secondary mtDNA mutations.
Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated mitochondrial DNA mutation
Pingping Jiang, Min Liang, Chaofan Zhang, Xiaoxu Zhao, Qiufen He, Limei Cui, Xiaoling Liu, Yan-Hong Sun, Qun Fu, Yanchun Ji, Yidong Bai, Taosheng Huang, Min-Xin Guan; Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated mitochondrial DNA mutation. Hum Mol Genet 2016; 25 (16): 3613-3625. doi: 10.1093/hmg/ddw199
Download citation file:
© 2017 Oxford University Press×
Sign in via your Institution
PurchaseSubscription prices and ordering
To purchase short term access, please sign in to your Oxford Academic account above.
Don't already have an Oxford Academic account? Register