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Updated: Apr 25, 2026
Author Spotlight: Mitochondrial Remodeling in Skeletal Muscle
Published on: December 1, 2023
Aggregate-prone desmin mutations impair mitochondrial calcium uptake in primary myotubes
Natalia Smolina1, Joseph Bruton2, Gunnar Sjoberg3
1Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Federal Almazov Medical Research Centre, St-Petersburg, Russia.
Abstract:
Desmin, being a major intermediate filament of mature muscle cell, interacts with mitochondria within the cell and participates in mitochondria proper localization. The goal of the present study was to assess the effect of aggregate-prone and non-aggregate-prone desmin mutations on mitochondrial calcium uptake. Primary murine satellite cells were transduced with lentiviruses carrying desmin in wild type or mutant form, and were induced to differentiate into myotubes. Four mutations resulting in different degree of desmin aggregates formation were analyzed. Tail domain mutation Asp399Tyr has the mildest impact on desmin filament polymerization, rod domain mutation Ala357Pro causes formation of large aggregates composed of filamentous material, and Leu345Pro and Leu370Pro are considered to be the most severest in their impact on desmin polymerization and structure. For mitochondrial calcium measurement cells were loaded with rhod 2-AM. We found that aggregate-prone mutations significantly decreased [Ca(2+)]mit, whereas non-aggregate-prone mutations did not decrease [Ca(2+)]mit. Moreover aggregate-prone desmin mutations resulted in increased resting cytosolic [Ca(2+)]. However this increase was not accompanied by any alterations in sarcoplasmic reticulum calcium release. We suggest that the observed decline in [Ca(2+)]mit was due to desmin aggregate accumulation resulting in the loss of desmin mitochondria interactions.
Insights
Aggregate-prone desmin mutations impair mitochondrial calcium uptake and increase cytosolic calcium. Non-aggregate-prone mutations had no effect, suggesting desmin aggregates disrupt muscle cell calcium homeostasis.
Area of Science:
- Muscle cell biology
- Mitochondrial function
- Calcium signaling
Background:
- Desmin is a key intermediate filament in muscle cells, crucial for mitochondrial localization and function.
- Desmin mutations can lead to aggregate formation, potentially disrupting cellular processes.
- Mitochondrial calcium ([Ca(2+)]mit) uptake is vital for cellular energy production and signaling.
Purpose of the Study:
- To investigate the impact of aggregate-prone versus non-aggregate-prone desmin mutations on mitochondrial calcium uptake.
- To determine if desmin aggregate formation influences cytosolic calcium levels and sarcoplasmic reticulum calcium release.
Main Methods:
- Primary murine satellite cells were genetically modified with wild-type or mutant desmin using lentiviral transduction.
- Cells were differentiated into myotubes to study desmin polymerization and aggregate formation.
- Mitochondrial calcium levels were measured using the fluorescent indicator rhod 2-AM.
Main Results:
- Aggregate-prone desmin mutations significantly reduced mitochondrial calcium uptake ([Ca(2+)]mit).
- Non-aggregate-prone desmin mutations did not affect [Ca(2+)]mit.
- Aggregate-prone mutations led to increased resting cytosolic calcium, without altering sarcoplasmic reticulum calcium release.
Conclusions:
- Desmin aggregate accumulation disrupts the interaction between desmin and mitochondria, impairing mitochondrial calcium uptake.
- Altered desmin structure, specifically aggregate formation, negatively impacts muscle cell calcium homeostasis.
- These findings highlight the pathological role of desmin aggregates in muscle dysfunction.
