Review
Molecular mechanism of mitochondrial membrane fusion
Erik E. Griffin, Scott A. Detmer, David C. Chan
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Division of Biology, California Institute of Technology, 1200 East California Blvd., MC114-96, Pasadena, CA 91125, USA
Received 16 January 2006; accepted 14 February 2006
Available online 9 March 2006
Abstract
Mitochondrial fusion requires coordinated fusion of the outer and inner membranes. This process leads to exchange of contents, controls the
shape of mitochondria, and is important for mitochondrial function. Two types of mitochondrial GTPases are essential for mitochondrial fusion.
On the outer membrane, the fuzzy onions/mitofusin proteins form complexes in trans that mediate homotypic physical interactions between
adjacent mitochondria and are likely directly involved in outer membrane fusion. Associated with the inner membrane, the OPA1 dynamin-family
GTPase maintains membrane structure and is a good candidate for mediating inner membrane fusion. In yeast, Ugo1p binds to both of these
GTPases to form a fusion complex, although a related protein has yet to be found in mammals. An understanding of the molecular mechanism of
fusion may have implications for Charcot–Marie–Tooth subtype 2A and autosomal dominant optic atrophy, neurodegenerative diseases caused by
mutations in Mfn2 and OPA1.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Membrane fusion; Mitochondrial dynamics; Mitochondrial fusion; GTPase; Organelles
1. Introduction
It has been known for decades that mitochondria have
plasticity of form and undergo fusion and fission [1], but only
recently has there been progress in elucidating the molecular
basis of these processes. A breakthrough was the identification
of the fuzzy onions gene product (Fzo) in the fusion of
mitochondria during Drosophila sperm differentiation [2]. Fzo
is the founding member of a family of mitochondrial outer
membrane GTPases essential for mitochondrial fusion from
yeast to mammals [2–4]. Subsequent genetic studies have
identified additional components of the fusion and fission
machinery.
The balance between fusion and fission plays a central role in
controlling mitochondrial morphology. In the absence of fusion,
mitochondria fragment into small spheres due to ongoing
fission [3–6]. Beyond its role in morphology, mitochondrial
fusion is required for mitochondrial function. Mammalian cells
lacking mitochondrial fusion grow slowly due to low respi-
ratory capacity [5]. Mice deficient in mitochondrial fusion die in
midgestation [4]. Moreover, mutations in components of the
fusion pathway have been implicated in human neurodegene-
rative diseases: Mfn2 in the peripheral neuropathy Charcot–
Marie–Tooth Disease subtype 2A and OPA1 in autosomal
dominant optic atrophy [7–11].
In this review, we discuss our current understanding of how
mitochondrial membranes fuse. To begin, we outline how lipid
bilayers fuse in the two best-studied experimental systems –
virus-mediated fusion and vesicle fusion – in order to highlight
general principles of membrane trafficking that may be
applicable to mitochondrial fusion.
2. Virus/host membrane fusion
In order for an enveloped virus to gain access to the
cellular compartment, it must direct fusion between the viral
membrane and the host cell membrane. This reaction is
mediated by virally encoded transmembrane glycoproteins
embedded in the viral envelope. Specificity of fusion is
provided by the binding of the viral glycoprotein to specific
cell surface receptors on the host cell. Class I viral fusion
proteins contain a short hydrophobic helix termed the fusion
peptide that is crucial to the fusion reaction. On native virions
(the prefusogenic state), the fusion peptide is buried in a
Biochimica et Biophysica Acta 1763 (2006) 482 –489
http://www.elsevier.com/locate/bba
⁎
Corresponding author. Tel.: +1 626 395 2670; fax: +1 626 395 8826.
E-mail address: dchan@caltech.edu (D.C. Chan).
0167-4889/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbamcr.2006.02.003