The mitochondrial transporter SLC25A25 links ciliary TRPP2 signaling and cellular metabolism
| Autor: | Elisabeth Michel, Albrecht Kramer-Zucker, Conny Schütze, Lea Osterried, Jingting Luan, Jerzy Adamski, Gerd Walz, Alexis Hofherr, Frieder Linden, Terry Watnick, Nils Wiedemann, Craig Montell, Tilman Busch, Claudia Seger, Edmund R.S. Kunji, Anna Artati, Barbara T. Wakimoto, Fiona M. Fitzpatrick, Michael Köttgen |
|---|---|
| Přispěvatelé: | Köttgen, Michael [0000-0003-2406-5039], Apollo - University of Cambridge Repository, Lo, Cecilia |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Embryology Amino Acid Transport Systems Physiology Mitochondrion Medical and Health Sciences Biochemistry Mitochondrial Membrane Transport Proteins Antiporters Ion Channels Transient receptor potential channel Transient Receptor Potential Channels Short Reports Animal Cells Medicine and Health Sciences Biology (General) Zebrafish Energy-Producing Organelles biology Physics General Neuroscience Cilium Eukaryota Animal Models Biological Sciences Mitochondria Cell biology Insects Electrophysiology Drosophila melanogaster Experimental Organism Systems Osteichthyes Vertebrates Physical Sciences Drosophila Cellular Structures and Organelles Cellular Types Signal transduction General Agricultural and Biological Sciences Signal Transduction Cell Physiology Heterozygote TRPP Cation Channels Arthropoda QH301-705.5 Amino Acid Transport Systems Acidic 1.1 Normal biological development and functioning Biophysics Neurophysiology Bioenergetics Research and Analysis Methods General Biochemistry Genetics and Molecular Biology Mitochondrial Proteins 03 medical and health sciences Model Organisms Underpinning research Genetics Animals Humans Cilia Ion channel Agricultural and Veterinary Sciences General Immunology and Microbiology Acidic Embryos Calcium-Binding Proteins Organisms Biology and Life Sciences Proteins Cell Biology biology.organism_classification Invertebrates Sperm Cell Metabolism Solute carrier family Fish Germ Cells 030104 developmental biology Calcium Generic health relevance Calcium Channels Developmental Biology Neuroscience Genetic screen |
| Zdroj: | PLoS Biology PLoS biology, vol 16, iss 8 PLoS Biol. 16:e2005651 (2018) PLOS Biology PLoS Biology, Vol 16, Iss 8, p e2005651 (2018) |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.2005651 |
| Popis: | Cilia are organelles specialized in movement and signal transduction. The ciliary transient receptor potential ion channel polycystin-2 (TRPP2) controls elementary cilia-mediated physiological functions ranging from male fertility and kidney development to left–right patterning. However, the molecular components translating TRPP2 channel–mediated Ca2+ signals into respective physiological functions are unknown. Here, we show that the Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier 25 A 25 (SLC25A25) acts downstream of TRPP2 in an evolutionarily conserved metabolic signaling pathway. We identify SLC25A25 as an essential component in this cilia-dependent pathway using a genome-wide forward genetic screen in Drosophila melanogaster, followed by a targeted analysis of SLC25A25 function in zebrafish left–right patterning. Our data suggest that TRPP2 ion channels regulate mitochondrial SLC25A25 transporters via Ca2+ establishing an evolutionarily conserved molecular link between ciliary signaling and mitochondrial metabolism. Author summary Cilia are extensions of the cell that project from the cell body and serve as cellular sensors that transduce extracellular stimuli into the cell. The molecular mechanisms involved in ciliary signal transduction include ciliary receptors and ion channels. The transient receptor potential channel polycystin-2 (TRPP2) is known to control cilia-dependent biological processes throughout the animal kingdom ranging from male fertility to left–right organ patterning. However, the mechanisms mediating TRPP2 function in vivo remain unclear. Here, we have analyzed these mechanisms in the fruit fly and zebrafish and identified the mitochondrial solute carrier 25 A 25 (SLC25A25) as an intracellular effector of Ca2+-permeable TRPP2 cation channel in cilia. We show that SLC25A25 cooperates with TRPP2 in an evolutionarily conserved metabolic signaling pathway acting as a Ca2+-activated mitochondrial ATP transporter. Loss of this signaling pathway impairs cellular metabolism and causes severe defects in flies and fish, such as left–right patterning or male fertility problems. Our findings establish a molecular link between ciliary signaling and mitochondrial metabolism, raising the fascinating question of how SLC25A25-mediated metabolic fluctuations control male fertility and organ patterning in vivo. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|