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Sci Rep. 2017 Jul 18;7(1):5704. doi: 10.1038/s41598-017-05571-y.

A novel ADOA-associated OPA1 mutation alters the mitochondrial function, membrane potential, ROS production and apoptosis.

Zhang J1,2,3, Liu X3, Liang X2, Lu Y4, Zhu L1,2, Fu R3,4, Ji Y1,2, Fan W3, Chen J3, Lin B3, Yuan Y3,4, Jiang P1,2, Zhou X5, Guan MX6,7,8.

Author information

1
Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
2
Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
3
School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
4
Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
5
School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China. zxt-dr@wz.zj.cn.
6
Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. gminxin88@zju.edu.cn.
7
Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China. gminxin88@zju.edu.cn.
8
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, 310058, China. gminxin88@zju.edu.cn.

Abstract

Autosomal dominant optic atrophy (ADOA) is a dominantly inherited optic neuropathy, affecting the specific loss of retinal ganglion cells (RGCs). The majority of affected cases of ADOA are associated with mutations in OPA1 gene. Our previous investigation identified the c.1198C > G (p.P400A) mutation in the OPA1 in a large Han Chinese family with ADOA. In this report, we performed a functional characterization using lymphoblostoid cell lines derived from affected members of this family and control subjects. Mutant cell lines exhibited the aberrant mitochondrial morphology. A ~24.6% decrease in the mitochondrial DNA (mtDNA) copy number was observed in mutant cell lines, as compared with controls. Western blotting analysis revealed the variable reductions (~45.7%) in four mtDNA-encoded polypeptides in mutant cell lines. The impaired mitochondrial translation caused defects in respiratory capacity. Furthermore, defects in mitochondrial ATP synthesis and mitochondrial membrane potential (ΔΨm) were observed in mutant cell lines. These abnormalities resulted in the accumulation of oxidative damage and increasing of apoptosis in the mutant cell lines, as compared with controls. All those alterations may cause the primary degeneration of RGCs and subsequent visual loss. These data provided the direct evidence for c.1198C > G mutation leading to ADOA. Our findings may provide new insights into the understanding of pathophysiology of ADOA.

PMID:
28720802
PMCID:
PMC5515948
DOI:
10.1038/s41598-017-05571-y
[Indexed for MEDLINE]
Free PMC Article

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