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Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations

Detmer, Scott A. and Chan, David C. (2007) Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. Journal of Cell Biology, 170 (4). pp. 405-414. ISSN 0021-9525. PMCID PMC2063976. doi:10.1083/jcb.200611080.

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Mfn2, an oligomeric mitochondrial protein important for mitochondrial fusion, is mutated in Charcot-Marie-Tooth disease (CMT) type 2A, a peripheral neuropathy characterized by axonal degeneration. In addition to homooligomeric complexes, Mfn2 also associates with Mfn1, but the functional significance of such heterooligomeric complexes is unknown. Also unknown is why Mfn2 mutations in CMT2A lead to cell type–specific defects given the widespread expression of Mfn2. In this study, we show that homooligomeric complexes formed by many Mfn2 disease mutants are nonfunctional for mitochondrial fusion. However, wild-type Mfn1 complements mutant Mfn2 through the formation of heterooligomeric complexes, including complexes that form in trans between mitochondria. Wild-type Mfn2 cannot complement the disease alleles. Our results highlight the functional importance of Mfn1–Mfn2 heterooligomeric complexes and the close interplay between the two mitofusins in the control of mitochondrial fusion. Furthermore, they suggest that tissues with low Mfn1 expression are vulnerable in CMT2A and that methods to increase Mfn1 expression in the peripheral nervous system would benefit CMT2A patients.

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Chan, David C.0000-0002-0191-2154
Additional Information:© The Rockefeller University Press, 2007. Submitted: 15 November 2006. Accepted: 16 January 2007. Published online 12 February 2007. We are grateful to Hsiuchen Chen for helpful comments on the manuscript, members of the laboratory for encouragement, and the Beckman Imaging Center for use of confocal microscopes. This work was supported by National Institutes of Health (NIH) grant GM062967. D.C. Chan was a Bren Scholar. S.A. Detmer was partially supported by NIH/National Research Service Award training grant 5T32GM07616. Online supplemental material: Fig. S1 shows the mitochondrial profi les of MEFs expressing Mfn2 CMT2A alleles; this data is summarized in Fig. 1 C. Fig. S2 shows mitochondrial aggregation in MEFs highly overexpressing Mfn2 CMT2A alleles. Fig. S3 shows that at low infection rates, recombinant Mfn2 is present at approximately fourfold the level of endogenous Mfn2. Online supplemental material is available at
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NIH Predoctoral Fellowship5T32GM07616
Issue or Number:4
PubMed Central ID:PMC2063976
Record Number:CaltechAUTHORS:DETjcb07
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7637
Deposited By: Archive Administrator
Deposited On:15 Mar 2007
Last Modified:08 Nov 2021 20:44

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