Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo
Abstract
Two human Fzo-homologs, mitofusins Mfn1 and Mfn2, are shown by RT-PCR and western blot to be ubiquitous mitochondrial proteins. Protease digestion experiments reveal that Mfn2 is an outer membrane protein with N-terminal and C-terminal domains exposed towards the cytosol. The transmembrane and C-terminal domains of Mfn2 (Mfn2-TMCT) are targeted to mitochondria and deletion of these domains leads to the cytosolic localization of truncated Mfn2 (Mfn2-NT). Mfn2 is targeted to the endoplasmic reticulum or to mitochondria when the C-terminal domain is replaced by short stretches of neutral/hydrophobic (Mfn2-IYFFT) or polar/basic (Mfn2-RRD) amino acids. The coiled-coil domains of Mfn2, upstream and downstream of the transmembrane domain, are also important for mitochondrial targeting: Mfn2-mutants deleted of any of its coiled-coil domains are only partially targeted to mitochondria and significant protein amounts remain cytosolic. We show that these coiled-coil domains interact with each other: mistargeted Mfn2-NT or Mfn2-IYFFT localize to mitochondria if co-expressed with Mfn2-TMCT. This relocalization is abolished when the coiled-coil domain is deleted in any of the co-transfected molecules. We also found that Mfn2 can cluster active mitochondria in the perinuclear region independently of the cytoskeleton,bring mitochondrial membranes into close contact and modify mitochondrial structure, without disturbing the integrity of the inner and outer membrane.
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Mfn2 participates in the maintenance of mitochondrial tubules or networks in mammalian cells.
“Mitofusin-2 (Mfn2) participates in the maintenance of mitochondrial tubules or networks in mammalian cells (23)(24)(25).”
From Expression of <i>Mfn2</i>, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [25]
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- Authors
- Rojo, M., Legros, F., Chateau, D., & Lombès, A.
- Affiliations
- Inserm (FR)
- INSERM U 523 — Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France
- Present address: INSERM U 505, Centre de Recherches Biomédicales des Cordeliers, 75006 Paris, France
- Corresponding author
- Rojo, Manuel
- ORCID
- Rojo, Manuel
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2002-04-15
- Volume
- 115
- Issue
- 8
- Pages
- 1663-1674
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2117041194
- Cited by
- 555
- References
- 45
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 28 · 2023: 18 · 2022: 18 · 2021: 24 · 2020: 29 · 2019: 32 · 2018: 28 · 2017: 23 · 2016: 29 · 2015: 21 · 2014: 18 · 2013: 24 · 2012: 33
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitofusins, Mfn1, mitofusin 2, mitochondrial targeting, membrane topology, mitochondrial outer membrane, coiled-coil domain, transmembrane domain, C-terminal domain, protein localization, mitochondrial clustering, mitochondrial structure
- MeSH terms
- Actins, Animals, Cell Fractionation, Cytoskeleton, HeLa Cells, Humans, Immunohistochemistry, Membrane Proteins, Microtubules, Mitochondria, Phylogeny, Protein Structure, Tertiary, GTP Phosphohydrolases, Mitochondrial Proteins, Membrane Transport Proteins, Drosophila Proteins, Mitochondrial Membrane Transport Proteins
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