Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons
Neuronal respiration is controlled by ATP demand and Ca2 but the roles played by each are unknown, as any Ca2 signal also impacts on ATP demand. Ca2 can control mitochondrial function through Ca2 -regulated mitochondrial carriers, the aspartate-glutamate and ATP-Mg/Pi carriers, ARALAR/AGC1 and SCaMC...
| Autores: | , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2013 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/667320 |
| Acceso en línea: | http://hdl.handle.net/10486/667320 https://dx.doi.org/10.1523/JNEUROSCI.0929-13.2013 |
| Access Level: | acceso abierto |
| Palabra clave: | Neuronal respiration Mitochondrial ARALAR-MAS Biología y Biomedicina / Biología |
| Sumario: | Neuronal respiration is controlled by ATP demand and Ca2 but the roles played by each are unknown, as any Ca2 signal also impacts on ATP demand. Ca2 can control mitochondrial function through Ca2 -regulated mitochondrial carriers, the aspartate-glutamate and ATP-Mg/Pi carriers, ARALAR/AGC1 and SCaMC-3, respectively, or in the matrix after Ca2 transport through the Ca2 uniporter. We have studied the role of Ca2 signaling in the regulation of mitochondrial respiration in intact mouse cortical neurons in basal conditions and in response to increased workload caused by increases in [Na ]cyt (veratridine, high-K depolarization) and/or [Ca2 ]cyt (carbachol). Respiration in nonstimulated neurons on 2.5–5mM glucose depends on ARALAR-malate aspartate shuttle (MAS), with a 46% drop in aralar KO neurons. All stimulation conditions induced increased OCR (oxygen consumption rate) in the presence of Ca2 , which was prevented by BAPTA-AM loading (to preserve the workload), or in Ca2 -free medium (which also lowers cell workload). SCaMC-3 limits respiration only in response to high workloads and robust Ca2 signals. In every condition tested Ca2 activation of ARALAR-MAS was required to fully stimulate coupled respiration by promoting pyruvate entry into mitochondria. In aralar KO neurons, respiration was stimulated by veratridine, but not by KCl or carbachol, indicating that the Ca2 uniporter pathway played a role in the first, but not in the second condition, even though KCl caused an increase in [Ca2 ]mit. The results suggest a requirement for ARALAR-MAS in priming pyruvate entry in mitochondria as a step needed to activate respiration by Ca2 in response to moderate workloads |
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