Effect of methylmalonate on ketone body metabolism in developing rat brain

Patel, Mulchand S.; Owen, Oliver E.; Raefsky, Cindy

doi:10.1016/0024-3205(76)90372-6

Cited by 10 publications

(5 citation statements)

References 18 publications

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“…Early investigations focused on the effects of methylmalonate on metabolite transport in the liver and brain 24–41 . Through studies using liver mitochondria isolated from rats and hepatocytes from guinea pigs, methylmalonate was proposed to inhibit malate oxidation as well as PC and downstream gluconeogenesis by blocking malate transport 24,25 .…”

Section: Biochemical Pathology Of Mmamentioning

confidence: 99%

“…In a study where methylmalonate was incubated on cortex slices from 1‐week‐old rats, 3‐HBDH activity was lower via measurement of 3‐hydroybutyrate conversion to acetoacetate and propionate inhibited cerebral lipid synthesis 31 . In studies carried out in both rat liver and brain tissues, methylmalonate addition led to inhibition of succinate dehydrogenase (SDH) as well as Complex I and Complex II + III, and therefore became the attributed cause of reduced mitochondrial respiration 32–38 .…”

Section: Biochemical Pathology Of Mmamentioning

confidence: 99%

“…In a study where methylmalonate was incubated on cortex slices from 1-week-old rats, 3-HBDH activity was lower via measurement of 3-hydroybutyrate conversion to acetoacetate and propionate inhibited cerebral lipid synthesis. 31 In studies carried out in both rat liver and brain tissues, methylmalonate addition led to inhibition of succinate dehydrogenase (SDH) as well as Complex I and Complex II + III, and therefore became the attributed cause of reduced mitochondrial respiration. [32][33][34][35][36][37][38] Decreased respiration in the brain was hypothesized to lead to increased lactate production and glucose uptake and perhaps contributed to the convulsions seen in rodents that were administered methylmalonate directly into the brain.…”

Section: Direct Toxicity Of Mmamentioning

confidence: 99%

“…Early investigations focused on the effects of methylmalonate on metabolite transport in the liver and brain. [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Through studies using liver mitochondria isolated from rats and hepatocytes from guinea pigs, methylmalonate was proposed to inhibit malate oxidation as well as PC and downstream gluconeogenesis by blocking malate transport. 24,25 Other experiments carried out in rat brains indicate methylmalonate incubation via subcutaneous injection at day 15 of life increased brain glucose uptake but decreased uptake of β-hydroxybutyrate and thus led to indirect inhibition of β-hydroxybutyrate dehydrogenase (HBDH).…”

Section: Direct Toxicity Of Mmamentioning

confidence: 99%

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New insights into the pathophysiology of methylmalonic acidemia

Head

Meier

Venditti

2023

J of Inher Metab Disea

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Methylmalonic acidemia (MMA) is a severe inborn error of metabolism that is characterized by pleiotropic metabolic perturbations and multiorgan pathology. Treatment options are limited and non-curative as the underlying causative molecular mechanisms remain unknown. While earlier studies have focused on the potential direct toxicity of metabolites such as methylmalonic and propionic acid as a mechanism to explain disease pathophysiology, new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA and potentially reduced function of all three indicates aberrant acylation may require clinical intervention. Therefore, targeting posttranslational modifications may represent a new therapeutic approach to treat MMA and related organic acidemias.

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Section: Biochemical Pathology Of Mmamentioning

confidence: 99%

Section: Biochemical Pathology Of Mmamentioning

confidence: 99%

Section: Direct Toxicity Of Mmamentioning

confidence: 99%

Section: Direct Toxicity Of Mmamentioning

confidence: 99%

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New insights into the pathophysiology of methylmalonic acidemia

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Meier

Venditti

2023

J of Inher Metab Disea

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“…The present study was undertaken to examine the possible metabolic pathways by which P-hydroxybutyrate contributes to ACh synthesis in adult brain cortex slices. The effect of selective inhibitors, (-)-hydroxycitrate for ATP-citrate lyase (Watson et al, 1969) and methylmalonate for P-hydroxybutyrate dehydrogenase (EC 1.1.1.30; Patel et al, 1976;Tan et al, 1975), on incorporation of label into ACh from glucose and p-hydroxybutyrate was studied. Dilution of label from these substrates by acetoacetate was also determined.…”

