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

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.