线粒体DNA遗传疾病及基因治疗研究现状

doi:10.16288/j.yczz.25-032

遗传 ›› 2025, Vol. 47 ›› Issue (12): 1300-1325.doi: 10.16288/j.yczz.25-032

线粒体DNA遗传疾病及基因治疗研究现状

唐成¹^,²(), 徐顺清¹, 李汉增¹()

1.海南大学环境科学与工程学院，海口 570228
2.海南大学生命健康学院，海口 570228

收稿日期:2025-02-07 修回日期:2025-05-23 出版日期:2025-05-27 发布日期:2025-05-27
通讯作者: 李汉增，博士，教授，研究方向：线粒体遗传。E-mail: hanzeng.li@hainanu.edu.cn
作者简介:唐成，硕士研究生，专业方向：基因工程。E-mail: 23220860010019@hainanu.edu.cn
基金资助:
海南省自然科学基金项目(823QN230);国家自然科学基金项目(32400724);国家自然科学基金项目(22466015)

Current understanding of mitochondrial DNA genetic diseases and gene therapy

Cheng Tang¹^,²(), Shunqing Xu¹, Hanzeng Li¹()

1. School of Environmental Science and Engineering, Hainan University, Haikou 570228, China
2. School of Life and Health Sciences, Hainan University, Haikou 570228, China

Received:2025-02-07 Revised:2025-05-23 Published:2025-05-27 Online:2025-05-27
Supported by:
Hainan Provincial Natural Science Foundation(823QN230);National Natural Science Foundation of China(32400724);National Natural Science Foundation of China(22466015)

摘要/Abstract

摘要：

线粒体作为真核细胞内关键的细胞器，其蛋白质和RNA由核基因组和线粒体基因组共同表达，参与能量调控、细胞代谢以及信号转导等众多生理活动，还与多种细胞器相互作用共同维持细胞稳态。另外，线粒体也可以通过迁移体等方式在细胞和组织间进行传输。线粒体DNA (mitochondrial DNA，mtDNA)的突变往往造成严重的遗传罕见病，具有组织特异性、异质性、多突变位点等特点，且难以根治。对mtDNA进行基因编辑有望从根本上治愈此类疾病。传统的基因编辑核酸酶如锌指核酸酶(zinc-finger nucleases，ZFN)和转录激活样效应因子核酸酶(transcription activator-like effector nuclease，TALEN)，以及新型基因编辑器双链DNA脱氨酶衍生的胞嘧啶碱基编辑器(DddA-derived cytosine base editors，DdCBEs)已被证明可以修正部分mtDNA突变。然而可编程性更简单、更高效的CRISPR技术则因向导RNA (single guide RNA，sgRNA)无法高效进入线粒体的技术瓶颈而受到限制。本文系统阐述了线粒体结构与功能、相关疾病及其基因编辑治疗的现状，并展望了未来需优化的治疗工具，以期解决sgRNA导入难题，突破线粒体DNA突变所引起遗传性罕见病的治疗困境。

关键词: 线粒体, 线粒体罕见病, 线粒体DNA编辑, CRISPR

Abstract:

Mitochondria, as crucial organelles within eukaryotic cells, have their proteins and RNAs encoded by both the nuclear genome and the mitochondrial genome. They play vital roles in energy regulation, cellular metabolism, signal transduction, and various other physiological activities. Additionally, mitochondria interact with multiple organelles to collectively maintain cellular homeostasis. Mitochondria can also be transferred between cells and tissues through mechanisms such as migrasomes. Mitochondrial DNA (mtDNA) mutations often cause severe inherited rare diseases, characterized by tissue specificity, heterogeneity, multiple mutation sites, and challenges in achieving a complete cure. Gene editing of mtDNA holds promise for fundamentally curing such diseases. Traditional gene-editing nucleases, such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nuclease (TALENs), as well as novel gene editors like DddA-derived cytosine base editors (DdCBEs), have been demonstrated to correct certain mtDNA mutations. However, CRISPR-based technologies—despite their superior programmability and efficiency—are currently limited due to the technical bottleneck of inefficient sgRNA delivery into mitochondria. This article systematically reviews the structure and function of mitochondria, related diseases, and the current state of mtDNA gene-editing therapies. Furthermore, it explores future directions for optimizing therapeutic tools to overcome the challenge of sgRNA delivery, thereby addressing the treatment barriers posed by pathogenic mtDNA mutations in inherited rare diseases.

Key words: mitochondria, mtDNA associated rare diseases, mtDNA editing, CRISPR

唐成, 徐顺清, 李汉增. 线粒体DNA遗传疾病及基因治疗研究现状[J]. 遗传, 2025, 47(12): 1300-1325.

Cheng Tang, Shunqing Xu, Hanzeng Li. Current understanding of mitochondrial DNA genetic diseases and gene therapy[J]. Hereditas(Beijing), 2025, 47(12): 1300-1325.

