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

BMC Biology

Anat Ben-Zvi¹  Dana Kasztan¹  Sara Dadon¹  Ofer Ovadia¹  Lana Meshnik¹  Mor Kishner¹  Tal Cohen¹  Dan Mishmar¹  Tali Neiger¹  Itay Valenci¹  Dan Bar-Yaacov²  Christopher J. Klein³  Jeffery M. Vance⁴  Stephan Züchner⁴  Yoram Nevo⁵ 

[1] Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel;Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel;Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer Sheva, Israel;Department of Neurology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;Dr. John T. Macdonald Foundation Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA;Institute of Neurology, Schneider Children’s Medical Center of Israel, Tel-Aviv University, Petach Tikva, Israel;

关键词: C. elegans;    fzo-1;    Heteroplasmy inheritance;    Mitofusin;    mtDNA;    PARKIN;    pdr-1;   

DOI  :  10.1186/s12915-022-01241-2

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY