Ca(2+) regulation of mitochondrial function in neurons

• Published in: Biochimica et biophysica acta Vol. 1837; no. 10; pp. 1617 - 1624
• Main Authors: Rueda, Carlos B, Llorente-Folch, Irene, Amigo, Ignacio, Contreras, Laura, González-Sánchez, Paloma, Martínez-Valero, Paula, Juaristi, Inés, Pardo, Beatriz, del Arco, Araceli, Satrústegui, Jorgina
• Format: Journal Article
• Language: English
• Published: Netherlands 01.10.2014
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Transport Systems, Acidic - metabolism; Animals; Antiporters - metabolism; Calcium - physiology; Cytosol - metabolism; Humans; Ion Transport; Mitochondria - metabolism; Mitochondria - physiology; Neurons - metabolism; Neurons - physiology; Pyruvic Acid - metabolism; Mitochondrion; Neuronal respiration; Aspartate–glutamate transporter; ATP-Mg/Pi transporter; Calcium; Calcium-regulated transport
• ISSN: 0006-3002; 1878-2434
• DOI: 10.1016/j.bbabio.2014.04.010

Calcium is thought to regulate respiration but it is unclear whether this is dependent on the increase in ATP demand caused by any Ca(2+) signal or to Ca(2+) itself. [Na(+)]i, [Ca(2+)]i and [ATP]i dynamics in intact neurons exposed to different workloads in the absence and presence of Ca(2+) clearly showed that Ca(2+)-stimulation of coupled respiration is required to maintain [ATP]i levels. Ca(2+) may regulate respiration by activating metabolite transport in mitochondria from outer face of the inner mitochondrial membrane, or after Ca(2+) entry in mitochondria through the calcium uniporter (MCU). Two Ca(2+)-regulated mitochondrial metabolite transporters are expressed in neurons, the aspartate-glutamate exchanger ARALAR/AGC1/Slc25a12, a component of the malate-aspartate shuttle, and the ATP-Mg/Pi exchanger SCaMC-3/APC2/Slc25a23, with S0.5 for Ca(2+) of 300nM and 3.4μM, respectively. The lack of SCaMC-3 results in a smaller Ca(2+)-dependent stimulation of respiration only at high workloads, as caused by veratridine, whereas the lack of ARALAR reduced by 46% basal OCR in intact neurons using glucose as energy source and the Ca(2+)-dependent responses to all workloads: a reduction of about 65-70% in the response to the high workload imposed by veratridine, and completely suppression of the OCR responses to moderate (K(+)-depolarization) and small (carbachol) workloads, effects reverted by pyruvate supply. For K(+)-depolarization, this occurs in spite of the presence of large [Ca(2+)]mit signals and increased formation of mitochondrial NAD(P)H. These results show that ARALAR-MAS is a major contributor of Ca(2+)-stimulated respiration in neurons by providing increased pyruvate supply to mitochondria. In its absence and under moderate workloads, matrix Ca(2+) is unable to stimulate pyruvate metabolism and entry in mitochondria suggesting a limited role of MCU in these conditions. This article was invited for a Special Issue entitled: 18th European Bioenergetic Conference.