Hepatic Accumulation of Pyrophosphate during Acetate Metabolism1

Yamada, Tōru; Inoue, Toru; Nishida, Toshirou; Furuya, Eisuke; Tagawa, Kunio

doi:10.1093/oxfordjournals.jbchem.a122561

Cited by 10 publications

(18 citation statements)

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“…Elevated acetate concentrations were shown to cause an influx of divalent cations, Ca 2+ and Mg 2+ into the liver mitochondria forming precipitates in the presence of 2 mM CaMgPPi. This process of rapid formation of complexes of CaMgPPi within the mitochondria is only compatible with the formation of the mitochondrial permeability transition pore provided that an opening of a calcium ion channel and activation of protein kinase A also occurs (Yamada et al, 1988). Beavis and Garlid demonstrated that depletion of Mg 2+ from the mitochondria matrix causes the formation of the unregulated mitochondrial permeability transition pore (Beavis and Garlid, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…In man, blood acetate can reach as high a level as 1.5 mM when consuming variable quantities of alcohol (Chen et al, 2009; Lundquist, 1962). It is therefore possible under certain hormonal conditions (Yamada et al, 1988), pore opening could occur during ethanol consumption and its metabolism in man. It is therefore possible that the ability of acetate to form the mitochondrial permeability transition pore, may under certain conditions, account for some ethanol related cerebral pathologies.…”

Section: Discussionmentioning

confidence: 99%

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Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

Pawlosky

Kashiwaya

Srivastava

et al. 2010

Alcoholism Clin & Exp Res

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Background Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Methods Rats were infused with solutions of sodium acetate, ethanol, or saline containing 13C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs’ cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Results Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of 13C-glucose into the brain compared to controls and the concentration of brain 13C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg2+ in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, α-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD+]/[NADH] was lower, the free mitochondrial [NAD+]/[NADH] and [CoQ]/[CoQH2] were oxidized and the ΔG′ of ATP lowered by acetate infusion from −61.4 kJ to −59.9 kJ/mol. Conclusions Animals with elevated levels of blood ethanol or acetate had decreased 13C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in 13C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in ΔG′ of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

Pawlosky

Kashiwaya

Srivastava

et al. 2010

Alcoholism Clin & Exp Res

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“…They have indicated that PPi is almost entirely intramitochondrial, and that treatment with glucagon and vasopressin increases the PPi concentration to 4 times that in control cells. In acetate metabolism, PPi is formed in both the cytosol and the mitochondria (Aas & Bremer, 1968; Barth et al, 1971), but and we (Yamada et al, 1988) also suggested that PP1 accumulated mainly in mitochondria. Under physiological conditions, mitochondria are not regarded as very important organelles in the regulation of cytosolic Ca2" (Somlyo et al, 1985;Carafoli, 1987), because of their low-affinity uptake system for the ion.…”

Section: Introductionmentioning

confidence: 61%

“…Acetate + ATP + CoA -+ acetyl-CoA + AMP + PP, Intraperitoneal injection of acetate into starved rats has been reported to increase the PP, concentration in the liver to more than 100 times that in normal liver (Veech et al, 1986;Veech & Gitomer, 1988). In a previous paper we reported that a high intracellular level of Ca2`caused by the synergistic actions of Ca2+-mobilizing hormones, such as noradrenaline, and glucagon is indispensable for the accumulation of PPi in perfused rat liver (Yamada et al, 1988). This observation is consistent with the findings that the accumulation of PP, was much less in fed animals (Veech et al, 1980(Veech et al, , 1986 & Gitomer, 1988; T. Inoue, unpublished work), and that isolated hepatocytes accumulated PPi in the presence of a Ca2ì onophore .…”

Section: Introductionmentioning

confidence: 95%

Ca2+-induced accumulation of pyrophosphate in mitochondria during acetate metabolism

Inoue

Yamada

Furuya

et al. 1989

Biochemical Journal

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The mechanism of pyrophosphate (PPi) accumulation in rat liver during acetate metabolism was investigated. Perfusion of the liver with acetate in the presence of noradrenaline and glucagon induced marked accumulation of PPi (2 mumol/g of liver, 200 times that of control). In contrast, perfusion with glutamine, which generates PPi only in the cytosol, caused little accumulation of PPi, even in the presence of the two hormones. The site of PPi accumulation was shown to be the mitochondria by the finding that isolated mitochondria from the liver perfused with acetate and the hormones contained 50 nmol of PPi/mg of protein. The addition of an uncoupler to mitochondria with accumulated PPi caused gradual decrease in their PPi content, with concomitant release of a stoichiometric amount of Ca2+. Similar accumulation of PPi was observed when isolated mitochondria were incubated with acetate and Ca2+. These results show that an increase in cytosolic Ca2+ caused by the co-administration of the two hormones induced uptake of the ion into mitochondria, and that PPi accumulated in mitochondria only when it was generated in the organelles with an elevated concentration of Ca2+. High mitochondrial concentrations of Ca2+ are considered to inhibit inorganic pyrophosphatase through the formation of a stable complex, CaPPi-. Mitochondria with accumulated PPi had normal respiratory activities, and their adenine nucleotide concentrations were increased 2-fold rather than being decreased, the increases also being considered to be caused by their high concentration of Ca2+.

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“…In liver, the mPTP is opened by a decrease in the ATP/ADP × Pi ratio subsequent to the metabolism of short‐chain fatty acids, and results in a massive uptake of CaMgPPi within the mitochondrial matrix (9, 10). Opening of the mPTP and intramitochondrial accumulation of CaMgPPi is facilitated by the presence of calcium mobilizing hormone and cyclic AMP (11). When TBI causes mPTP opening, acute cell death or initiation of slower cell death by apoptosis is likely to follow.…”

Section: Pathophysiologymentioning

confidence: 99%

The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury

2012

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Summary The pathological consequences of traumatic head injury result largely from the opening of the mitochondrial permeability transition pore, mPTP. The mPTP opens due to a decrease in brain phosphorylation energy resulting in a further decrease in brain ATP production and a measurable increase in brain heat generation and temperature. The increase in brain temperature can be measured transcranially by near infrared spectroscopy which can be used to diagnoses TBI and to monitor treatment. Effective therapy of TBI can be achieved by closure of the mPTP by administration of cyclosporine A or by oral administration of ketone body esters. While ketosis has previously been known to prevent damage from TBI, the availability of oral ketone esters presents the first practical modality of achieving therapeutic levels of ketone bodies.

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Hepatic Accumulation of Pyrophosphate during Acetate Metabolism1

Cited by 10 publications

References 0 publications

Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

Ca2+-induced accumulation of pyrophosphate in mitochondria during acetate metabolism

The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury

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