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.
Bibliographical noteFunding Information:
3 Supported by the BK21 Plus Program from the Ministry of Education (MOE), Korea.
4Supported by National Research Foundation of Korea (NRF) Grant 2016R1A2B4014565. To whom correspondence may be addressed: Dept. of Physiology, Yonsei University Wonju College of Medicine, 20 Ilsan-Ro, Wonju, Gangwon-Do 26426, Korea. Tel.: 82-33-741-0294; Fax: 82-33-745-6461; E-mail: email@example.com.
5Supported by the National Creative Research Initiatives grant through the National Research Foundation of Korea (NRF) funded by the Minis-try of Science, ICT, and Future Planning (MSIP), Korea (Grant 2010-0018291). To whom correspondence may be addressed: Institute of Molecular Biology and Genetics, Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul 08826, Korea. Tel.: 82-2-880-4399. Fax: 82-2-876-4401; E-mail: firstname.lastname@example.org.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology