Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance.

Chance, Britton; Leigh, J. S.; Kent, Jane A.; McCully, Kevin K.; Nioka, Shoko; Clark, Benjamin R.; Maris, J.; Graham, Thomas J. A.

doi:10.1073/pnas.83.24.9458

Cited by 237 publications

(141 citation statements)

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“…2). It is known from brain studies on animal models that it is pos sible to recognize stable and unstable states of me tabolism by knowing the ADP concentration (Clark et al, 1987;Delivoria-Papadopulos and Chance, 1988), the relationship between the rate of mito chondrial ATP biosynthesis and [ADP] having the characteristics of a rectangular hyperbola (Chance et al, 1985(Chance et al, ,1986. Therefore, an increased cytosolic free [ADP] indicates that the brain tissue operates nearer to the asymptote of the hyperbola and that brain cells are in a more unstable metabolic condi tion.…”

Section: Discussionmentioning

confidence: 99%

Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Barbiroli

Montagna

Martinelli

et al. 1993

J Cereb Blood Flow Metab

102

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Summary:We studied brain energy metabolism by phos phorus magnetic resonance spectroscopy e1p MRS) in 28 patients with mitochondrial cytopathies, and 20 normal control subjects. Fourteen patients had myopathy alone, six had only mild brain symptoms, and eight showed dif ferent degrees of brain involvement. Brain 31p MRS showed a low phosphocreatine content in all patients, accompanied by a high inorganic phosphate in 14 of 28 patients. The average value of the Pi concentration in the patient group was significantly (p = 0.009) different from the control group. The cytosolic pH was normal. From these data were derived a high concentration of ADP (calMitochondrial cytopathies are a heterogeneous group of diseases thought to be due to inherited disorders of mitochondrial function (Schneck et aI., 1973; Berenberg et aI., 1977; Di Mauro et aI., 1985), and characterized by a wide variety of clinical phe notypes (Schneck et aI., 1973; Berenberg et aI., 1977; Pavlakis et aI., 1984; Di Mauro et aI., 1985; Hurko and McKann, 1985; Bourd et aI., 1987; Frackowiak et aI., 1988;Wallace et at., 1988; Berk ovic et aI., 1989). Many patients show symptoms and signs involving multiple organs as in Kearns Sayre syndrome (KSS), in myoclonic epilepsy and Received July 30, 1992; final revision received December 9, 1992; accepted December 9, 1992.Address correspondence and reprint requests to Prof. B. Barbiroli at Istituto di Clinic a N eurologica, via U. Foscolo 7, 40123 Bologna, Italy.Abbreviations used: CPEO, chronic progressive external oph thalmoplegia; DRESS, depth-resolved surface-coil spectros copy; FID, free induction decay; KSS, Kearns-Sayre syndrome; LHON, Leber's hereditary optic neuropathy; MELAS, mito chondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy and ragged-red fibers; MRS, magnetic resonance spectroscopy; PCr, phosphocreatine; PP, phosphorylation potential. 469culated from the creatine kinase equilibrium), a high per cent value of V/V max for ATP biosynthesis, and a low phosphorylation potential, all features showing a de rangement of brain energy metabolism, in all patients with mitochondrial cytopathies. 31p MRS proved to be sensitive enough to disclose a deficit of mitochondrial functionality not only in the affected patients, but also in those without clinically evident brain symptoms. Key Words: Brain bioenergetics-Impaired brain energy me tabolism-Mitochondrial cytopathies-Brain MR spec troscopy.

