Mutant <i>C. elegans</i> mitofusin leads to selective removal of mtDNA heteroplasmic deletions at different rates across generations

Meshnik, Lana; Bar-Yaacov, Dan; Kasztan, Dana; T, Neiger; Cohen, T.; Kishner, Mor; Valenci, Itay; Dadon, Sara; Klein, Catherine J.; Jm, Vance; Nevo, Yoram; Züchner, Stephan; Mo, Dan; Ben‐Zvi, Anat

doi:10.1101/610758

Cited by 2 publications

(2 citation statements)

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“…Consistent with the importance of fragmentation in selection, recent work has also demonstrated that inducing sustained fragmentation by deleting the profusion factor fzo-1 (the C. elegans homolog of human Mitofusin 2) results in the complete and selective elimination of mutant mtDNA in the uaDf5 strain in just three generations (96). Reexpressing fzo-1 resulted in the rise of the mutant species in the population (96). Therefore, mitochondrial fragmentation appears to be necessary and sufficient for selection against mtDNA in the worm germline, as has been observed in D. melanogaster (30,90).…”

Section: Timing and Mechanisms Of Purifying Selection In Caenorhabditis Elegansmentioning

confidence: 71%

“…Whether selection is first initiated at these stages remains unknown. Consistent with the importance of fragmentation in selection, recent work has also demonstrated that inducing sustained fragmentation by deleting the profusion factor fzo-1 (the C. elegans homolog of human Mitofusin 2) results in the complete and selective elimination of mutant mtDNA in the uaDf5 strain in just three generations (96). Reexpressing fzo-1 resulted in the rise of the mutant species in the population (96).…”

Section: Timing and Mechanisms Of Purifying Selection In Caenorhabditis Elegansmentioning

confidence: 73%

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Avoiding Extinction: Recent Advances in Understanding Mechanisms of Mitochondrial DNA Purifying Selection in the Germline

Jeedigunta

Minenkova

Palozzi

et al. 2021

Annu. Rev. Genom. Hum. Genet.

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Mitochondria are unusual organelles in that they contain their own genomes, which are kept apart from the rest of the DNA in the cell. While mitochondrial DNA (mtDNA) is essential for respiration and most multicellular life, maintaining a genome outside the nucleus brings with it a number of challenges. Chief among these is preserving mtDNA genomic integrity from one generation to the next. In this review, we discuss what is known about negative (purifying) selection mechanisms that prevent deleterious mutations from accumulating in mtDNA in the germline. Throughout, we focus on the female germline, as it is the tissue through which mtDNA is inherited in most organisms and, therefore, the tissue that most profoundly shapes the genome. We discuss recent progress in uncovering the mechanisms of germline mtDNA selection, from humans to invertebrates. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Timing and Mechanisms Of Purifying Selection In Caenorhabditis Elegansmentioning

confidence: 71%

Section: Timing and Mechanisms Of Purifying Selection In Caenorhabditis Elegansmentioning

confidence: 73%

Avoiding Extinction: Recent Advances in Understanding Mechanisms of Mitochondrial DNA Purifying Selection in the Germline

Jeedigunta

Minenkova

Palozzi

et al. 2021

Annu. Rev. Genom. Hum. Genet.

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Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness

et al. 2022

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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.

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Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions at different rates across generations

Cited by 2 publications

References 47 publications

Avoiding Extinction: Recent Advances in Understanding Mechanisms of Mitochondrial DNA Purifying Selection in the Germline

Avoiding Extinction: Recent Advances in Understanding Mechanisms of Mitochondrial DNA Purifying Selection in the Germline

Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness

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