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BNIP3介导线粒体自噬在m.3635G>A相关Leber遗传性视神经病变中的作用机制
刘贞
管威
张娟娟
管敏鑫
作者及单位信息
·
DOI： 10.3760/cma.j.cn511374-20221101-00574
Mechanism of BNIP3-mediated mitophagy in m. 3635G>A related Leber hereditary optic neuropathy
Liu Zhen
Guan Wei
Zhang Juanjuan
Guan Minxin
Authors Info & Affiliations
Liu Zhen
School of Laboratory Medicine and Life Sciences, Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
Guan Wei
School of Laboratory Medicine and Life Sciences, Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
Zhang Juanjuan
School of Laboratory Medicine and Life Sciences, Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
State Key Laboratory of Ophthalmology, Optometry and Vision Science, Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Guan Minxin
School of Laboratory Medicine and Life Sciences, Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
Institute of Genetics, Zhejiang University, Zhejiang Provincial Key Lab of Genetic and Developmental Disorders, Hangzhou, Zhejiang 310058, China
·
DOI： 10.3760/cma.j.cn511374-20221101-00574
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摘要

目的探讨BNIP3介导线粒体自噬在m.3635G>A变异相关Leber遗传性视神经病变(LHON)中的作用机制。

方法选取2013年9月于温州医科大学附属眼视光医院就诊的1例携带m.3635G>A变异的中国LHON患者的转线粒体细胞系为研究对象，同时纳入1例具有相同线粒体背景的正常受试者的转线粒体细胞系作为对照，通过免疫荧光、实时荧光定量PCR(RT-qPCR)和蛋白免疫印迹等方法检测细胞中自噬相关蛋白的表达，探究BNIP3介导线粒体自噬对m.3635G>A变异相关LHON的作用。本研究已通过温州医科大学附属眼视光医院医学伦理委员会的审查(批准号：2023-J-096)。

结果①与对照组细胞比较，变异组(m.3635G>A)细胞中自噬相关蛋白LC3(LC3-Ⅱ/LC3-Ⅰ)和LAMP1的蛋白表达水平均显著降低( P<0.05)，其中大自噬相关蛋白ATG12、ATG7和ATG5的蛋白表达水平均显著降低( P<0.05)。②与对照组细胞比较，变异组细胞中线粒体自噬相关蛋白BNIP3的mRNA与蛋白表达水平均显著降低( P<0.05)。

结论m.3635G>A变异可抑制BNIP3介导线粒体自噬的作用，进而导致LHON的发生。

Leber遗传性视神经病变;线粒体DNA;基因变异;自噬;线粒体自噬
ABSTRACT

ObjectiveTo explore the mechanism of BNIP3-mediated mitophagy in m. 3635G>A related Leber′s hereditary optic neuropathy (LHON).

MethodsA transmitochondrial cybrid cell line derived from a Chinese LHON patient carrying the m. 3635G>A, diagnosed at the Eye Hospital of Wenzhou Medical University in September 2013, was selected as the study subject. A transmitochondrial cybrid cell line from a healthy control with an identical mitochondrial background was included as a control. Immunofluorescence, real-time quantitative PCR (RT-qPCR), and Western blotting were employed to assess the expression of autophagy-related proteins, aiming to explore the role of BNIP3-mediated mitophagy in m. 3635G>A related LHON. This study was approved by the Medical Ethics Committee of the Eye Hospital of Wenzhou Medical University (Ethics No. 2023-J-096).

Results① Compared with the control group, the protein expression levels of autophagy-related markers LC3 (LC3-Ⅱ/LC3-Ⅰ) and LAMP1 were significantly reduced in the variant group ( P<0.05). Additionally, the protein levels of macroautophagy-related proteins ATG12, ATG7, and ATG5 were also significantly decreased ( P<0.05). ② Compared with the control cells, the mRNA and protein expression levels of mitophagy-associated protein BNIP3 were significantly reduced in the cells of the variant group ( P<0.05). Compared with the control group, both mRNA and protein expression levels of the mitophagy-related protein BNIP3 were significantly reduced in the variant group ( P<0.05).

ConclusionThe m. 3635G>A inhibits BNIP3-mediated mitophagy, thereby contributing to the pathogenesis of LHON.

Leber hereditary optic neuropathy;Mitochondrial DNA;Gene variation;Autophagy;Mitophagy
Guan Minxin, Email: nc.defudabe.ujz88nixnimg
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引用本文

刘贞,管威,张娟娟,等. BNIP3介导线粒体自噬在m.3635G>A相关Leber遗传性视神经病变中的作用机制[J]. 中华医学遗传学杂志,2025,42(02)：198-205.

DOI:10.3760/cma.j.cn511374-20221101-00574

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Leber遗传性视神经病变(Leber′s hereditary optic neuropathy，LHON)是一种与线粒体DNA(mitochondrial DNA，mtDNA)变异相关的母系遗传性眼病，发病率约为1：50 000～1：30 000 [ 1 ]。1871年德国眼科医生Theodor Leber首次对该病的临床特征进行了详细的描述，因此临床上也将其称为"Leber氏病" [ 2 ]。LHON主要累及视网膜神经节细胞(retinal ganglion cells，RGCs)及其轴突，患者通常表现为双眼先后或同时有不同程度的视力损伤，中心或旁中心暗点，同时可伴有中心视野缺失及色觉障碍，以青壮年男性多发 [ 3 , 4 , 5 ]。
自噬是一种进化保守的清除机制，负责细胞中"废物"的清除和回收，在维持细胞内稳态以及机体健康方面发挥重要作用，因此也被冠以"长寿"的标签 [ 6 , 7 , 8 ]。但在某些情况下，自噬反而会促进癌症、器官损伤以及神经退行性病变的发生，甚至会导致细胞死亡 [ 8 , 9 , 10 ]。BNIP3蛋白在各种细胞中广泛表达，既是Bcl-2家族的促凋亡成员，也是一种线粒体受体，可将受损线粒体与自噬体结合并清除，因此其在线粒体自噬与继发性线粒体功能障碍疾病中存在潜在作用机制 [ 11 ]。
近年来，已发现60多个mtDNA变异位点与LHON相关，其中m.11778G>A变异可促进细胞自噬 [ 12 ]；m.14484T>C与m.3460G>A变异可抑制细胞自噬 [ 13 , 14 ]。m.3635G>A变异已被报道可导致NADH脱氢酶亚单位1(NADH dehydrogenase subunit 1，ND1)的亲水性发生变化，通过PINK1/Parkin信号通路抑制线粒体自噬 [ 15 , 16 ]。为进一步探究m.3635G>A变异是否影响BNIP3蛋白介导的线粒体自噬，本研究选取1例携带m.3635G>A变异的中国LHON患者的转线粒体细胞系作为研究对象，通过免疫荧光、实时荧光定量PCR(real-time fluorescence quantitative PCR，RT-qPCR)和蛋白免疫印迹等技术，揭示BNIP3蛋白介导线粒体自噬在m.3635G>A变异相关LHON发生发展中的分子作用，旨在为临床诊治该病提供更多依据。
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备注信息
A
管敏鑫，Email： nc.defudabe.ujz88nixnimg
B

刘贞：实验操作、数据整理、论文撰写；管威：实验操作；张娟娟：研究指导、论文修改、实验经费支持；管敏鑫：研究指导、论文修改

C
所有作者均声明不存在利益冲突
D
国家自然科学基金 (82071007)
浙江省自然科学基金 (LY24C060001)
温州市基础性医疗卫生科技项目 (Y20220152)
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