The regulation of brain mitochondrial calcium-ion transport. The role of ATP in the discrimination between kinetic and membrane-potential-dependent calcium-ion efflux mechanisms

Nicholls, David G.; Scott, Ian G.

doi:10.1042/bj1860833

Cited by 149 publications

(71 citation statements)

References 39 publications

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“…After the addition of Ca 2ϩ (40 nmol/mg protein, giving 5 M free Ca 2ϩ ), most of it was taken up by energized mitochondria. However, the total amount of Ca 2ϩ taken up after glutamate addition was higher in the absence than in the presence of Na ϩ (about 41 Ϯ 1.6 versus 26.6 Ϯ 3.7 nmol/mg protein in MSK and MSKNa, respectively), as observed previously with rat brain mitochondria (58,67). Interestingly, MAS activity measured in these two conditions varied inversely with the accumulated Ca 2ϩ .…”

Section: Activitysupporting

confidence: 55%

Calcium Signaling in Brain Mitochondria

Contreras

Satrústegui

2009

Journal of Biological Chemistry

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Ca2؉ signaling in mitochondria has been mainly attributed to Ca 2؉ entry to the matrix through the Ca 2؉ uniporter and activation of mitochondrial matrix dehydrogenases. However, mitochondria can also sense increases in cytosolic Ca 2؉ and activation of mitochondrial dehydrogenases (mitDH) (1). However, mitochondria can also sense increases in cytosolic Ca 2ϩ through a mechanism that involves the aspartate-glutamate carriers (AGCs) and not the CaU (2-5). Aralar (Slc25a12), also named aralar1, the AGC isoform with predominant expression in brain (6 -8), is a component of the NADH malateaspartate shuttle (MAS), which in brain is activated by extramitochondrial Ca 2ϩ (S 0.5 324 nM) (4). Immunocytochemistry and in situ hybridization data and mRNA levels in acutely isolated brain cells indicate that aralar is localized preferentially in neurons (8 -12). This is consistent with a higher MAS activity in neuronal than astrocyte cultures (8) and with aralar being one of the more enriched proteins during differentiation of P19 cells to a neuronal phenotype (13). It is also consistent with the higher levels of aralar in total than in synaptosome-free mitochondrial fractions (9).Studies in cultured neurons, which have aralar as only AGC isoform, showed that small Ca 2ϩ signals that have limited access to mitochondria are able to activate the aralar-MAS pathway (4). However, large Ca 2ϩ signals that induce robust mitochondrial Ca 2ϩ transients fail to activate the pathway (4). This suggested that in neuronal mitochondria the aralar-MAS pathway is inhibited under conditions in which the CaUmitDH pathway is activated. This surprising result indicates that Ca 2ϩ activation of the malate aspartate shuttle and tricarboxylic acid cycle activity are somehow mutually exclusive in neurons. We have now studied the interplay between the AGG-MAS and CaU-mitDH pathways in brain mitochondria under Ca 2ϩ -stimulation conditions. Our results show that the shared metabolite ␣KG controls the relationship between the second transporter of MAS, the oxoglutarate carrier (OGC, Slc25a11), and ␣KGDH in the Krebs cycle, by virtue of the effects of Ca 2ϩ on the kinetics of ␣KGDH. Interestingly, the inhibition of OGC and MAS is fully reversible, in parallel with Ca 2ϩ egress from mitochondria. Behaviorally evoked brain activation results in an increased cerebral blood flow and increased glucose utilization, but paradoxically, this is not accompanied with an equivalent increase in oxygen utilization (14, 15). As a consequence, the oxygen glucose index, which is close to 6 when glucose is fully oxidized in resting conditions, falls to about 5 (16). This is accompanied by an increase in brain lactate production (14, 16 -19). Our results suggest that MAS inhibition during Ca 2ϩ -induced Krebs cycle activation would drive pyruvate to lactate formation and may play a role in lactate formation during brain activation. EXPERIMENTAL PROCEDURESAnimals and Materials-3-Month-old C57BL/6xSv129 mice were housed with a 12-h light cycle and fed ad libitum on standa...

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Section: Activitysupporting

confidence: 55%

Calcium Signaling in Brain Mitochondria

Contreras

Satrústegui

2009

Journal of Biological Chemistry

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“…The inner membranes of mammalian mitochondria, including those in the ␤-cell (418), possess a Ca 2ϩ uniporter (MCU) (36, 113) together with additional, incompletely characterized, accessory proteins (13, 102); uniporter activity increases as the 2.5 power of the ambient Ca 2ϩ concentration (557 ] c falls below the set-point and influx becomes slower than efflux (376). An early study of isolated mitochondria from transplanted insulinomas (418) showed that their calcium transport properties were broadly similar to those previously described for brain mitochondria (384), including a sodium-dependent efflux pathway, with the ability to buffer extramitochondrial free calcium in the 0.4 -0.8 M range.…”

Section: Calcium Interactions With Endoplasmic Reticulum and Mitomentioning

confidence: 87%

The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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The pancreatic ␤-cell secretes insulin in response to elevated plasma glucose. This review applies an external bioenergetic critique to the central processes of glucose-stimulated insulin secretion, including glycolytic and mitochondrial metabolism, the cytosolic adenine nucleotide pool, and its interaction with plasma membrane ion channels. The control mechanisms responsible for the unique responsiveness of the cell to glucose availability are discussed from bioenergetic and metabolic control standpoints. The concept of coupling factor facilitation of secretion is critiqued, and an attempt is made to unravel the bioenergetic basis of the oscillatory mechanisms controlling secretion. The need to consider the physiological constraints operating in the intact cell is emphasized throughout. The aim is to provide a coherent pathway through an extensive, complex, and sometimes bewildering literature, particularly for those unfamiliar with the field.

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“…In resting cells, the concentration of Ca 2+ in the cytosol has been estimated in the range of <100 nM to 300 nM (Carafoli, 1987;Cobbold and Rink, 1987;Crompton, 1985;Fiskum, 1985;Rasmussen and Barrett, 1984). The 'set-point' or cytosolic concentration at which Ca 2+ is accumulated in mitochondria has been determined to be ~500 nM (Nicholls and Scott, 1980), yet depending on the cell type it may also be much lower, as has been shown for hypoglossal motoneurons (von Lewinski and Keller, 2005). Mitochondria thus act as temporary sinks (in addition to endoplasmic reticulum [ER]) to protect cells from toxic Ca 2+ levels before releasing the Ca 2+ into the cytosol (Nicholls, 1985(Nicholls, , 1986.…”

Section: Ca 2+ Bufferingmentioning

confidence: 99%

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Foster

Galeffi

Gerich

et al. 2006

Progress in Neurobiology

164

135

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Mitochondria are critical for cellular ATP production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca 2+ levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. Among the techniques discussed are the uses of classic imaging techniques such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multi-photon imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

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The regulation of brain mitochondrial calcium-ion transport. The role of ATP in the discrimination between kinetic and membrane-potential-dependent calcium-ion efflux mechanisms

Cited by 149 publications

References 39 publications

Calcium Signaling in Brain Mitochondria

Calcium Signaling in Brain Mitochondria

The Pancreatic β-Cell: A Bioenergetic Perspective

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

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