Abstract

Heteroplasmy refers to the coexistence of more than one variant of the mitochondrial genome (mtDNA). Mutated or partially deleted mtDNAs can induce chronic metabolic impairment and cause mitochondrial diseases when their heteroplasmy levels exceed a critical threshold. These mutant mtDNAs can be maternally inherited or can arise de novo. Compelling evidence has emerged showing that mutant mtDNA levels can vary and change in a nonrandom fashion across generations and amongst tissues of an individual. However, our lack of understanding of the basic cellular and molecular mechanisms of mtDNA heteroplasmy dynamics has made it difficult to predict who will inherit or develop mtDNA-associated diseases. More recently, with the advances in technology and the establishment of tractable model systems, insights into the mechanisms underlying the selection forces that modulate heteroplasmy dynamics are beginning to emerge. In this review, we summarize evidence from different organisms, showing that mutant mtDNA can experience both positive and negative selection. We also review the recently identified mechanisms that modulate heteroplasmy dynamics. Taken together, this is an opportune time to survey the literature and to identify key cellular pathways that can be targeted to develop therapies for diseases caused by heteroplasmic mtDNA mutations.

摘要

异质性是指线粒体基因组（mtDNA）的一种以上变体共存。当线粒体DNA的异质性水平超过临界阈值时，突变或部分缺失的线粒体DNA可诱发慢性代谢损伤并导致线粒体疾病。这些突变的 mtDNA 可以是母系遗传的，也可以是从头产生的。令人信服的证据表明，突变 mtDNA 水平可以在代际和个体组织之间以非随机方式变化和变化。然而，我们对 mtDNA 异质性动力学的基本细胞和分子机制缺乏了解，导致很难预测谁将遗传或发展 mtDNA 相关疾病。最近，随着技术的进步和易于处理的模型系统的建立，对调节异质性动力学的选择力背后的机制的见解开始出现。在这篇综述中，我们总结了来自不同生物体的证据，表明突变体 mtDNA 可以经历正选择和负选择。我们还回顾了最近发现的调节异质性动力学的机制。综合起来，