Mitofusin 2 tethers endoplasmic reticulum to mitochondria
Open accessAbstract
Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.
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Other important MAM tethering proteins are B-cell receptor-associated protein 31, mitochondrial fission 1 protein, and mitofusin.
“Other important MAM tethering proteins are B-cell receptor–associated protein 31, mitochondrial fission 1 protein [96], and mitofusin [97].”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [97]
MFN2, but not MFN1, is expressed on mitochondria-associated endoplasmic reticulum membranes (MAM) and to a lesser extent on ER/SR.
“MFN2, and not MFN1, is expressed on the mitochondria-associated endoplasmic reticulum membranes (MAM) and, to a lesser extent, to the endoplasmic/sarcoplasmic reticulum (ER/SR) [63, 64].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [63]
MFN2 bridges mitochondria to ER/SR, facilitating processes linked to ER-mitochondria interactions like calcium homeostasis and modulation of the UPR during ER stress via PERK.
“Indeed, MFN2 bridges mitochondria to ER/SR, facilitating critical processes linked to ER–mitochondria interactions like calcium homeostasis and the modulation of the UPR during ER stress via PERK [63, 65–68].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [63]
ER stress is induced by the decrease of the ER-mitochondria tethering protein Mfn2 and the down- and upregulation of the ER chaperones calnexin and Bip/Grp78, respectively.
“ER stress is induced by the decrease of the ER–mitochondria tethering protein Mfn2 and the down- and upregulation of the ER chaperones calnexin and Bip/Grp78, respectively [63, 65, 66, 213].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [63]
Mfn1 and Mfn2 possess several distinct properties, suggesting that they fulfill different roles in fusion.
“Despite some redundancies in their function, the two proteins possess several distinct properties, suggesting that they fulfill different roles in fusion (de Brito and Scorrano, 2008; Eura et al., 2003; Ishihara et al., 2004).”
From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as de Brito and Scorrano, 2008
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- Authors
- de Brito, O. M., & Scorrano, L.
- Affiliations
- University of Geneva (CH)
- Corresponding author
- Scorrano, Luca
- ORCID
- Scorrano, Luca
- Venue
- Nature
- Published
- 2008-12-01
- Volume
- 456
- Issue
- 7222
- Pages
- 605-610
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2166432730
- Cited by
- 2,442
- References
- 35
- Citations by year
- 2026: 105 · 2025: 142 · 2024: 136 · 2023: 142 · 2022: 139 · 2021: 188 · 2020: 186 · 2019: 148 · 2018: 132 · 2017: 175 · 2016: 129 · 2015: 119 · 2014: 132 · 2013: 133 · 2012: 145
- FWCI
- 39.45
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-09-10)
- Open access
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitofusin 2, mitochondrial calcium uptake, inositol 1,4,5-trisphosphate, calcium signaling, dynamin-related proteins, ER morphology, calcium homeostasis
- MeSH terms
- Animals, Calcium, Charcot-Marie-Tooth Disease, Endoplasmic Reticulum, Fibroblasts, HeLa Cells, Humans, Membrane Proteins, Mitochondria, Inositol 1,4,5-Trisphosphate, Calcium Signaling, GTP Phosphohydrolases, Mitochondrial Proteins, Mice, Organelle Shape
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