图/表 4

表1

表2

表3

现有线粒体编辑方法应用统计"

名称	编辑序列偏好性	部分体内外应用研究	编辑位点	编辑效率	脱靶概率	参考文献
mtZFNs	/	人骨肉瘤143B细胞	/	四个周期后m.8993T>G异质性从80%降到7%	较为显著	[138]
mtZFNs	/	小鼠胚胎成纤维细胞(MEF)、小鼠	/	在MEF细胞中，异质性比例从65%下降到了45%；小鼠心脏细胞内的突变mtDNA比例从73%下降到37%	未说明	[139]
mitoTALENs	/	小鼠胚胎成纤维细胞(MEF)、小鼠	/	在MEF细胞中，异质性降低的比例大概在20%~60%；在小鼠中，各个部位的异质性比例也有所降低	未检测到mtDNA大片段缺失	[142]
mitoTALENs	/	水稻、油菜	/	无定量数据/(主要用于开发新品种作物)	未说明	[143]
mitoARCUS	/	小鼠胚胎成纤维细胞(MEF)、小鼠	/	在MEF细胞中m.5024C>T突变降低从50%降低至约25%~30%；在幼鼠和成年鼠中突变mtDNA均能降低约90%	未说明	[123]
mitoARCUS	/	人骨肉瘤143B细胞、异种移植小鼠模型	/	在人骨肉瘤143B细胞中3天内突变mtDNA从95%到0.3%；在种移植小鼠模型中，最高剂量组肿瘤组织中野生型mtDNA比例从6.5%提升至13.9%	未说明	[144]
mitoDdCBE	第一版有严格的5′-TC序列依赖性，优化过的第二版除5′-TC环境外，可进一步编辑5′-AC和5′-CC。	HEK293T	/	在MT-ND6基因位点编辑效率在16%~27%；MT-ND1、MT-ND2、MT-ND4、MT-ND5和MT-ATP8基因位点编辑效率在4.6%~49%	未检测到显著性突变	[124]
		HEK293T		DddA6的碱基编辑器将TC编辑效率平均提高了3.3倍；DddA11变体将AC和CC位点的平均编辑效率从<10%提升至15%~30%	未检测到显著性突变	[129]
		人类3PN胚胎		60% (8细胞阶段)、25% (3PN胚胎)	未说明	[147]
		双细胞胚胎		46%~72%	出现大量核基因脱靶突变	[148]
		HEK293T		未给出明确数据	0.46%~17.51% (核基因脱靶)	[149]
TALED	/	HEK293T	A>G	sTALEDs平均A>G编辑频率为27%±3%，平均C>T编辑频率为32%±4%；mTALEDs和dTALEDs的平均编辑频率为19%±4%	sTALEDs平均脱靶频率为0.019%± 0.002%；mTALEDs和dTALEDs分别为0.009%±0.001%和0.008%±0.001%	[125]
TALED	/	植物叶绿体	A>G	46% (rrn16)；25% (psbA)；51% (psaA)	未检测到显著性突变	[152]
mitoBEs	/	小鼠	A>G或G>C	在F₀小鼠MT-ATP6基因的T8591C和MT-ND5基因的A12784G，mitoABEv2的平均编辑效率分别是46%和44%，最大效率分别为68%和82%；mitoABE的平均效率为30%和38%，最大效率为50%和55%	未检测到显著性突变	[153]

表3

图1

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分类	中文名称	英文名称	部分常见突变基因及位点	参考文献
异质点突变相关疾病	线粒体脑肌病伴乳酸酸中毒和中风样发作	Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)	MT-TL1基因m.3243A>G等	[52]
	利氏综合征	Leigh syndrome (LS)	MT-ATP6基因m.8993T>C以及MT-ND3基因m.10191T>C等	[53]
	共济失调和视网膜色素变性	Neuropathy, ataxia, and retinitis pigmentosa (NARP)	MT-ATP6基因m.8993T>G/C等	[54,55]
	肌阵挛性癫痫伴红色粗纤维	Myoclonic epilepsy with ragged red fibers (MERRF)	MT-TK基因m.8344A>G等	[56]
同质点突变相关疾病	Leber遗传性视神经病变	Leber hereditary optic neuropathy (LHON)	MT-ND1基因m.3460G>A、MT-ND4基因m.11778G>A、MT-ND6基因m.14484T>C等	[57,58]

分类	中文名称	英文名称	编辑位点	治疗策略	参考文献
线粒体靶向核酸酶对线粒体进行编辑	线粒体靶向定位的锌指核酸酶	Mitochondrial zinc-finger nucleases (mtZFNs)	无	降低异质性	[121]
	线粒体靶向转录激活样效应因子核酸酶	Mitochondria-targeted transcription activator- like effector nucleases (mitoTALENs)	无		[122]
	线粒体靶向定位的巨核核酸酶	Mitochondrial-targeted ARCUS (mitoARCUS)	无		[123]
碱基编辑器对线粒体进行编辑	线粒体靶向的DddA衍生胞嘧啶碱基编辑器	Mitochondrial-targeted DddA-derived cytosine base editor (mitoDdCBE)	C>T	纠正突变位点	[124]
	TALE连接的腺嘌呤脱氨酶	TALE-linked deoxyadenosine deaminase (TALED)	A>G		[125]
	线粒体DNA碱基编辑器	Mitochondrial base editors (mitoBEs)	A>G或C>T		[126]

线粒体DNA遗传疾病及基因治疗研究现状

Current understanding of mitochondrial DNA genetic diseases and gene therapy

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