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Updated: Sep 7, 2025
Author Spotlight: Mitochondrial Remodeling in Skeletal Muscle
Published on: December 1, 2023
TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy
Li Zhang1, Felicia Dietsche, Bruno Seitaj2
1Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Abstract:
Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake. Under steady-state conditions, loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix caused by attenuated exchange of these ions. To identify the in vivo consequences of TMBIM5 dysfunction, we generated mice carrying a mutation in the channel pore. These mutant mice display increased embryonic or perinatal lethality and a skeletal myopathy which strongly correlates with tissue-specific disruption of cristae architecture, early opening of the mitochondrial permeability transition pore, reduced calcium uptake capability, and mitochondrial swelling. Our results demonstrate that TMBIM5 is an essential and important part of the mitochondrial ion transport system machinery with particular importance for embryonic development and muscle function.
Insights
The protein TMBIM5 is crucial for mitochondrial ion transport, impacting calcium uptake and energy production. Its dysfunction leads to developmental issues and skeletal myopathy in mice.
Area of Science:
- Mitochondrial biology
- Ion transport mechanisms
- Cellular physiology
Background:
- Ion fluxes across the inner mitochondrial membrane are vital for cellular functions.
- TMBIM5 is a conserved protein homologous to ion channels, implicated in mitochondrial structure and energy production.
Purpose of the Study:
- To investigate the role of TMBIM5 in mitochondrial ion transport and its physiological consequences.
- To elucidate the in vivo function of TMBIM5 in embryonic development and muscle tissue.
Main Methods:
- Overexpression of TMBIM5 to study calcium uptake.
- Generation and analysis of TMBIM5 mutant mice.
- Assessment of mitochondrial ion levels, cristae architecture, and permeability transition pore opening.
Main Results:
- TMBIM5 mediates mitochondrial calcium uptake.
- Loss of TMBIM5 alters mitochondrial matrix potassium and proton levels.
- TMBIM5 dysfunction causes embryonic lethality, skeletal myopathy, disrupted cristae, and mitochondrial swelling.
Conclusions:
- TMBIM5 is essential for mitochondrial ion transport, particularly potassium and proton exchange.
- TMBIM5 plays a critical role in embryonic development and skeletal muscle function.
- TMBIM5 is a key component of the mitochondrial ion transport machinery.
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