While it is well understood that mitochondrial DNA (mtDNA) deletion mutations cause incurable diseases and contribute to aging, little is known about the transcriptional products that arise from these DNA structural variants. We hypothesized that mitochondrial genomes containing deletion mutations express chimeric mitochondrial RNAs. To test this, we analyzed human and rat RNA sequencing data to identify, quantitate, and characterize chimeric mitochondrial RNAs. We observed increased chimeric mitochondrial RNA frequency in samples from patients with mitochondrial genetic diseases and in samples from aged humans. The spectrum of chimeric mitochondrial transcripts reflected the known pattern of mtDNA deletion mutations. To test the hypothesis that mtDNA deletions induce chimeric RNA transcripts, we treated 18 mo and 34 mo rats with guanidinopropionic acid to induce high levels of skeletal muscle mtDNA deletion mutations. With mtDNA deletion induction, we demonstrate that the chimeric mitochondrial transcript frequency also increased and correlated strongly with an orthogonal DNA-based mutation assay performed on identical samples. Further, we show that the frequency of chimeric mitochondrial transcripts predicts expression of both nuclear and mitochondrial genes central to mitochondrial function, demonstrating the utility of these events as metrics of age-induced metabolic change. Mapping and quantitation of chimeric mitochondrial RNAs provides an accessible, orthogonal approach to DNA-based mutation assays, offers a potential method for identifying mitochondrial pathology in widely accessible datasets, and opens a new area of study in mitochondrial genetics and transcriptomics.

中文翻译：

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嵌合线粒体 RNA 转录本可预测线粒体遗传病和衰老中的线粒体基因组缺失突变


虽然众所周知，线粒体 DNA （mtDNA） 缺失突变会导致不治之症并导致衰老，但人们对这些 DNA 结构变异产生的转录产物知之甚少。我们假设包含缺失突变的线粒体基因组表达嵌合线粒体 RNA。为了测试这一点，我们分析了人类和大鼠的 RNA 测序数据，以识别、定量和表征嵌合线粒体 RNA。我们观察到线粒体遗传病患者样本和老年人样本中的嵌合线粒体 RNA 频率增加。嵌合线粒体转录本的谱反映了 mtDNA 缺失突变的已知模式。为了检验 mtDNA 缺失诱导嵌合 RNA 转录本的假设，我们用胍基丙酸处理 18 个月和 34 个月的大鼠以诱导高水平的骨骼肌 mtDNA 缺失突变。通过 mtDNA 缺失诱导，我们证明嵌合线粒体转录频率也增加，并且与对相同样本进行的基于正交 DNA 的突变测定密切相关。此外，我们表明嵌合线粒体转录物的频率预测了对线粒体功能至关重要的核基因和线粒体基因的表达，证明了这些事件作为年龄诱导的代谢变化指标的效用。嵌合线粒体 RNA 的定位和定量为基于 DNA 的突变测定提供了一种可访问的正交方法，为在广泛可访问的数据集中鉴定线粒体病理学提供了一种潜在的方法，并开辟了线粒体遗传学和转录组学的新研究领域。