Received for publication, October 31, 2016, and in revised form, July 13, 2017, Published, Papers in Press, July 18, 2017, DOI 10.1074/jbc.M116.765578
Sekyu Choi‡1, Xianglan Quan§1,2, Sunhoe Bang‡1,3, Heesuk Yoo‡3, Jiyoung Kim‡, Jiwon Park‡3, Kyu-Sang Park§4, and Jongkyeong Chung‡3,5
From the ‡National Creative Research Initiatives Center for Energy Homeostasis Regulation, Institute of Molecular Biology and Genetics and School of Biological Sciences, Seoul National University, Seoul 08826, Korea and the §Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-Do 26426, Korea
Edited by John M. Denu
Mitochondrial calcium plays critical roles in diverse cellular processes ranging from energy metabolism to cell death. Previous
studies have demonstrated that mitochondrial calcium uptake is mainly mediated by the mitochondrial calcium uniporter (MCU) complex. However, the roles of the MCU complex in calcium transport, signaling, and dysregulation by oxidative
stress still remain unclear. Here, we confirmed that Drosophila MCU contains evolutionarily conserved structures and requires essential MCU regulator (EMRE) for its calcium channel activities. We generated Drosophila MCU loss-of-function mutants, which lacked mitochondrial calcium uptake in response to caffeine stimulation. Basal metabolic activities were not significantly affected in these MCU mutants, as observed in examinations of body weight, food intake, body sugar level, and starvation-induced autophagy. However, oxidative stress-induced increases in mitochondrial calcium, mitochondrial membrane potential depolarization, and cell death were prevented in these mutants. We also found that inositol 1,4,5-trisphosphate receptor genetically interacts with Drosophila MCU and effectively modulates mitochondrial calcium uptake upon oxidative stress. Taken together, these results support the idea that Drosophila MCU is responsible for endoplasmic reticulum-to-mitochondrial calcium transfer and for cell death due to mitochondrial dysfunction under oxidative stress.
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