A Caltech Library Service

The Role of Mitofusin Proteins in Mitochondrial Fusion and Disease


Detmer, Scott A. (2007) The Role of Mitofusin Proteins in Mitochondrial Fusion and Disease. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/7MXP-WS63.


We have investigated the role of mitofusin proteins in mitochondrial fusion and Charcot-Marie-Tooth disease Type 2A (CMT2A). Mitofusins (Mfn1 and Mfn2) are required for mammalian mitochondrial fusion. In structure-function analysis, we have identified loss-of-function mutations in mitofusin GTPase and heptad-repeat domains that disrupt homotypic and heterotypic domain interactions. Mutations in Mfn2 cause CMT2A, a progressive peripheral neuropathy. We have functionally characterized Mfn2 disease mutations and find that wild-type Mfn1, but not Mfn2, can efficiently complement nonfunctional CMT2A alleles to restore mitochondrial fusion. This finding demonstrates the importance of Mfn1-Mfn2 heterooligomers and suggests that Mfn1 expression is important in determining the cell-type specificity of CMT2A. To study the consequences of an Mfn2 CMT2A allele in vivo, we generated transgenic mice that express Mfn2 T105M in motor neurons. These animals demonstrate gait impairments due to distal muscle loss, axonopathy and altered mitochondrial morphology and distribution in motor neurons. In a second approach, we have generated CMT2A knock-in mice by replacing the endogenous genomic Mfn2 with Mfn2 alleles L76P or R94Q. Preliminary characterizations suggest that heterozygous animals have no disease symptoms, but homozygous Mfn2 R94Q animals are severely affected. Together, these mouse models provide means to assess the pathology of Mfn2 CMT2A alleles and the role of mitochondrial dynamics in vivo.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Charcot-Marie-Tooth; fusion; mitochondria; mitofusin
Degree Grantor:California Institute of Technology
Major Option:Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Chan, David C.
Thesis Committee:
  • Bjorkman, Pamela J. (chair)
  • Chan, David C.
  • Deshaies, Raymond Joseph
  • Fraser, Scott E.
Defense Date:1 March 2007
Record Number:CaltechETD:etd-04132007-181115
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1376
Deposited By: Imported from ETD-db
Deposited On:19 Apr 2007
Last Modified:22 Feb 2020 00:32

Thesis Files

PDF (detmer_thesis.pdf) - Final Version
See Usage Policy.


Repository Staff Only: item control page