Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.

线粒体携带自己的遗传信息，编码蛋白质编码基因的子集和细胞呼吸和代谢所必需的翻译机制。尽管线粒体基因组很小，但由于其细胞拷贝数的变化、非孟德尔遗传模式和突变倾向，使用批量测序方法研究线粒体基因组、其自然遗传变异和分子表型一直具有挑战性。在这里，我们重点介绍旨在捕获单个细胞间线粒体遗传变异的新兴策略，用于谱系追踪和研究原代人类细胞和临床标本中的线粒体遗传学。我们回顾了单细胞线粒体基因组测序及其与功能基因组读数整合的最新进展，包括利用体细胞线粒体 DNA 突变作为克隆标记，可以解决复杂人体组织中的细胞群体动态。最后，我们讨论如何利用单细胞全线粒体基因组测序方法来研究线粒体遗传学及其对细胞异质性和疾病的贡献。