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

Lana Meshnik,Dan Mishmar,Dana Kasztan,Dan Bar-Yaacov,Tal Cohen,Ofer Ovadia,Yoram Nevo,Stephan Züchner,Jeffery M Vance,Itay Valenci,Sara Dadon,Christopher J Klein,Anat Ben-Zvi,Mor Kishner,Tali Neiger

doi:10.1186/s12915-022-01241-2

Abstract

BackgroundMitochondrial 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.ResultsWe 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.ConclusionsTaken 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.

Highlights

IntroductionMitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though character‐ ized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy)
Mitochondrial DNA is present at high copy numbers in animal cells, and though character‐ ized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist
A heteroplasmic deletion reduces the fitness of C. elegans mitofusin mutant The stable heteroplasmic C. elegans strain uaDf5/+ harbors a mixture of intact (+mtDNA) and ~ 60% of a 3.1 kb mtDNA deletion (ΔmtDNA) [27]

Summary

Introduction

Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though character‐ ized 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, mitochon‐ drial 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. Reduction in heteroplasmy levels of potentially deleterious mtDNA mutations was observed when components of the fusion machinery were compromised in Drosophila model systems, especially in germ cells [12, 21, 22] In consistence with this notion, cell culture experiments revealed that a mixture of mtDNA molecules differing in sequence in the same cell can complement each other by the diffusion of products via the mitochondrial network, which in turn leads to restoration of mitochondrial function [1, 15, 16, 23]. We hypothesized that interfering with the intracellular mitochondrial network by compromising the fusion machinery would hamper mitochondrial functional complementation and impede the inheritance of heteroplasmic mutants

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Discussion

Conclusion