The subcellular location of isozymes of NADP-isocitrate dehydrogenase in tissues from pig, ox and rat

Plaut, G.W.E.; Cook, Michael N.; Aogaichi, Tadashi

doi:10.1016/0304-4165(83)90177-0

Cited by 68 publications

(35 citation statements)

References 21 publications

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“…However, in the latter hearts, ATP is produced almost exclusively from CHO metabolism (97 Ϯ 7%) compared with 49 Ϯ 5% in controls. Second, perfused PPAR␣ null mouse hearts displayed an approximately threefold increase in citrate efflux and a 22% higher activity of NADP ϩ -isocitrate dehydrogenase, which reflects predominantly the mitochondrial isoform (32), although other measured CAC-related parameters were similar to those of controls, including the anaplerotic PC-to-CS flux ratio and tissue levels of CAC intermediates.…”

Section: Discussionmentioning

confidence: 94%

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

Gélinas¹,

Labarthe²,

Bouchard³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA ␤-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wkold peroxisome proliferator-activating receptor-␣ (PPAR␣) null mice (a model of FA ␤-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPAR␣ null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P Ͻ 0.001) at both preloads, PPAR␣ null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyruvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPAR␣ null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state. isolated working mouse heart perfusion; citric acid cycle; 13 C isotopomer analysis; glycolysis; ATP-citrate lyase; peroxisome proliferator-activated receptor-␣ IN THE HEALTHY adult heart, the concerted regulation of longchain fatty acid (LCFA) and carbohydrate (CHO) metabolism ensures optimal energy production, in which LCFAs are often considered to be the predominant energy substrate under most conditions. This contrasts with the hypertrophied and/or failing heart, which displays a shift from LCFAs toward CHOs utilization that has been attributed, at least in part, to the deactivation of peroxisome proliferator-activated receptor-␣ (PPAR␣) (5,12,28,36,41). This nuclear transcription factor, which is highly expressed in the heart, is known to be activated by fatty acids (FAs) and to regulate the expression of genes encoding for LCFA uptake and oxidation (7). Although this shift from LCFAs to CHOs for energy production has been shown to be benef...

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Section: Discussionmentioning

confidence: 94%

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

Gélinas¹,

Labarthe²,

Bouchard³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…In contrast with yeast, mammals possess two NADP-dependent isocitrate dehydrogenases, a mitochondrial (IDPm) and a cytosolic (IDPc) isoform [79], although the latter has also been ascribed to peroxisomes [80]. Both isoforms are major sources of NADPH supply in mammals.…”

Section: Nadp-dependent Dehydrogenases In Mammalsmentioning

confidence: 99%

The power to reduce: pyridine nucleotides – small molecules with a multitude of functions

Pollak

Dölle

Ziegler

2007

Biochemical Journal

634

550

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The pyridine nucleotides NAD and NADP play vital roles in metabolic conversions as signal transducers and in cellular defence systems. Both coenzymes participate as electron carriers in energy transduction and biosynthetic processes. Their oxidized forms, NAD + and NADP + , have been identified as important elements of regulatory pathways. In particular, NAD + serves as a substrate for ADP-ribosylation reactions and for the Sir2 family of NAD + -dependent protein deacetylases as well as a precursor of the calcium mobilizing molecule cADPr (cyclic ADP-ribose). The conversions of NADP + into the 2 -phosphorylated form of cADPr or to its nicotinic acid derivative, NAADP, also result in the formation of potent intracellular calcium-signalling agents. Perhaps, the most critical function of NADP is in the maintenance of a pool of reducing equivalents which is essential to counteract oxidative damage and for other detoxifying reactions. It is well known that the NADPH/NADP + ratio is usually kept high, in favour of the reduced form. Research within the past few years has revealed important insights into how the NADPH pool is generated and maintained in different subcellular compartments. Moreover, tremendous progress in the molecular characterization of NAD kinases has established these enzymes as vital factors for cell survival. In the present review, we summarize recent advances in the understanding of the biosynthesis and signalling functions of NAD(P) and highlight the new insights into the molecular mechanisms of NADPH generation and their roles in cell physiology.

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“…However, because of the low biosynthetic capacity of heart and muscle, it is unlikely to be important for mitochondria from these tissues. Furthermore, the activity of tricarboxylic acid transporters [24,25] in heart mitochondria, and of NADP-ICDH in the cytosol of heart cells [26,27] are very low. In summary, earlier hypotheses for the function of H+-Thase and NADP-ICDH might be partly correct when applied to liver but they do not adequately explain the high activities of these enzymes in heart and muscle.…”

Section: H+-transhydrogenasementioning

confidence: 99%

Proton‐translocating transhydrogenase and NAD‐ and NADP‐linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria

1994

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H'-transhydrogenase (H'-Thase) and NADP-linked isocitrate dehydrogenase (NADP-ICDH) are very active in animal mitochondria but their physiological function is only poorly understood. This is especially so in the case of the heart and muscle, where there are no major consumers of NADPH. We propose here that H'-Thase and NADP-ICDH have a combined function in the fine regulation of the activity of the tricarboxylic acid (TCA) cycle, providing enhanced sensitivy to changes in energy demand. This is achieved through cycling of substrates by NAD-linked ICDH, NADP-linked ICDH and H'-Thase. It is proposed that NAD-ICDH operates in the forward direction of the TCA cycle, but NADP-ICDH is driven in reverse by elevated levels of NADPH resulting from the action of the transmembrane proton electrochemical potential gradient (dp) on H'-Thase. This has the effect of increasing the sensitivity to allosteric modifiers of NAD-ICDH (NADH, ADP, ATP, Ca" etc), potentially giving rise to large changes in the net flux from iso-citrate to a-ketoglutarate. Furthermore, changes in the level of Ap resulting from changes in the demand for ATP would, via H'-Thase, shift the redox state of the NADP pool and this, in turn, would lead to a change in the rate of the reaction catalysed by NADP-ICDH and hence to an additional and complementary effect on the net metabolic flux from isocitrate to a-ketoglutarate.Other consequences of this substrate cycle are, (i) the production of heat at the expense of Ap, which may contribute to thermoregulation in the animal, and (ii) an increased rate of dissipation of Ap (leak).

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The subcellular location of isozymes of NADP-isocitrate dehydrogenase in tissues from pig, ox and rat

Cited by 68 publications

References 21 publications

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

The power to reduce: pyridine nucleotides – small molecules with a multitude of functions

Proton‐translocating transhydrogenase and NAD‐ and NADP‐linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria

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