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Identification of unique and shared mitochondrial DNA mutations in neurodegeneration and cancer by single-cell mitochondrial DNA structural variation sequencing (MitoSV-seq)

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@article{c54791712571415ebdf0afccd2a52396,
title = "Identification of unique and shared mitochondrial DNA mutations in neurodegeneration and cancer by single-cell mitochondrial DNA structural variation sequencing (MitoSV-seq)",
abstract = "BACKGROUND: Point mutations and structural variations (SVs) in mitochondrial DNA (mtDNA) contribute to many neurodegenerative diseases. Technical limitations and heteroplasmy, however, have impeded their identification, preventing these changes from being examined in neurons in healthy and disease states.METHODS: We have developed a high-resolution technique-Mitochondrial DNA Structural Variation Sequencing (MitoSV-seq)-that identifies all types of mtDNA SVs and single-nucleotide variations (SNVs) in single neurons and novel variations that have been undetectable with conventional techniques.FINDINGS: Using MitoSV-seq, we discovered SVs/SNVs in dopaminergic neurons in the Ifnar1-/- murine model of Parkinson disease. Further, MitoSV-seq was found to have broad applicability, delivering high-quality, full-length mtDNA sequences in a species-independent manner from human PBMCs, haematological cancers, and tumour cell lines, regardless of heteroplasmy. We characterised several common SVs in haematological cancers (AML and MDS) that were linked to the same mtDNA region, MT-ND5, using only 10 cells, indicating the power of MitoSV-seq in determining single-cancer-cell ontologies. Notably, the MT-ND5 hotspot, shared between all examined cancers and Ifnar1-/- dopaminergic neurons, suggests that its mutations have clinical value as disease biomarkers.INTERPRETATION: MitoSV-seq identifies disease-relevant mtDNA mutations in single cells with high resolution, rendering it a potential drug screening platform in neurodegenerative diseases and cancers.FUNDING: The Lundbeck Foundation, Danish Council for Independent Research-Medicine, and European Union Horizon 2020 Research and Innovation Programme.",
keywords = "Disease biomarker, Mitochondrial DNA, Neurodegeneration, Neuron, Single-Cell Sequencing",
author = "Elham Jaberi and Emilie Tresse and Kirsten Gr{\o}nb{\ae}k and Joachim Weischenfeldt and Shohreh Issazadeh-Navikas",
note = "Copyright {\textcopyright} 2020 The Author(s). Published by Elsevier B.V. All rights reserved.",
year = "2020",
month = jul,
doi = "10.1016/j.ebiom.2020.102868",
language = "English",
volume = "57",
pages = "102868",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

RIS

TY - JOUR

T1 - Identification of unique and shared mitochondrial DNA mutations in neurodegeneration and cancer by single-cell mitochondrial DNA structural variation sequencing (MitoSV-seq)

AU - Jaberi, Elham

AU - Tresse, Emilie

AU - Grønbæk, Kirsten

AU - Weischenfeldt, Joachim

AU - Issazadeh-Navikas, Shohreh

N1 - Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

PY - 2020/7

Y1 - 2020/7

N2 - BACKGROUND: Point mutations and structural variations (SVs) in mitochondrial DNA (mtDNA) contribute to many neurodegenerative diseases. Technical limitations and heteroplasmy, however, have impeded their identification, preventing these changes from being examined in neurons in healthy and disease states.METHODS: We have developed a high-resolution technique-Mitochondrial DNA Structural Variation Sequencing (MitoSV-seq)-that identifies all types of mtDNA SVs and single-nucleotide variations (SNVs) in single neurons and novel variations that have been undetectable with conventional techniques.FINDINGS: Using MitoSV-seq, we discovered SVs/SNVs in dopaminergic neurons in the Ifnar1-/- murine model of Parkinson disease. Further, MitoSV-seq was found to have broad applicability, delivering high-quality, full-length mtDNA sequences in a species-independent manner from human PBMCs, haematological cancers, and tumour cell lines, regardless of heteroplasmy. We characterised several common SVs in haematological cancers (AML and MDS) that were linked to the same mtDNA region, MT-ND5, using only 10 cells, indicating the power of MitoSV-seq in determining single-cancer-cell ontologies. Notably, the MT-ND5 hotspot, shared between all examined cancers and Ifnar1-/- dopaminergic neurons, suggests that its mutations have clinical value as disease biomarkers.INTERPRETATION: MitoSV-seq identifies disease-relevant mtDNA mutations in single cells with high resolution, rendering it a potential drug screening platform in neurodegenerative diseases and cancers.FUNDING: The Lundbeck Foundation, Danish Council for Independent Research-Medicine, and European Union Horizon 2020 Research and Innovation Programme.

AB - BACKGROUND: Point mutations and structural variations (SVs) in mitochondrial DNA (mtDNA) contribute to many neurodegenerative diseases. Technical limitations and heteroplasmy, however, have impeded their identification, preventing these changes from being examined in neurons in healthy and disease states.METHODS: We have developed a high-resolution technique-Mitochondrial DNA Structural Variation Sequencing (MitoSV-seq)-that identifies all types of mtDNA SVs and single-nucleotide variations (SNVs) in single neurons and novel variations that have been undetectable with conventional techniques.FINDINGS: Using MitoSV-seq, we discovered SVs/SNVs in dopaminergic neurons in the Ifnar1-/- murine model of Parkinson disease. Further, MitoSV-seq was found to have broad applicability, delivering high-quality, full-length mtDNA sequences in a species-independent manner from human PBMCs, haematological cancers, and tumour cell lines, regardless of heteroplasmy. We characterised several common SVs in haematological cancers (AML and MDS) that were linked to the same mtDNA region, MT-ND5, using only 10 cells, indicating the power of MitoSV-seq in determining single-cancer-cell ontologies. Notably, the MT-ND5 hotspot, shared between all examined cancers and Ifnar1-/- dopaminergic neurons, suggests that its mutations have clinical value as disease biomarkers.INTERPRETATION: MitoSV-seq identifies disease-relevant mtDNA mutations in single cells with high resolution, rendering it a potential drug screening platform in neurodegenerative diseases and cancers.FUNDING: The Lundbeck Foundation, Danish Council for Independent Research-Medicine, and European Union Horizon 2020 Research and Innovation Programme.

KW - Disease biomarker

KW - Mitochondrial DNA

KW - Neurodegeneration

KW - Neuron

KW - Single-Cell Sequencing

UR - http://www.scopus.com/inward/record.url?scp=85087206293&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2020.102868

DO - 10.1016/j.ebiom.2020.102868

M3 - Journal article

C2 - 32629384

VL - 57

SP - 102868

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 102868

ER -

ID: 62030525