Effects of maleate on the content of CoA and its derivatives in rat kidney mitochondria.

Pacanis, Anastasis; Strzelecki, T; Rogulski, J

doi:10.1016/s0021-9258(18)43001-3

Cited by 25 publications

(3 citation statements)

References 17 publications

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“…Maleyl-CoA reacts with amino acids and proteins of the renal brush border and uncouples sodium-dependent solute transport (58). Furthermore, maleyl-CoA reacts with free CoA to form a stable inert thioether, a form of CoA sequestration (62,63). Our data show that maleate is formed from propionate and from 3HP by different processes.…”

Section: Discussionmentioning

confidence: 75%

Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism

Wilson

Han

Zhang

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds, and ammonium accumulate in body fluids of patients with disorders of propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations of propionate, 3HP, and methylcitrate persist in body fluids. We hypothesized that conserved metabolic perturbations occurring in transplanted patients result from the simultaneous presence of propionate and 3HP in body fluids. We investigated the inter-relations of propionate and 3HP metabolism in perfused livers from normal rats using metabolomic and stable isotopic technologies. In the presence of propionate, 3HP, or both, we observed the following metabolic perturbations. First, the citric acid cycle (CAC) is overloaded but does not provide sufficient reducing equivalents to the respiratory chain to maintain the homeostasis of adenine nucleotides. Second, there is major CoA trapping in the propionyl-CoA pathway and a tripling of liver total CoA within 1 h. Third, liver proteolysis is stimulated. Fourth, propionate inhibits the conversion of 3HP to acetyl-CoA and its oxidation in the CAC. Fifth, some propionate and some 3HP are converted to nephrotoxic maleate by different processes. Our data have implications for the clinical management of propionic acidemia. They also emphasize the perturbations of the liver intermediary metabolism induced by supraphysiological, i.e., millimolar, concentrations of labeled propionate used to trace the intermediary metabolism, in particular, inhibition of CAC flux and major decreases in the [ATP]/[ADP] and [ATP]/[AMP] ratios.

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Section: Discussionmentioning

confidence: 75%

Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism

Wilson

Han

Zhang

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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“…The effect, observed by Wang et al [190], of the acetyl-CoA\CoA ratio on β-oxidation flux could be due to complete acylation. Some inhibitors of β-oxidation have been postulated to act by sequestration of intramitochondrial CoA [197,198].…”

Section: Control By Feedback Inhibition and The Acylation Statementioning

confidence: 99%

Mammalian mitochondrial β-oxidation

Eaton

Bartlett

Pourfarzam

1996

Biochemical Journal

384

253

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The enzymic stages of mammalian mitochondrial beta-oxidation were elucidated some 30-40 years ago. However, the discovery of a membrane-associated multifunctional enzyme of beta-oxidation, a membrane-associated acyl-CoA dehydrogenase and characterization of the carnitine palmitoyl transferase system at the protein and at the genetic level has demonstrated that the enzymes of the system itself are incompletely understood. Deficiencies of many of the enzymes have been recognized as important causes of disease. In addition, the study of these disorders has led to a greater understanding of the molecular mechanism of beta-oxidation and the import, processing and assembly of the beta-oxidation enzymes within the mitochondrion. The tissue-specific regulation, intramitochondrial control and supramolecular organization of the pathway is becoming better understood as sensitive analytical and molecular techniques are applied. This review aims to cover enzymological and organizational aspects of mitochondrial beta-oxidation together with the biochemical aspects of inherited disorders of beta-oxidation and the intrinsic control of beta-oxidation.

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“…In a study using alpha-methyl-D-glucoside uptake, MA impaired glucose transport in renal proximal tubules by inhibiting D-glucose movement from the cytoplasm across the antiluminal membrane into the blood and stimulated movement back across the brush-border membrane into urine [ 31 ]. A study measured and compared isolated mitochondria from the kidney and liver with and without MA treatment [ 32 ]. With MA, the CoA-SH content decreased as low as 10% of the original.…”

Section: Discussionmentioning

confidence: 99%

Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury

Lin,

Liang,

Yang

et al. 2024

Apoptosis

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Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI.

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Effects of maleate on the content of CoA and its derivatives in rat kidney mitochondria.

Cited by 25 publications

References 17 publications

Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism

Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism

Mammalian mitochondrial β-oxidation

Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury

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