BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function

Dogan Grepper; Cassandra Tabasso; Nadège Zanou; Axel K F Aguettaz; Mauricio Castro-Sepulveda; Dorian V Ziegler; Sylviane Lagarrigue; Yoan Arribat; Adrien Martinotti; Ammar Ebrahimi; Jean Daraspe; Lluis Fajas; Francesca Amati

doi:10.1016/j.isci.2024.110510

BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function

iScience. 2024 Jul 14;27(8):110510. doi: 10.1016/j.isci.2024.110510. eCollection 2024 Aug 16.

Authors

Dogan Grepper¹, Cassandra Tabasso¹, Nadège Zanou², Axel K F Aguettaz^{1

3}, Mauricio Castro-Sepulveda¹, Dorian V Ziegler⁴, Sylviane Lagarrigue¹, Yoan Arribat¹, Adrien Martinotti^{1

3}, Ammar Ebrahimi^{1

3}, Jean Daraspe⁵, Lluis Fajas⁴, Francesca Amati^{1

3}

Affiliations

¹ Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland.
² Institute of Sport Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland.
³ Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Vaud 1011, Switzerland.
⁴ Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland.
⁵ Electron Microscopy Facility, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland.

Abstract

The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca²⁺) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca²⁺ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca²⁺ release and mitochondrial Ca²⁺ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca²⁺ signaling, contributes to proper skeletal muscle function.

Keywords: cell biology; pharmacology.