Complementation between mouse Mfn1+Mfn2 protects mitochondrial fusion in CMT2A

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J Cell Biol. 2007 Feb 12;176(4):405-14.

Complementation between mouse Mfn1 and Mfn2 protects mitochondrial

fusion defects caused by CMT2A disease mutations.

Detmer SA, Chan DC.

Division of Biology, California Institute of Technology, Pasadena,

CA 91125.

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.