Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle
Open accessAbstract
As muscle contraction requires ATP and Ca(2+), skeletal muscle function is highly dependent on communication between two major intracellular organelles: mitochondria and sarcoplasmic reticulum (SR). In adult skeletal muscle, mitochondria located within the I-band of the sarcomere are connected to the SR by small ∼10 nm electron dense tethers that bridge the outer mitochondrial membrane to the region of SR that is ∼130 nm from the site of Ca(2+) release. However, the molecular composition of tethers and their precise impact on mitochondrial Ca(2+) uptake in skeletal muscle is unclear. Mitofusin-2 (Mfn2) is a transmembrane GTPase present in both mitochondria and ER/SR membranes that forms trans-dimers and participates in mitochondrial fusion. Here we evaluated the role Mfn2 plays in mitochondrial morphology, localization, and functional SR-mitochondrial Ca(2+) crosstalk in adult skeletal muscle. Compared to a non-targeting (CTRL) siRNA, in vivo electroporation of 400 nM Mfn2 siRNA (Mfn2 KD) into mouse footpads resulted in a marked acute reduction (67±3%) in Mfn2 protein levels in flexor digitorum brevis (FDB) muscles that occurred without a change in other key Ca(2+) regulatory proteins. Electron microscopy analyses revealed that Mfn2 knockdown resulted in a change in mitochondria morphology and mis-localization of some mitochondria from the I-band to the A-band region of the sarcomere. To assess the role of Mfn2 in SR-mitochondrial crosstalk, we measured mitochondrial Ca(2+) uptake and myoplasmic Ca(2+) transients with rhod-2 and mag-fluo-4, respectively, during repetitive high frequency tetanic stimulation (5×100 Hz tetani, 500 ms/tetani, 0.2 duty cycle) in CTRL and Mfn2 KD fibers. Mitochondrial Ca(2+) uptake during repetitive tetanic stimulation was significantly reduced (40%) in Mfn2 KD FDB fibers, which was accompanied by a parallel elevation in the global electrically evoked myoplasmic Ca(2+) transient. Mfn2 KD also resulted in a reduction of the mitochondrial membrane potential, which contributed to the observed decrease in activity-dependent mitochondrial Ca(2+) uptake. Consistent with this idea, a similar decrease in mitochondrial Ca(2+) uptake was also observed in wild type fibers following a comparable reduction in mitochondrial membrane potential induced by acute exposure to a low concentration (50 nM) of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP). In addition, both global and mitochondrial Ca(2+) transients during repetitive tetanic stimulation were similarly reduced by both slow (EGTA) and fast (BAPTA) Ca(2+) chelating agents. Together, these results indicate that Mfn2 promotes proper mitochondrial morphology, localization, and membrane potential required for optimal activity-dependent mitochondrial Ca(2+) uptake and buffering of the global myoplasmic Ca(2+) transient in adult skeletal muscle.
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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 [68]
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- Authors
- Ainbinder, A., Boncompagni, S., Protasi, F., & Dirksen, R. T.
- Affiliations
- University of Rochester Medicine (US)
- University of Chieti-Pescara (IT)
- Corresponding author
- Dirksen, Robert T.
- Venue
- Cell Calcium
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 57
- Issue
- 1
- Pages
- 14-24
- ISSN
- 0143-4160 (ISSN-L)
- PMC
- PMC4300280
- OpenAlex
- W2031318456
- Cited by
- 122
- References
- 45
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 10 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 11 · 2019: 12 · 2018: 14 · 2017: 11 · 2016: 5 · 2015: 3
- FWCI
- 2.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cell Calcium (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (AR059646)
- MDA (MDA275574)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitofusin 2, mitochondrial calcium uptake, skeletal muscle, sarcoplasmic reticulum, mitochondrial fusion, mitochondrial morphology, mitochondrial membrane potential, tetanic stimulation, mitochondrial localization, flexor digitorum brevis, siRNA knockdown, muscle contraction
- MeSH terms
- Animals, Calcium, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Egtazic Acid, Mice, Inbred C57BL, Mitochondria, Sarcoplasmic Reticulum, Muscle Fibers, Skeletal, Microscopy, Confocal, GTP Phosphohydrolases, RNA Interference, RNA, Small Interfering, Mice, Membrane Potential, Mitochondrial
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