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Section: Discussionmentioning

confidence: 99%

Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Barbiroli

Montagna

Martinelli

et al. 1993

J Cereb Blood Flow Metab

102

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“…ATP-consuming activity during muscular contraction (Chance et al, 1986;Katz et al, 1988) or during gluconeogenesis and ureogenesis (Tanaka et al, 1989), and upstream of the respiratory chain by reducing equivalent availability, i.e. dehydrogenase activity depending on the respiratory substrate metabolized (Berry et al, 1983;Nobes et al, 1990;Hassinen et al, 1990) and on calcium activation (Katz et al, 1988).…”

Section: Interactions Between Glucose Metabolism and Oxidative Phosphmentioning

confidence: 99%

“…We measured their activities under anaerobiosis and aerobiosis in the presence or absence of ethanol. the label at the level of fructose 1,6-bisphosphate by the action of aldolase and triosephosphate isomerase (den Hollander et al, 1979) and (b) the fructose-l,6-bisphosphatase activity (den Hollander et al, 1979(den Hollander et al, , 1986a. Using [l-"C]glucose or [6-'3C]glucose as substrate, it has been demonstrated that most of this scrambling is due to the aldolase and triosephosphate isomerase steps ; the contribution of the transaldolase pathway does not exceed 10% of the total for derepressed cells (den Hollander et al, 1986a).…”

Section: Atp-consuming Processes Linked To Glucose Metabolism Under Ementioning

confidence: 99%

Interactions between glucose metabolism and oxidative phosphorylations on respiratory‐competent Saccharomyces cerevisiae cells

Beauvoit

Rigoulet

Bunoust

et al. 1993

European Journal of Biochemistry

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The purpose of this work was to analyze the interactions between oxidative phosphorylations and glucose metabolism on yeast cells aerobically grown on lactate as carbon source and incubated in a resting cell medium. On such respiratory-competent yeast cells, four different metabolic steady states have particularly been studied: (a) glucose feeding under anaerobiosis, (b) ethanol supply under aerobiosis, (c) glucose supply under aerobiosis and (d) glucose plus ethanol under aerobiosis. For each condition, we measured: (a) the cellular ATP/ADP ratio and NADH content sustained under these conditions, (b) the glucose consumption rate (glucose conditions) and the respiratory rate (aerobic conditions).Under aerobic conditions, when ethanol is used as substrate, the ATP/ADP ratio and NADH level are very high as compared with glucose feeding. However, the rate of oxygen consumption is similar under both conditions. The main observation is a large increase in the respiratory rate when both glucose and ethanol are added. This increase corresponds to an ATP/ADP ratio and a NADH level lower than those observed with ethanol but higher than those with glucose. Therefore the response of the respiratory rate to the ATP/ADP ratio depends on the redox potential. We studied the way in which the ATP-consuming activity was increased under glucose + ethanol conditions. By NMR experiments, it appears that neither the futile cycle at the level of the phosphofructo-lkinase/fructo-l,6-bisphosphatase couple nor the synthesis of carbohydrate stores could account for the increase in oxidative phosphorylation. However, it is shown that, in the presence of glucose + ethanol, ATP consumption is strongly stimulated. It is hypothesized that this consumption is essentially due to the combination of the well-known plasma membrane proton-ATPase activation by glucose and the high phosphate potential due to oxidative ethanol metabolism. While it is well documented that oxidative phosphorylations inhibit the glycolytic flux, i.e. the Pasteur effect, we clearly show in this work that the glycolytic pathway limits the ability of mitochondria to maintain a cellular phosphate potential.Studies on isolated mitochondria have demonstrated that the ATP synthesis flux coupled to respiratory rate is controlled by the intramitochondrial phosphate potential value according to both the presence and the nature of the intra-or extramatricial ADP-regenerating system (Kuster et al

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“…47 Therefore, the differences in mitochondrial function ation of mitochondrial oxidative phosphorylation. [37][38][39] Therefore, the measurement of free ADP provides important infor-and ATP level between the two groups might be partly associated with the differences in the circulating TNF-a levels, mation with respect to the energy metabolism in the liver. Measurement of total ADP levels from tissue extracts overes-because enhanced TNF-a binding leads to reduction in circulating TNF-a levels in CK transgenic mice fed with creatine.…”

