A role for BCL2L13 and autophagy in germline purifying selection of mtDNA

Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mut...

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Published inPLoS genetics Vol. 19; no. 1; p. e1010573
Main Authors Kremer, Laura S., Bozhilova, Lyuba V., Rubalcava-Gracia, Diana, Filograna, Roberta, Upadhyay, Mamta, Koolmeister, Camilla, Chinnery, Patrick F., Larsson, Nils-Göran
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 06.01.2023
Public Library of Science (PLoS)
Subjects
Analysis
Animal models
Animals
Autophagy
Autophagy (Cytology)
Autophagy - genetics
Biology and Life Sciences
Cell death
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Engineering and Technology
Female
Females
Gene expression
Gene mutations
Genetic aspects
Genetic engineering
Genetic research
Germ Cells - metabolism
Health aspects
Infectious Disease Transmission, Vertical
Kinases
Mammals - genetics
Methods
Mice
Mitochondria
Mitochondria - genetics
Mitochondrial diseases
Mitochondrial DNA
Molecular modelling
Mothers
Mutation
Parkin protein
Prevention
Proteins
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Recombination
Research and Analysis Methods
Risk factors
Statistical analysis
Stochasticity
Sweden
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Abstract Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNA Ala gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin , Bcl2l13 , Ulk1 , and Ulk2 . Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2 , while no statistically significant impact is seen for knockout of Parkin . This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.
AbstractList Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNAAla gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.
Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNA Ala gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin , Bcl2l13 , Ulk1 , and Ulk2 . Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2 , while no statistically significant impact is seen for knockout of Parkin . This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes. We have addressed the role of autophagy on purifying selection of mtDNA by mating different autophagy-deficient mouse models, including knockouts of Parkin , Bcl2l13 , Ulk1 , and Ulk2 , to female mice with high levels of the pathogenic tRNA Ala gene mutation. We identified a robust effect of Bcl2l13 on the selection process, weaker effects of Ulk1 and Ulk2 , whereas Parkin had no statistically significant impact. Our study thus provides strong experimental evidence for distinctive roles of autophagy in germline purifying selection of mtDNA. Furthermore, the experimental strategy and statistical methods we have developed in the manuscript provide a novel framework for future studies of the enigmatic purifying selection process in mammals.
Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNA.sup.Ala gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.
Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNAAla gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNAAla gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin, Bcl2l13, Ulk1, and Ulk2. Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2, while no statistically significant impact is seen for knockout of Parkin. This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.
Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as deleterious mtDNA mutations must be eliminated to avoid a mutational meltdown over generations. At least two mechanisms that can decrease the mutation load during maternal transmission are operational: a stochastic bottleneck for mtDNA transmission from mother to child, and a directed purifying selection against transmission of deleterious mtDNA mutations. However, the molecular mechanisms controlling these processes remain unknown. In this study, we systematically tested whether decreased autophagy contributes to purifying selection by crossing the C5024T mouse model harbouring a single pathogenic heteroplasmic mutation in the tRNA Ala gene of the mtDNA with different autophagy-deficient mouse models, including knockouts of Parkin , Bcl2l13 , Ulk1 , and Ulk2 . Our study reveals a statistically robust effect of knockout of Bcl2l13 on the selection process, and weaker evidence for the effect of Ulk1 and potentially Ulk2 , while no statistically significant impact is seen for knockout of Parkin . This points at distinctive roles of these players in germline purifying selection. Overall, our approach provides a framework for investigating the roles of other important factors involved in the enigmatic process of purifying selection and guides further investigations for the role of BCL2L13 in the elimination of non-synonymous mutations in protein-coding genes.
Audience Academic
Author Koolmeister, Camilla
Upadhyay, Mamta
Chinnery, Patrick F.
Filograna, Roberta
Kremer, Laura S.
Larsson, Nils-Göran
Rubalcava-Gracia, Diana
Bozhilova, Lyuba V.
AuthorAffiliation 3 Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
1 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
2 MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
University of Cologne, GERMANY
AuthorAffiliation_xml – name: 3 Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
– name: 2 MRC Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
– name: 1 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
– name: University of Cologne, GERMANY
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  givenname: Laura S.
  surname: Kremer
  fullname: Kremer, Laura S.
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  surname: Bozhilova
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– sequence: 3
  givenname: Diana
  surname: Rubalcava-Gracia
  fullname: Rubalcava-Gracia, Diana
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  surname: Filograna
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  orcidid: 0000-0001-7092-0468
  surname: Upadhyay
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  surname: Larsson
  fullname: Larsson, Nils-Göran
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License Copyright: © 2023 Kremer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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I have read the journal’s policy and the authors of this manuscript have the following competing interests: N.G.L. is inventor of the C5024T mutant mouse licensed to the pharmaceutical industry by the Max Planck Society. N.G.L. is a scientific founder and holds stock in Pretzel Therapeutics Inc. The other authors have no competing interests.
ORCID 0000-0001-7092-0468
0000-0003-2784-2040
0000-0002-7065-6617
0000-0001-5100-996X
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Snippet Mammalian mitochondrial DNA (mtDNA) is inherited uniparentally through the female germline without undergoing recombination. This poses a major problem as...
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SubjectTerms Analysis
Animal models
Animals
Autophagy
Autophagy (Cytology)
Autophagy - genetics
Biology and Life Sciences
Cell death
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Engineering and Technology
Female
Females
Gene expression
Gene mutations
Genetic aspects
Genetic engineering
Genetic research
Germ Cells - metabolism
Health aspects
Infectious Disease Transmission, Vertical
Kinases
Mammals - genetics
Methods
Mice
Mitochondria
Mitochondria - genetics
Mitochondrial diseases
Mitochondrial DNA
Molecular modelling
Mothers
Mutation
Parkin protein
Prevention
Proteins
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Recombination
Research and Analysis Methods
Risk factors
Statistical analysis
Stochasticity
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Title A role for BCL2L13 and autophagy in germline purifying selection of mtDNA
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