The mitochondrial DNA (mtDNA) is replicated and canonically functions within intracellular mitochondria, but recent discoveries reveal that the mtDNA has another exciting extracellular life. mtDNA fragments and mitochondria-containing vesicular structures are detected at high concentrations in cell-free forms, in different biofluids. Commonly referred to as cell-free mtDNA (cf-mtDNA), the field is currently without a comprehensive classification system that acknowledges the various biological forms of mtDNA and whole mitochondria existing outside the cell. This absence of classification hampers the creation of precise and consistent quantification methods across different laboratories, which is crucial for unraveling the molecular and biological characteristics of mtDNA. In this article, we integrate recent findings to propose a classification for different types of Extracellular mtDNA [ex-mtDNA]. The major biologically distinct types include: Naked mtDNA [N-mtDNA], mtDNA within non-mitochondrial Membranes [M-mtDNA], Extracellular mitochondria [exM-mtDNA], and mtDNA within Mitochondria enclosed in a Membrane [MM-mtDNA]. We outline the challenges associated with accurately quantifying these ex-mtDNA types, suggest potential physiological roles for each ex-mtDNA type, and explore how this classification could establish a foundation for future research endeavors and further analysis and definitions for ex-mtDNA. By proposing this classification of circulating mtDNA forms, we draw a parallel with the clinically recognized forms of cholesterol, such as HDL and LDL, to illustrate potential future significance in a similar manner. While not directly analogous, these mtDNA forms may one day be as biologically relevant in clinical interpretation as cholesterol fractions are currently. We also discuss how advancing methodologies to reliably quantify distinct ex-mtDNA forms could significantly enhance their utility as health or disease biomarkers, and how their application may offer innovative therapeutic approaches.

中文翻译：

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解读细胞外 mtDNA 的性质和复杂性：类型及其对健康和疾病的影响

线粒体 DNA (mtDNA) 在细胞内线粒体内复制并正常发挥作用，但最近的发现表明，mtDNA 还具有另一种令人兴奋的细胞外生命。在不同的生物流体中以无细胞形式检测到高浓度的 mtDNA 片段和含有线粒体的囊泡结构。通常被称为无细胞 mtDNA (cf-mtDNA)，该领域目前还没有一个全面的分类系统来承认细胞外存在的 mtDNA 和整个线粒体的各种生物形式。这种分类的缺乏阻碍了不同实验室之间精确、一致的定量方法的创建，而这对于揭示 mtDNA 的分子和生物学特征至关重要。在本文中，我们整合了最新的研究结果，提出了不同类型的细胞外 mtDNA [ex-mtDNA] 的分类。主要的生物学不同类型包括：裸 mtDNA [N-mtDNA]、非线粒体膜内的 mtDNA [M-mtDNA]、细胞外线粒体 [exM-mtDNA] 和膜内封闭的线粒体内的 mtDNA [MM-mtDNA]。我们概述了与准确量化这些前线粒体DNA类型相关的挑战，提出了每种前线粒体DNA类型的潜在生理作用，并探讨了这种分类如何为未来的研究工作以及前线粒体DNA的进一步分析和定义奠定基础。通过提出这种循环 mtDNA 形式的分类，我们将其与临床上公认的胆固醇形式（例如 HDL 和 LDL）进行了比较，以类似的方式说明未来的潜在意义。虽然不直接相似，但这些 mtDNA 形式有一天可能会像目前的胆固醇分数一样在临床解释中具有生物学相关性。我们还讨论了先进的方法学来可靠地量化不同的前线粒体DNA形式可以显着增强它们作为健康或疾病生物标志物的效用，以及它们的应用如何提供创新的治疗方法。