TY - JOUR
T1 - Mutant C. Elegans Mitofusin Leads to Selective Removal of mtDNA Heteroplasmic Deletions Across Generations to Maintain Fitness
AU - Meshnik, Lana
AU - Bar-Yaacov, Dan
AU - Kasztan, Dana
AU - Neiger, Tali
AU - Cohen, Tal
AU - Kishner, Mor
AU - Valenci, Itay
AU - Dadon, Sara
AU - Klein, Christopher J
AU - Vance, Jeffery M
AU - Nevo, Yoram
AU - Züchner, Stephan
AU - Ovadia, Ofer
AU - Mishmar, Dan
AU - Ben-Zvi, Anat
N1 - Funding Information:
Strains, CU5991, VC1024, and LB138 (after outcrossing ABZ271, ABZ283, and ABZ270, respectively), were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). Strains, VC40128 and VC20469 (after outcrossing ABZ275 and ABZ279, respectively), were provided by the C. elegans Reverse Genetics Core Facility at the University of British Columbia, which is part of the international C. elegans Gene Knockout Consortium.
Funding Information:
This study was funded by the Israel Science Foundation (ISF) grant 278/18 to ABZ and grant 372/17 to DM. L.M. was supported by the Ministry of Science and Technology, Yitzhak Navon Ph.D. fellowship, and Kreitman Biotech scholarship. D.B. and T.C. were supported by the Kreitman Negev scholarships.
Funding Information:
Strains, CU5991, VC1024, and LB138 (after outcrossing ABZ271, ABZ283, and ABZ270, respectively), were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2/9
Y1 - 2022/2/9
N2 - 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.
AB - 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.
KW - C. elegans
KW - fzo-1
KW - Heteroplasmy inheritance
KW - Mitofusin
KW - mtDNA
KW - PARKIN
KW - pdr-1
UR - http://www.scopus.com/inward/record.url?scp=85124750249&partnerID=8YFLogxK
U2 - 10.1186/s12915-022-01241-2
DO - 10.1186/s12915-022-01241-2
M3 - Article
C2 - 35139855
SN - 1741-7007
VL - 20
JO - BMC Biology
JF - BMC Biology
IS - 1
M1 - 40
ER -