The regulatory role of BCL2LL3 in skeletal muscle inter-organelle communication


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PhD thesis: a PhD thesis.
The regulatory role of BCL2LL3 in skeletal muscle inter-organelle communication
Grepper Dogan
Amati Francesca
Regazzi Romano
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Université de Lausanne, Faculté de biologie et médecine
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Skeletal muscle regulates essential physiological functions such as body temperature, maintenance of body posture, and voluntary movement. Loss of skeletal muscle mass and function has devastating effects on overall health. Energy supply by mitochondria plays a crucial role to maintain skeletal muscle homeostasis. The interaction of mitochondria with other organelles at membrane contact sites is essential to adjust mitochondrial ATP production, and substrate use to skeletal muscle energy demands.
Here, we investigate the role of two candidate genes, BCL2L13 and STOML2, as key actors of inter-organelle communication at membrane contact sites. ln the first study, we use a cellular approach to measure mitochondrial turnover. We conclude that the role of BCL2L13 in mitophagy is negligible.
ln the second study, we generate a bc/2/13 knockout model in zebrafish. An incremental swimming test suggests decreased skeletal muscle function in bc/2/13 knockout fish. Proteomics analysis reveals altered expression of calcium signaling proteins. We discover the localization of BCL2L13 at mitochondria-ER contact sites in skeletal muscle cells and demonstrate the regulatory effect of BCL2L13 on intracellular calcium homeostasis. We conclude that BCL2L13 regulates ER-mitochondria calcium transmission to protect skeletal muscle from apoptotic calcium signais.
ln the third study, we investigate modifications of mitochondrial metabolism induced by reduction of stom/2 expression in zebrafish. We implement an shRNA approach, that can be adapted to induce tissue-specific target gene knockdown. Furthermore, we identify a STOML2 splice variant as a novel tether for mitochondria and lipid droplets.
Overall, we highlight the vital role of inter-organelle communication in the regulation of physiological and pathological conditions.
Create date
21/02/2023 10:10
Last modification date
22/02/2023 7:52
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