Mitofusin 1 and 2 differentially regulate mitochondrial function underlying Ca²⁺ signaling and proliferation in rat...

Mitochondria play a substantial role in cytosolic Ca²⁺ buffering and energy metabolism. We recently demonstrated that mitofusin 2 (Mfn2) regulated Ca²⁺ signaling by tethering mitochondria and sarcoplasmic reticulum (SR), and thus, facilitated mitochondrial function and the proliferation of vascular smooth muscle cells (VSMCs). However, the physiological role of mitofusin 1 (Mfn1) on Ca²⁺ signaling and mitochondrial function remains unclear. Herein, the roles of Mfn1 and Mfn2 in mitochondrial function underlying Ca²⁺ signaling, ATP production, and cell proliferation were examined in rat aortic smooth muscle A10 cells. Following an arginine vasopressin-induced increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt), Mfn2 siRNA (siMfn2) reduced cytosolic Ca²⁺ removal and mitochondrial Ca²⁺ uptake. However, Mfn1 siRNA (siMfn1) attenuated mitochondrial Ca²⁺ uptake, facilitated Ca²⁺ removal from mitochondria, and resulted in increased [Ca²⁺]_cyt, which was mediated by the downregulation of mitochondrial Ca²⁺ uniporter (MCU) expression and the upregulation of mitochondrial Na⁺/Ca²⁺ exchanger (NCLX) expression. Furthermore, siMfn1 increased the mitochondrial membrane potential, ATP production by adenine nucleotide translocase (ANT), and cell proliferation, whereas siMfn2 exhibited the opposite responses. In conclusion, Mfn1 modulates the expressions of MCU, NCLX, and ANT, and Mfn2 tethers mitochondria to SR, which demonstrates their different mitochondrial functions for Ca²⁺ signaling, ATP production, and the proliferation of VSMCs.