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Mitochondrial genetics through the lens of single-cell multi-omics

Nature Genetics volume 56, pages 1355–1365 (2024)Cite this article

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Abstract

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.

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Fig. 1: Fundamental aspects of mitochondrial genetics.
Fig. 2: Emerging biomedical research avenues of mtDNA.
Fig. 3: Overview of single-cell multi-omic assays for genomic profiling and the co-detection of mtDNA mutations.
Fig. 4: Revealing in situ clonal tracing by mtDNA genetic variation.
Fig. 5: Examples of biological insights into hematopoiesis and the immune system afforded by single-cell mtDNA sequencing.

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Acknowledgements

We are grateful to the members of the Lareau and Ludwig labs for valuable discussions. This work was supported by NIH K99/R00 HG012579 (C.A.L.), UM1 HG012076 (C.A.L. and L.S.L.), the MDC-NYU exchange program (L.N.), the Hector Fellow Academy (L.N. and L.S.L.), a Longevity Impetus Grant (L.S.L.), the Paul Ehrlich Foundation (L.S.L.), the EMBO Young Investigator Programme (L.S.L.), an Emmy Noether fellowship (LU 2336/2-1) and grants by the German Research Foundation (DFG, LU 2336/3-1, LU 2336/6-1, STA 1586/5-1, TRR241, SFB1588, Heinz Maier-Leibnitz Award to L.S.L.). Individual figures and panels were created with BioRender.com. We apologize to all our colleagues whose work could not be specifically mentioned due to space restrictions.

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Authors and Affiliations

  1. Berlin Institute of Health at Charité Universitätsmedizin Berlin, Berlin, Germany

    Lena Nitsch & Leif S. Ludwig

  2. Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association, Berlin Institute for Medical Systems Biology, Berlin, Germany

    Lena Nitsch & Leif S. Ludwig

  3. Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany

    Lena Nitsch

  4. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Caleb A. Lareau

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L.N., C.A.L. and L.S.L. conceived and wrote the manuscript.

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Correspondence to Caleb A. Lareau or Leif S. Ludwig.

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The Broad Institute has filed for patents relating to the use of technologies described in this paper where C.A.L. and L.S.L., are named inventors (US patent applications 17/251,451 and 17/928,696). C.A.L. and L.S.L. are consultants to Cartography Biosciences. L.N. declares no competing interests.

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Nitsch, L., Lareau, C.A. & Ludwig, L.S. Mitochondrial genetics through the lens of single-cell multi-omics. Nat Genet 56, 1355–1365 (2024). https://doi.org/10.1038/s41588-024-01794-8

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