Glucagon Regulation of Oxidative Phosphorylation Requires an Increase in Matrix Adenine Nucleotide Content through Ca2+ Activation of the Mitochondrial ATP-Mg/Pi Carrier SCaMC-3

Amigo, Ignácio; Traba, Javier; Barroso, Gérard; Rueda, Carlos B.; Fernández, Margarita; Rial, Eduardo; Sánchez, Aránzazu; Satrústegui, Jorgina; Arco, Araceli del

doi:10.1074/jbc.m112.409144

Cited by 50 publications

(51 citation statements)

References 54 publications

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“…All experiments were performed in MSK devoid of EDTA at 30°C in the presence of 1 mM MgCl 2 and respiratory substrates (5 mM succinate plus 2 M rotenone), and in the presence or absence of AdNs (ATP or ADP). Mitochondrial swelling in liver mitochondria was measured by monitoring the decrease in absorbance of the suspension at 540 nm, reflecting decreased light scattering, as previously described (Amigo et al, 2012), using a Nicolet Evolution 300 spectrophotometer (Thermo Scientific) provided with temperature control and continuous stirring. Swelling was monitored through sequential additions of 200 -1000 nmol CaCl 2 .…”

Section: Cortical Neuron Cultures and Glutamate Treatmentmentioning

confidence: 99%

“…The detrimental role of PARP-1 activation in excitotoxicity has been attributed to the PAR polymer (Andrabi et al, 2006), whose formation depletes cytosolic NAD ϩ , which would lead to an impairment of the NAD ϩ -dependent steps of glycolysis (Alano et al, 2010) or to a reduction of cytosolic ATP as a result of ATP use in the resynthesis of NAD ϩ . However, little is known of the effects of PARP-1 activation on mitochondrial NAD ϩ and ATP levels, particularly within the time window of the immediate response to glutamate/NMDA.…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known of the effects of PARP-1 activation on mitochondrial NAD ϩ and ATP levels, particularly within the time window of the immediate response to glutamate/NMDA. SCaMCs/APCs are mitochondrial ATP-Mg/Pi carriers (Aprille, 1993;Fiermonte et al, 2004;del Arco and Satrú stegui, 2004) involved in Ca 2ϩ stimulation of mitochondrial respiration in liver and in increasing the Ca 2ϩ retention capacity (CRC) of mitochondria in cancer cells (Traba et al, 2012;Amigo et al, 2013 , resulting in changes in the total adenine nucleotide (AdN) concentration (ATP plus ADP plus AMP) in the mitochondrial matrix (Nosek et al, 1990). SCaMC-3/APC2/Slc25a23 expressed in liver and brain, and it is activated to half maximal levels at ϳ3.3 M Ca .…”

Section: Introductionmentioning

confidence: 99%

“…Another important player is poly(ADP ribose) polymerase-1 (PARP-1), activated by DNA strand breaks, which uses NAD ϩ to produce ADP-ribose polymers bound to proteins (Andrabi et al, 2006). Glutamate excitotoxicity causes the production of reactive oxygen species (ROS) and reactive nitrogen species (BrennanMinnella et al, 2013), which damage DNA and activate PARP-1, and neurons treated with PARP-1 inhibitors (Abramov and Duchen, 2008;Duchen, 2012) and PARP-1 KO mice are remarkably resistant to glutamate/NMDA excitotoxicity (Eliasson et al, 1997;Mandir et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-Dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons

et al. 2015

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Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca 2ϩ and Na ϩ influx, activation of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca 2ϩ deregulation. Mitochondria undergo early changes in membrane potential during excitotoxicity, but their precise role in these events is still controversial. Using primary cortical neurons derived from mice, we show that NMDA exposure results in a rapid fall in mitochondrial ATP in neurons deficient in SCaMC-3/Slc25a23, a Ca 2ϩ -regulated mitochondrial ATP-Mg/Pi carrier. This fall is associated with blunted increases in respiration and a delayed decrease in cytosolic ATP levels, which are prevented by PARP-1 inhibitors or by SCaMC-3 activity promoting adenine nucleotide uptake into mitochondria. SCaMC-3 KO neurons show an earlier delayed Ca 2ϩ deregulation, and SCaMC-3-deficient mitochondria incubated with ADP or ATP-Mg had reduced Ca 2ϩ retention capacity, suggesting a failure to maintain matrix adenine nucleotides as a cause for premature delayed Ca 2ϩ deregulation. SCaMC-3 KO neurons have higher vulnerability to in vitro excitotoxicity, and SCaMC-3 KO mice are more susceptible to kainate-induced seizures, showing that early PARP-1-dependent fall in mitochondrial ATP levels, counteracted by SCaMC-3, is an early step in the excitotoxic cascade.

