Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2024-06-05 DOI:10.1042/BCJ20230262
Tiago M Bernardino Gomes, Amy E Vincent, Katja E Menger, James B Stewart, Thomas J Nicholls
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Abstract

Human mitochondria possess a multi-copy circular genome, mitochondrial DNA (mtDNA), that is essential for cellular energy metabolism. The number of copies of mtDNA per cell, and their integrity, are maintained by nuclear-encoded mtDNA replication and repair machineries. Aberrant mtDNA replication and mtDNA breakage are believed to cause deletions within mtDNA. The genomic location and breakpoint sequences of these deletions show similar patterns across various inherited and acquired diseases, and are also observed during normal ageing, suggesting a common mechanism of deletion formation. However, an ongoing debate over the mechanism by which mtDNA replicates has made it difficult to develop clear and testable models for how mtDNA rearrangements arise and propagate at a molecular and cellular level. These deletions may impair energy metabolism if present in a high proportion of the mtDNA copies within the cell, and can be seen in primary mitochondrial diseases, either in sporadic cases or caused by autosomal variants in nuclear-encoded mtDNA maintenance genes. These mitochondrial diseases have diverse genetic causes and multiple modes of inheritance, and show notoriously broad clinical heterogeneity with complex tissue specificities, which further makes establishing genotype-phenotype relationships challenging. In this review, we aim to cover our current understanding of how the human mitochondrial genome is replicated, the mechanisms by which mtDNA replication and repair can lead to mtDNA instability in the form of large-scale rearrangements, how rearranged mtDNAs subsequently accumulate within cells, and the pathological consequences when this occurs.

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人类线粒体 DNA 复制和缺失形成的机制和病理。
人类线粒体拥有多拷贝环状基因组--线粒体 DNA(mtDNA),它对细胞能量代谢至关重要。每个细胞的 mtDNA 副本数量及其完整性由核编码的 mtDNA 复制和修复机制维持。异常的 mtDNA 复制和 mtDNA 断裂被认为会导致 mtDNA 的缺失。这些缺失的基因组位置和断点序列在各种遗传性和获得性疾病中显示出相似的模式,在正常衰老过程中也能观察到,这表明缺失的形成有一个共同的机制。然而,由于对 mtDNA 复制机制的争论不休,因此很难建立清晰、可检验的模型来说明 mtDNA 重排是如何在分子和细胞水平上产生和传播的。如果细胞内的 mtDNA 副本比例过高,这些缺失就会损害能量代谢,原发性线粒体疾病就会出现这种情况,这些疾病可能是偶发病例,也可能是由核编码的 mtDNA 维护基因中的常染色体变异引起的。这些线粒体疾病具有不同的遗传原因和多种遗传方式,临床表现出广泛的异质性和复杂的组织特异性,这使得建立基因型与表型之间的关系变得更具挑战性。在这篇综述中,我们旨在介绍我们目前对人类线粒体基因组如何复制、mtDNA 复制和修复导致大规模重排形式的 mtDNA 不稳定性的机制、重排的 mtDNA 随后如何在细胞内积累以及发生这种情况时的病理后果的理解。
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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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