Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
Abstract Background Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of fact...
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| Format: | Article |
| Language: | English |
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BMC
2022-02-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-022-01241-2 |
| _version_ | 1818330554766983168 |
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| author | Lana Meshnik Dan Bar-Yaacov Dana Kasztan Tali Neiger Tal Cohen Mor Kishner Itay Valenci Sara Dadon Christopher J. Klein Jeffery M. Vance Yoram Nevo Stephan Züchner Ofer Ovadia Dan Mishmar Anat Ben-Zvi |
| author_facet | Lana Meshnik Dan Bar-Yaacov Dana Kasztan Tali Neiger Tal Cohen Mor Kishner Itay Valenci Sara Dadon Christopher J. Klein Jeffery M. Vance Yoram Nevo Stephan Züchner Ofer Ovadia Dan Mishmar Anat Ben-Zvi |
| author_sort | Lana Meshnik |
| collection | DOAJ |
| description | Abstract Background Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network. Here, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. Results We assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin (fzo-1). Animals displayed severe embryonic lethality and developmental delay. Strikingly, observed phenotypes were relieved during subsequent generations in association with complete loss of ΔmtDNA molecules. Moreover, deletion loss rates were negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. Introducing the ΔmtDNA into a fzo-1;pdr-1;+/ΔmtDNA (PARKIN ortholog) double mutant resulted in a skewed Mendelian progeny distribution, in contrast to the normal distribution in the fzo-1;+/ΔmtDNA mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. Conclusions Taken together, our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection while inherited through generations. Moreover, our findings underline the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. |
| first_indexed | 2024-12-13T13:05:48Z |
| format | Article |
| id | doaj.art-b201b8a14eb44511992dfb57115e956e |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-13T13:05:48Z |
| publishDate | 2022-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-b201b8a14eb44511992dfb57115e956e2022-12-21T23:44:50ZengBMCBMC Biology1741-70072022-02-0120111710.1186/s12915-022-01241-2Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitnessLana Meshnik0Dan Bar-Yaacov1Dana Kasztan2Tali Neiger3Tal Cohen4Mor Kishner5Itay Valenci6Sara Dadon7Christopher J. Klein8Jeffery M. Vance9Yoram Nevo10Stephan Züchner11Ofer Ovadia12Dan Mishmar13Anat Ben-Zvi14Department of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Neurology, Department of Laboratory Medicine and Pathology, Mayo ClinicDr. John T. Macdonald Foundation Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of MiamiInstitute of Neurology, Schneider Children’s Medical Center of Israel, Tel-Aviv UniversityDr. John T. Macdonald Foundation Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of MiamiDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the NegevAbstract Background Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network. Here, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. Results We assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin (fzo-1). Animals displayed severe embryonic lethality and developmental delay. Strikingly, observed phenotypes were relieved during subsequent generations in association with complete loss of ΔmtDNA molecules. Moreover, deletion loss rates were negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. Introducing the ΔmtDNA into a fzo-1;pdr-1;+/ΔmtDNA (PARKIN ortholog) double mutant resulted in a skewed Mendelian progeny distribution, in contrast to the normal distribution in the fzo-1;+/ΔmtDNA mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. Conclusions Taken together, our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection while inherited through generations. Moreover, our findings underline the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy.https://doi.org/10.1186/s12915-022-01241-2C. elegansfzo-1Heteroplasmy inheritanceMitofusinmtDNAPARKIN |
| spellingShingle | Lana Meshnik Dan Bar-Yaacov Dana Kasztan Tali Neiger Tal Cohen Mor Kishner Itay Valenci Sara Dadon Christopher J. Klein Jeffery M. Vance Yoram Nevo Stephan Züchner Ofer Ovadia Dan Mishmar Anat Ben-Zvi Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness BMC Biology C. elegans fzo-1 Heteroplasmy inheritance Mitofusin mtDNA PARKIN |
| title | Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness |
| title_full | Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness |
| title_fullStr | Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness |
| title_full_unstemmed | Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness |
| title_short | Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness |
| title_sort | mutant c elegans mitofusin leads to selective removal of mtdna heteroplasmic deletions across generations to maintain fitness |
| topic | C. elegans fzo-1 Heteroplasmy inheritance Mitofusin mtDNA PARKIN |
| url | https://doi.org/10.1186/s12915-022-01241-2 |
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