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Section: Cortical Neuron Cultures and Glutamate Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-Dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons

et al. 2015

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“…Elevations in mitochondrial calcium significantly influence metabolism by increasing the rates of key reactions in the tricarboxylic acid (TCA) cycle and in electron transport, including those catalysed by pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase [44][45][46]. Increases in mitochondrial calcium may have other effects, such as those on the rate of transport of metabolites and adenine nucleotides, which may also affect gluconeogenesis [47][48][49]. Calcium-mediated increases in mitochondrial TCA cycle flux and substrate transport may prove to be an underappreciated site of action for glucagon in its regulation of hepatic glucose metabolism.…”

Section: Glucagon Modulation Of Hepatic Calcium Signalling and Mitochmentioning

confidence: 99%

Glucagon: acute actions on hepatic metabolism

Miller

Birnbaum

2016

Diabetologia

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Type 2 diabetes mellitus is the result of impaired systemic control of glucose homeostasis, in part through the dysregulation of the hormone glucagon. Glucagon acts on the liver to increase glucose production through alterations in hepatic metabolism, and reducing the elevated glucagon signalling in diabetic patients is an attractive strategy for the treatment of hyperglycaemia. Here we review the actions of the hormone in the liver, focusing on the acute alterations of metabolic pathways. This review summarises

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Extracellular ATP and glutamate drive pyruvate production and energy demand to regulate mitochondrial respiration in astrocytes

Juaristi

Llorente‐Folch

Satrústegui

et al. 2019

Glia

Self Cite

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Astrocytes respond to energetic demands by upregulating glycolysis, lactate production, and respiration. This study addresses the role of respiration and calcium regulation of respiration as part of the astrocyte response to the workloads caused by extracellular ATP and glutamate. Extracellular ATP (100 μM to 1 mM) causes a Ca2+‐dependent workload and fall of the cytosolic ATP/ADP ratio which acutely increases astrocytes respiration. Part of this increase is related to a Ca2+‐dependent upregulation of cytosolic pyruvate production. Conversely, glutamate (200 μM) causes a Na+, but not Ca2+, dependent workload even though glutamate‐induced Ca2+ signals readily reach mitochondria. The glutamate workload triggers a rapid fall in the cytosolic ATP/ADP ratio and stimulation of respiration. These effects are mimicked by D‐aspartate a nonmetabolized agonist of the glutamate transporter, but not by a metabotropic glutamate receptor agonist, indicating a major role of Na+‐dependent workload in stimulated respiration. Glutamate‐induced increase in respiration is linked to a rapid increase in glycolytic pyruvate production, suggesting that both glutamate and extracellular ATP cause an increase in astrocyte respiration fueled by workload‐induced increase in pyruvate production. However, glutamate‐induced pyruvate production is partly resistant to glycolysis blockers (iodoacetate), indicating that oxidative consumption of glutamate also contributes to stimulated respiration. As stimulation of respiration by ATP and glutamate are similar and pyruvate production smaller in the first case, the results suggest that the response to extracellular ATP is a Ca2+‐dependent upregulation of respiration added to glycolysis upregulation. The global contribution of astrocyte respiratory responses to brain oxygen consumption is an open question.

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Glucagon Regulation of Oxidative Phosphorylation Requires an Increase in Matrix Adenine Nucleotide Content through Ca2+ Activation of the Mitochondrial ATP-Mg/Pi Carrier SCaMC-3

Cited by 50 publications

References 54 publications

Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-Dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons

Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-Dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons

Glucagon: acute actions on hepatic metabolism

Extracellular ATP and glutamate drive pyruvate production and energy demand to regulate mitochondrial respiration in astrocytes

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