Reference - Detail
|Author||Choi S, Quan X, Bang S, Yoo H, Kim J, Park J, Park KS, Chung J.|
|Title||Mitochondrial calcium uniporter in Drosophila transfers calcium between the endoplasmic reticulum and mitochondria in oxidative stress-induced cell death.|
|Journal||J Biol Chem|
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.
|MeSH||Animals Animals, Genetically Modified Apoptosis* / drug effects Autophagy / drug effects Caffeine / pharmacology Calcium Channels / chemistry Calcium Channels / genetics Calcium Channels / metabolism* Calcium Signaling* / drug effects Cation Transport Proteins / chemistry Cation Transport Proteins / genetics Cation Transport Proteins / metabolism* Cell Line Central Nervous System Stimulants / pharmacology Drosophila Proteins / antagonists & inhibitors Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / drug effects Drosophila melanogaster / genetics Drosophila melanogaster / growth & development Drosophila melanogaster / metabolism Endoplasmic Reticulum / drug effects Endoplasmic Reticulum / metabolism* Gene Silencing Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors Inositol 1,4,5-Trisphosphate Receptors / chemistry Inositol 1,4,5-Trisphosphate Receptors / genetics Inositol 1,4,5-Trisphosphate Receptors / metabolism Larva / drug effects Larva / genetics Larva / growth & development Larva / metabolism Membrane Potential, Mitochondrial / drug effects Mitochondria, Muscle / drug effects Mitochondria, Muscle / metabolism* Mutation Oxidative Stress* / drug effects Protein Sorting Signals / drug effects RNA Interference Recombinant Proteins / chemistry Recombinant Proteins / metabolism|