Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons
Entity
UAM. Departamento de Biología MolecularPublisher
Society for NeuroscienceDate
2013-08-30Citation
10.1523/JNEUROSCI.0929-13.2013
Journal of Neuroscience 33.35 (2013): 13957–13971
ISSN
0270-6474 (print); 1529-2401 (online)DOI
10.1523/JNEUROSCI.0929-13.2013Funded by
This work was supported by the Ministerio de Economía Grant BFU2011-30456, by CIBERER (an initiative of the ISCIII), by the Comunidad de Madrid Grant S2010/BMD-2402 MITOLAB-CM (to J.S.), by ISCIII Grant PI080610 (to A.d.A.), and by an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. C.B.R is a recipient of a FPU fellowship from the Ministerio de Educación y Ciencia. .Project
Comunidad de Madrid. S2010/BMD-2402/MITOLABEditor's Version
http://dx.doi.org/10.1523/JNEUROSCI.0929-13.2013Subjects
Neuronal respiration; Mitochondrial; ARALAR-MAS; Biología y Biomedicina / BiologíaRights
© 2013 the authorsAbstract
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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Google Scholar:Llorente-Folch, Irene
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Rueda, Carlos
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Amigo, Ignacio
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Arco, Araceli del
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Saheki, Takeyori
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Pardo Merino, Beatriz
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Satrustegui Gil Delgado, Jorgina
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