mentioning

confidence: 99%

β‐Hydroxybutyrate as a Precursor to the Acetyl Moiety of Acetylcholine

Sterling¹,

McCafferty²,

O’Neill³

1981

Journal of Neurochemistry

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Rat brain cortex slices were incubated with 10 mM-glucose and trace amounts of [6-3H]glucose and [3-14C]beta-hydroxybutyrate. The effects of (-)-hydroxycitrate, an inhibitor of ATP-citrate lyase; methylmalonate, an inhibitor of beta-hydroxybutyrate dehydrogenase; and increasing concentrations of unlabeled acetoacetate were examined. The incorporation of label into lactate, citrate, malate, and acetylcholine (ACh) was measured and 3H:14C ratios calculated. Incorporation of [14C]beta-hydroxybutyrate into lactate was limited because of the low activity of gluconeogenic enzymes in brain, whereas incorporation of 14C label into Krebs cycle intermediates and ACh was higher than in previous experiments with [3H-,14C]-glucose. (-)-Hydroxycitrate (5.0 mM) reduced incorporation of [3H]glucose and [14C]beta-hydroxybutyrate into ACh. In contrast, slices incubated with methylmalonate (1 mM) showed a decrease in 14C incorporation without appreciably affecting glucose metabolism. The effects of high concentrations of methylmalonate were nonselective and yielded a generalized decrease in metabolism. Acetoacetate (1 mM) also produced a decreased 14C incorporation into ACh and its precursors. At 10 mM, acetoacetate reduced 3H and 14C incorporation into ACh without substantially affecting total ACh content. From the results, it is suggested that in adult rats beta-hydroxybutyrate can contribute to the acetyl moiety of ACh, possibly via the citrate cleavage pathway, though it is quantitatively less important than glucose and pyruvate. This contribution of ketone bodies could become significant should their concentration become abnormally high or glucose metabolism be reduced.

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Oxidation of amino acids, Krebs cycle intermediates, fatty acids and ketone bodies by Raja erinacea liver mitochondria

1986

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The oxidation of amino acids, Krebs cycle intermediates, fatty acids and ketone bodies was examined in a well-coupled mitochondria1 preparation from the liver of the little skate, Raja erinaceu Glutamate was the preferred amino acid on the basis of both the respiratory control ratio (RCR; 7.97 0.60 SE) and the state 3 rate (12.50 (+ 1.16 SE) nmoles 0 min (mg protein-'). Other amino acids, including sarcosine and 0-alanine, were oxidized at less than one third the rate of glutamate with RCRs less than 4. Oxidation of ornithine and arginine was not detected. Of the Krebs cycle intermediates tested, isocitrate had the best RCR and state 3 rate. Malate enhanced the oxidation of tricarboxylic acids (isocitrate and citrate) and aketoglutarate, probably by stimulation of transport into the mitochondria. Oxaloacetate and succinyl CoA were not oxidized at detectable rates. Pyruvate oxidation was low, even at high concentrations (10 mM). Fatty acids (as carnitine esters) were oxidized at high rates, especially hexanoyl (C-6), octanoyl (C-€9, decanoyl (C-101, lauroyl (C-121, and myristoyl (C-14) carnitine. Acetoacetate oxidation was not detected, but high rates of oxygen consumption were observed in response to 1 mM 0-hydroxybutyrate. Oxidation of this ketone body was malonate-sensitive, although 14C02 production from 3 (14C)-p-hydroxybutyrate was minimal, indicating that ketone body carbon was not entering the Krebs cycle. The malonate sensitivity of the oxidation process was due to direct inhibition of 0-hydroxybutyrate dehydrogenase (150 for malonate = 0.558 (k 0.031 SE) mM). The liver of this skate appears to be well suited to utilize fatty acids rather than ketone bodies or carbohydrate.Interest in the intermediary metabolism of skates has largely been confined to amino acid metabolism in relation to cell volume regulation. Skates maintain high intracellular levels of 0-alanine (BALA) and sarcosine.

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Effect of methylmalonate on ketone body metabolism in developing rat brain

Cited by 10 publications

References 18 publications

New insights into the pathophysiology of methylmalonic acidemia

New insights into the pathophysiology of methylmalonic acidemia

β‐Hydroxybutyrate as a Precursor to the Acetyl Moiety of Acetylcholine

Oxidation of amino acids, Krebs cycle intermediates, fatty acids and ketone bodies by Raja erinacea liver mitochondria

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