Section: Hours 48 Hours 72 Hours Dose Of Lps (Mg/kg) (%) (%) (%)mentioning

confidence: 99%

Induction of Endotoxin Tolerance in Transgenic Mouse Liver Expressing Creatine Kinase

et al. 1996

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bacterial outer membrane and interacts with cells of the imThe liver plays an important role in maintaining homune system, triggering activated monocytes and macromeostasis during endotoxin-triggered systemic inflamphages to release an excess of various inflammatory mediamatory response. To study the effects of phosphocretors. atine on hepatic energy metabolism after endotoxin Therefore, biological strategies directed at either altering administration, we used transgenic mice whose livers the circulating levels of LPS 2 or reducing levels of mediators express creatine kinase (CK). CK catalyzes a phosphoin response to LPS 3 have been used in attempts to improve creatine/creatine reaction, that is, an adenosine triphosthe recovery of septic patients. To date, however, none of phate (ATP) reservoir system. Because dietary supplethese substances, including antibodies to LPS, 4 antibodies to mentation with creatine leads to an accumulation of tumor necrosis factor a (TNF-a), 5 or the interleukin-1 (IL-1) creatine and phosphocreatine in transgenic livers, we compared the CK transgenic mice fed with creatine with receptor antagonist, 6 have been proven unequivocally to be the normally fed CK transgenic mice. In the creatine-fed effective in treating septic patients. It is not known whether mice, hepatic ATP, energy charge ([ATP / 0.5 adenosine anticytokine therapy can be effectively titrated to limit the diphosphate (ADP)]/[ATP / ADP / adenosine mono-harmful side-effects while also preserving the benefits of cytophosphate (AMP)]), and mitochondrial oxidative phos-kine. The immunosuppressive effects of one or more of the phorylation activities remained at high levels after in-mediator antagonists may have a negative effect on bacterial jection of 10 mg/kg of lipopolysaccharide (LPS) as clearance and tissue reparative processes. compared with those in normally fed mice. Furthermore, On the other hand, the liver plays an important role in there were beneficial effects on the functional reserve maintaining homeostasis during systemic inflammatory refor ATP synthesis and work-cost performance, as calcu-sponse with endotoxin. The hepatic response to acute inflamlated by free cytoplasmic ADP and the Michaelis con-mation includes compensation for the systemic metabolic destant (K m ). Interestingly, a reduction of tissue necrosis rangement and secretion of acute phase proteins that have factor a and interleukin-1a (IL-1a), and suppresion of roles in maintaining homeostasis through the inactivation of the decrease in glucose levels after LPS injection were proteases, facilitating wound healing, scavanging free oxygen observed in the creatine fed mice. Survival rates at 72 radicals, and producing macrophage opsonins. 7 Furthermore, hours after injection of 10 mg/kg of LPS significantly the liver is not only the most important organ in clearing increased in the creatine fed mice compared with the LPS, but also in inactivating it. 8 normally fed mice (80% vs. 24%, P õ .001). Therefore, weIn endotoxemia, activated neutrophils produ...

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Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance.

Abstract: Three types of metabolic control of oxidative metabolism are observed in the various tissues that have been studied by phosphorous magnetic resonance spectroscopy. The principal control of oxidative metabolism in skeletal muscle is by ADP (or P1/phosphocreatine). This

Cited by 237 publications

References 25 publications

Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Interactions between glucose metabolism and oxidative phosphorylations on respiratory‐competent Saccharomyces cerevisiae cells

Induction of Endotoxin Tolerance in Transgenic Mouse Liver Expressing Creatine Kinase

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Multiple controls of oxidative metabolism in living tissues as studied by phosphorus magnetic resonance.

Abstract: Three types of metabolic control of oxidative metabolism are observed in the various tissues that have been studied by phosphorous magnetic resonance spectroscopy. The principal control of oxidative metabolism in skeletal muscle is by ADP (or P1/phosphocreatine). This

Cited by 237 publications

References 25 publications

Defective Brain Energy Metabolism Shown by in vivo31P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Defective Brain Energy Metabolism Shown by in vivo31P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Interactions between glucose metabolism and oxidative phosphorylations on respiratory‐competent Saccharomyces cerevisiae cells

Induction of Endotoxin Tolerance in Transgenic Mouse Liver Expressing Creatine Kinase

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Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies

Defective Brain Energy Metabolism Shown by in vivo³¹P MR Spectroscopy in 28 Patients with Mitochondrial Cytopathies