Reducing Equivalent Shuttles in Developing Porcine Myocardium: Enhanced Capacity in the Newborn Heart

Scholz, Thomas; Koppenhafer, Stacia L.

doi:10.1203/00006450-199508000-00015

Cited by 32 publications

(21 citation statements)

References 22 publications

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“…1). The activity of mitGPDH in heart mitochondria was not detectable under the conditions of this study, in agreement with the data of Scholz et al (42,43) who found a marked decrease of glycerol 3-phosphate shuttle activity in the heart with development. The enzyme requires Ca 2ϩ in the intermembrane space, as full activation is obtained in the presence of RR in all tissues.…”

Section: Regulation Of Mas and Glycerol-3-p Dehydrogenase Activity Bysupporting

confidence: 82%

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: Regulation Of Mas and Glycerol-3-p Dehydrogenase Activity Bysupporting

confidence: 82%

Calcium Signaling in Brain Mitochondria

Contreras

Satrústegui

2009

Journal of Biological Chemistry

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“…It is therefore possible that adult cardiomyocytes have different mechanisms to handle and respond to cytosolic NADH increases. For example, the adult heart has a much lower NADH shuttle capacity compared with the neonatal heart (42). In support of a cytosolic source of NADH-induced ROS in the heart, Mohazzab et al (38) demonstrated that lactate induced superoxide production in calf cardiomyocytes by lucigenin assay.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Liu

O’Rourke

2013

Journal of Biological Chemistry

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Background: Regulation of the sarcolemmal Na ϩ /Ca 2ϩ exchanger (NCX) modulates cardiac excitation-contraction coupling, and NCX contributes to ischemia-reperfusion injury. Results: Increased cytosolic NADH inhibits NCX through a ROS-dependent mechanism. Conclusion: Regulation by cytosolic NADH reveals a novel way that NCX responds to changes in energy metabolism. Significance: NADH-dependent regulation of NCX regulation represents a potential therapeutic target for ameliorating ischemia-reperfusion injury or chronic cardiovascular disease.

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“…Capacity of the malate/aspartate shuttle was determined as described previously (25,26,28). Cytosolic components were added in saturating concentrations to 50 g of intact cardiac mitochondria, and the rate of oxidation of NADH was monitored at 340 nm at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Correlation between myocardial malate/aspartate shuttle activity and EAAT1 protein expression in hyper- and hypothyroidism

Ralphe

Bedell

Segar

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Correlation between myocardial malate/aspartate shuttle activity and EAAT1 protein expression in hyper-and hypothyroidism. Am J Physiol Heart Circ Physiol 288: H2521-H2526, 2005. First published December 22, 2004; doi:10.1152/ajpheart.00991.2004.-In the heart, elevated thyroid hormone leads to upregulation of metabolic pathways associated with energy production and development of hypertrophy. The malate/aspartate shuttle, which transfers cytosolicreducing equivalents into the cardiac mitochondria, is increased 33% in hyperthyroid rats. Within the shuttle, the aspartate-glutamate carrier is rate limiting. The excitatory amino acid transporter type 1 (EAAT1) functions as a glutamate carrier in the malate/aspartate shuttle. In this study, we hypothesize that EAAT1 is regulated by thyroid hormone. Adult rats were injected with triiodothyronine (T 3) or saline over a period of 8 -9 days or provided with propylthiouracil (PTU) in their drinking water for 2 mo. Steady-state mRNA levels of EAAT1 and aralar1 and citrin (both cardiac mitochondrial aspartate-glutamate transporters) were determined by Northern blot analysis and normalized to 18S rRNA. A spectrophotometric assay of maximal malate/ aspartate shuttle activity was performed on isolated cardiac mitochondria from PTU-treated and control animals. Protein lysates from mitochondria were separated by SDS-PAGE and probed with a human anti-EAAT1 IgG. Compared with control, EAAT1 mRNA levels (arbitrary units) were increased nearly threefold in T3-treated (3.1 Ϯ 0.5 vs. 1.1 Ϯ 0.2; P Ͻ 0.05) and decreased in PTU-treated (2.0 Ϯ 0. 3 vs. 5.2 Ϯ 1; P Ͻ 0.05) rats. Aralar1 mRNA levels were unchanged in T3-treated and somewhat decreased in PTU-treated (7.1 Ϯ 1.0 vs. 9.3 Ϯ 0.1, P Ͻ 0.05) rats. Citrin mRNA levels were decreased in T3-treated and unchanged in PTU-treated rats. EAAT1 protein levels (arbitrary units) in T3-treated cardiac mitochondria were increased compared with controls (8.9 Ϯ 0.4 vs. 5.9 Ϯ 0.6; P Ͻ 0.005) and unchanged in PTU-treated mitochondria. No difference in malate/ aspartate shuttle capacity was found between PTU-treated and control cardiac mitochondria. Hyperthyroidism in rats is related to an increase in cardiac expression of EAAT1 mRNA and protein. The 49% increase in EAAT1 mitochondrial protein level shows that malate/ aspartate shuttle activity increased in hyperthyroid rat cardiac mitochondria. Although hypothyroidism resulted in a decrease in EAAT1 mRNA, neither the EAAT1 protein level nor shuttle activity was affected. EAAT1 regulation by thyroid hormone may facilitate increased metabolic demands of the cardiomyocyte during hyperthyroidism and impact cardiac function in hyperthyroidism. thyroid hormone; myocardial hypertrophy GIVEN THE CENTRAL ROLE OF the heart in responding to physiological changes and the high energy requirements of the myocardium, it is not surprising that cardiac myocytes are sensitive to the effects of thyroid hormone. Thyroid hormone acts on the heart through mechanisms that are both independent of and dependent on gene tra...

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Reducing Equivalent Shuttles in Developing Porcine Myocardium: Enhanced Capacity in the Newborn Heart

Cited by 32 publications

References 22 publications

Calcium Signaling in Brain Mitochondria

Calcium Signaling in Brain Mitochondria

Regulation of the Na+/Ca2+ Exchanger by Pyridine Nucleotide Redox Potential in Ventricular Myocytes

Correlation between myocardial malate/aspartate shuttle activity and EAAT1 protein expression in hyper- and hypothyroidism

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