Progress of therapy for mitochondrial diseases caused by mitochondrial genome mutations
YANG Zhen1, RENG Kaiqun1, GU Feng1,2
1. The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University,Changsha 410013, China; 2. Guangxiu Hospital Affiliated with Hunan Normal University /Hunan Guangxiu Hospital , Changsha 410205, China
Abstract：Mitochondrial diseases refer to a group of multi-system diseases caused by mitochondrial DNA（mtDNA）or nuclear DNA（nDNA）mutations that cause functional defects of mitochondrial metabolic enzymes,leading to adenosine triphosphate（ATP）synthesis disorders and insufficient energy production. It can involve nerves,muscles,eyes,ears,digestion,endocrine,cardiovascular,kidney and blood system alone or simultaneously. The genetic properties of mtDNA are very complex because there are multiple copies of mtDNA in each cell,and mtDNA mutations can be homogeneous（basically all mtDNA is a mutant）or heterogeneous（a mixture of mutated and wild-type mtDNA）. Dysfunction occurs only when the proportion of mutant mtDNA reaches a critical threshold. Not only can mitochondrial diseases occur at any age,but they can cause symptoms in any organ system. Therefore,it is of great significance to study gene therapy for mitochondrial diseases. The new generation of biotechnology has given birth to the treatment ideas and methods for mitochondrial diseases caused by mitochondrial genome mutations. In the present paper,we summarize the clinical application and the related exploratory research work in the research stage and highlight the bottlenecks for the treatments. It may pave a way for the development of novel therapeutic methods for mitochondrial diseases.
[1] Obrador E,Salvador-Palmer R,López-Blanch R,et al.The Link between Oxidative Stress,Redox Status,Bioenergetics and Mitochondria in the Pathophysiology of ALS[J]. Int J Mol Sci,2021,22(12):6352. [2] Nunnari J,Suomalainen A.Mitochondria:in sickness and in health[J]. Cell,2012,148(6):1145-1159. [3] Picard M,McEwen BS. Psychological Stress and Mitochondria:A Conceptual Framework[J]. Psychosom Med,2018,80(2):126-140. [4] Johnston IG,Williams BP.Evolutionary Inference across Eukaryotes Identifies Specific Pressures Favoring Mitochondrial Gene Retention[J]. Cell Syst,2016,2(2):101-111. [5] Reznik E,Miller ML,Şenbabaoğlu Y,et al.Mitochondrial DNA copy number variation across human cancers[J]. Elife,2016,5:e10769. [6] Anderson S,Bankier AT,Barrell BG,et al.Sequence and organization of the human mitochondrial genome[J]. Nature,1981,290(5806):457-465. [7] Saki M,Prakash A.DNA damage related crosstalk between the nucleus and mitochondria[J]. Free Radic Biol Med,2017,107:216-227. [8] Rossignol R,Faustin B,Rocher C,et al.Mitochondrial threshold effects[J]. Biochem J,2003,370(Pt 3):751-762. [9] Schaefer AM,Taylor RW,Turnbull DM,et al.The epidemiology of mitochondrial disorders--past,present and future[J]. Biochim Biophys Acta,2004,1659(2-3):115-120. [10] Sheng N,Zhang Z,Zheng H,et al.Scutellarin Rescued Mitochondrial Damage through Ameliorating Mitochondrial Glucose Oxidation via the Pdk‐Pdc Axis[J]. Adv Sci(Weinh),2023,10(32): e2303584. [11] Adashi EY,Rubenstein DS,Mossman JA,et al.Mitochondrial disease:Replace or edit?[J]. Science,2021,373(6560):1200-1201. [12] Zhang J,Liu H,Luo S,et al.Live birth derived from oocyte spindle transfer to prevent mitochondrial disease[J]. Reprod Biomed Online,2017,34(4):361-368. [13] Fan XY,Guo L,Chen LN,et al.Reduction of mtDNA heteroplasmy in mitochondrial replacement therapy by inducing forced mitophagy[J]. Nat Biomed Eng,2022,6(4):339-350. [14] Sharma H,Singh D,Mahant A,et al.Development of mitochondrial replacement therapy:A review[J]. Heliyon,2020,6(9):e04643. [15] Reddy P,Ocampo A,Suzuki K,et al.Selective elimination of mitochondrial mutations in the germline by genome editing[J]. Cell,2015,161(3):459-469. [16] Bacman SR,Kauppila JHK,Pereira CV,et al.MitoTALEN reduces mutant mtDNA load and restores tRNA(Ala)levels in a mouse model of heteroplasmic mtDNA mutation[J]. Nat Med,2018,24(11):1696-1700. [17] Komor AC,Kim YB,Packer MS,et al.Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage[J]. Nature,2016,533(7603):420-424. [18] Gammage PA,Moraes CT,Minczuk M.Mitochondrial Genome Engineering:The Revolution May Not Be CRISPR-Ized[J]. Trends Genet,2018,34(2):101-110. [19] Wang G,Chen HW,Oktay Y,et al.PNPASE regulates RNA import into mitochondria[J]. Cell,2010,142(3):456-467. [20] Hussain SA,Yalvac ME,Khoo B,et al.Adapting CRISPR/Cas9 System for Targeting Mitochondrial Genome[J]. Front Genet,2021,12:627050. [21] Wang B,Lv X,Wang Y,et al.CRISPR/Cas9-mediated mutagenesis at microhomologous regions of human mitochondrial genome[J]. Sci China Life Sci,2021,64(9):1463-1472. [22] Mok BY,De Moraes MH,Zeng J,et al.A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing[J]. Nature,2020,583(7817):631-637. [23] Mok BY,Kotrys AV,Raguram A,et al.CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA[J]. Nat Biotechnol,2022,40(9):1378-1387. [24] Mi L,Shi M,Li YX,et al.DddA homolog search and engineering expand sequence compatibility of mitochondrial base editing[J]. Nat Commun,2023,14(1):874. [25] Guo J,Yu W,Li M,et al. A DddA ortholog-based and transactivator-assisted nuclear and mitochondrial cytosine base editors with expanded target compatibility [J]. Mol Cell,2023,83(10):1710-1724. e7. [26] Cho SI,Lee S,Mok YG,et al. Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases [J]. Cell,2022,185(10):1764-1776. e12. [27] Mok YG,Hong S,Bae SJ,et al.Targeted A-to-G base editing of chloroplast DNA in plants[J]. Nat Plants,2022,8(12):1378-1384. [28] Huang J,Lin Q,Fei H,et al. Discovery of deaminase functions by structure-based protein clustering [J]. Cell,2023,186(15):3182-3195. e14. [29] Lei Z,Meng H,Liu L,et al.Mitochondrial base editor induces substantial nuclear off-target mutations[J]. Nature,2022,606(7915):804-811. [30] Wei Y,Li Z,Xu K,et al.Mitochondrial base editor DdCBE causes substantial DNA off-target editing in nuclear genome of embryos[J]. Cell Discov,2022,8(1):27. [31] Lee S,Lee H,Baek G,et al.Precision mitochondrial DNA editing with high-fidelity DddA-derived base editors[J]. Nat Biotechnol,2023,41(3):378-386. [32] Bi C,Wang L,Fan Y,et al.Single-cell individual full-length mtDNA sequencing by iMiGseq uncovers unexpected heteroplasmy shifts in mtDNA editing[J]. Nucleic Acids Res,2023,51(8):e48. [33] Bi C,Wang L,Fan Y,et al.Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes,blastoids,and pluripotent stem cells[J]. Nucleic Acids Res,2023,51(8):3793-3805. [34] Mok YG,Lee JM,Chung E,et al.Base editing in human cells with monomeric DddA-TALE fusion deaminases[J]. Nat Commun,2022,13(1):4038. [35] Wei Y,Xu C,Feng H,et al.Human cleaving embryos enable efficient mitochondrial base-editing with DdCBE[J]. Cell Discov,2022,8(1):7. [36] Chen X,Liang D,Guo J,et al.DdCBE-mediated mitochondrial base editing in human 3PN embryos[J]. Cell Discov,2022,8(1):8. [37] Guo J,Zhang X,Chen X,et al.Precision modeling of mitochondrial diseases in zebrafish via DdCBE-mediated mtDNA base editing[J]. Cell Discov,2021,7(1):78. [38] Silva-Pinheiro P,Nash PA,Van Haute L,et al.In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue[J]. Nat Commun,2022,13(1):750. [39] Qi X,Tan L,Zhang X,et al.Expanding DdCBE-mediated targeting scope to aC motif preference in rat[J]. Mol Ther Nucleic Acids,2023,32:1-12. [40] Tan L,Qi X,Kong W,et al. A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon [J]. Sci Adv,2023,9(15):eadf2695. [41] Yi Z,Zhang X,Tang W,et al. Strand-selective base editing of human mitochondrial DNA using mitoBEs [J]. Nat Biotechnol,2023,Online ahead of print. [42] Hu J,Sun Y,Li B,et al. Strand-preferred base editing of organellar and nuclear genomes using CyDENT [J]. Nat Biotechnol,2023,Online ahead of print.
2023, Vol. 20 
