Current understanding of mitochondrial DNA genetic diseases and gene therapy
Received date: 2025-02-07
Revised date: 2025-05-23
Online published: 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)
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
Cheng Tang, Shunqing Xu, Hanzeng Li . Current understanding of mitochondrial DNA genetic diseases and gene therapy[J]. Hereditas(Beijing), 2025 , 47(12) : 1300 -1325 . DOI: 10.16288/j.yczz.25-032
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