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Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development
Open accessAbstract
Mitochondrial morphology is determined by a dynamic equilibrium between organelle fusion and fission, but the significance of these processes in vertebrates is unknown. The mitofusins, Mfn1 and Mfn2, have been shown to affect mitochondrial morphology when overexpressed. We find that mice deficient in either Mfn1 or Mfn2 die in midgestation. However, whereas Mfn2 mutant embryos have a specific and severe disruption of the placental trophoblast giant cell layer, Mfn1-deficient giant cells are normal. Embryonic fibroblasts lacking Mfn1 or Mfn2 display distinct types of fragmented mitochondria, a phenotype we determine to be due to a severe reduction in mitochondrial fusion. Moreover, we find that Mfn1 and Mfn2 form homotypic and heterotypic complexes and show, by rescue of mutant cells, that the homotypic complexes are functional for fusion. We conclude that Mfn1 and Mfn2 have both redundant and distinct functions and act in three separate molecular complexes to promote mitochondrial fusion. Strikingly, a subset of mitochondria in mutant cells lose membrane potential. Therefore, mitochondrial fusion is essential for embryonic development, and by enabling cooperation between mitochondria, has protective effects on the mitochondrial population.
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In the citing paper
“Genetic loss of MFN1 induces a higher degree of mitochondrial fragmentation than MFN2 deletion [60].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [60]
In the citing paper
“Mitochondrial fusion rates correlate with the OXPHOS capacity, higher in oxidative fibers than in glycolytic fibers [60].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [60]
In the citing paper
“The full knockout mice of either Mfn1, Mfn2, or OPA1 result in embryonic lethality of mice, demonstrating the biological importance of mitochondrial fusion in early development [60, 178].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [60]
In the citing paper
“Both Mfn proteins mediate fusion through their active GTPase domains by tethering opposing mitochondrial membranes (Chen et al., 2003; Eura et al., 2003).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Chen et al., 2003
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Metadata
- Authors
- Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., & Chan, D. C.
- Affiliations
- California Institute of Technology (US)
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2003-01-13
- Volume
- 160
- Issue
- 2
- Pages
- 189-200
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2172648
- OpenAlex
- W2073095545
- Cited by
- 2,601
- References
- 52
- Citations by year
- 2026: 111 · 2025: 132 · 2024: 143 · 2023: 149 · 2022: 173 · 2021: 192 · 2020: 170 · 2019: 149 · 2018: 160 · 2017: 127 · 2016: 121 · 2015: 115 · 2014: 126 · 2013: 103 · 2012: 112
- FWCI
- 14.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Warwick Research Archive Portal (University of Warwick) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (1 R01 GM62967-01, R01GM062967, T32GM007616, GM07616)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitofusins, Mfn1, mitofusin 2, mitochondrial fusion, mitochondrial fission, mitochondrial morphology, embryonic development, mitochondrial membrane potential, mitochondrial fragmentation, embryonic fibroblasts, mouse mutants
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Cytoskeletal Proteins, Embryo, Mammalian, Female, Embryonic and Fetal Development, Fetus, Genes, Lethal, Intracellular Membranes, Male, Membrane Potentials, Membrane Proteins, Mitochondria, Placenta, Trophoblasts, Mice, Knockout, Gene Expression Regulation, Developmental, GTP Phosphohydrolases, Embryo Loss, Mitochondrial Proteins, Membrane Transport Proteins, Mitochondrial Membrane Transport Proteins, Macromolecular Substances, Utrophin, Mice
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