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
Affiliations
Dogan Grepper
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland
Cassandra Tabasso
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland
Nadège Zanou
Institute of Sport Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland
Axel K.F. Aguettaz
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland; Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Vaud 1011, Switzerland
Mauricio Castro-Sepulveda
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland
Dorian V. Ziegler
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland
Sylviane Lagarrigue
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland
Yoan Arribat
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland
Adrien Martinotti
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland; Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Vaud 1011, Switzerland
Ammar Ebrahimi
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland; Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Vaud 1011, Switzerland
Jean Daraspe
Electron Microscopy Facility, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland
Lluis Fajas
Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud 1015, Switzerland
Francesca Amati
Aging and Muscle Metabolism Lab, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Bugnon 7, Lausanne, Vaud 1005, Switzerland; Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Vaud 1011, Switzerland; Corresponding author
Summary: 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.
