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Maleic Acid--but Not Structurally Related Methylmalonic Acid--Interrupts Energy Metabolism by Impaired Calcium Homeostasis.

ABSTRACT: Maleic acid (MA) has been shown to induce Fanconi syndrome via disturbance of renal energy homeostasis, though the underlying pathomechanism is still under debate. Our study aimed to examine the pathomechanism underlying maleic acid-induced nephrotoxicity. Methylmalonic acid (MMA) is structurally similar to MA and accumulates in patients affected with methymalonic aciduria, a defect in the degradation of branched-chain amino acids, odd-chain fatty acids and cholesterol, which is associated with the development of tubulointerstitial nephritis resulting in chronic renal failure. We therefore used MMA application as a control experiment in our study and stressed hPTECs with MA and MMA to further validate the specificity of our findings. MMA did not show any toxic effects on proximal tubule cells, whereas maleic acid induced concentration-dependent and time-dependent cell death shown by increased lactate dehydrogenase release as well as ethidium homodimer and calcein acetoxymethyl ester staining. The toxic effect of MA was blocked by administration of single amino acids, in particular L-alanine and L-glutamate. MA application further resulted in severe impairment of cellular energy homeostasis on the level of glycolysis, respiratory chain, and citric acid cycle resulting in ATP depletion. As underlying mechanism we could identify disturbance of calcium homeostasis. MA toxicity was critically dependent on calcium levels in culture medium and blocked by the extra- and intracellular calcium chelators EGTA and BAPTA-AM respectively. Moreover, MA-induced cell death was associated with activation of calcium-dependent calpain proteases. In summary, our study shows a comprehensive pathomechanistic concept for MA-induced dysfunction and damage of human proximal tubule cells.

SUBMITTER: Tuncel AT

PROVIDER: S-EPMC4473014 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Maleic Acid--but Not Structurally Related Methylmalonic Acid--Interrupts Energy Metabolism by Impaired Calcium Homeostasis.

Tuncel Ali Tunç AT Ruppert Thorsten T Wang Bei-Tzu BT Okun Jürgen Günther JG Kölker Stefan S Morath Marina Alexandra MA Sauer Sven Wolfgang SW

PloS one 20150618 6

Maleic acid (MA) has been shown to induce Fanconi syndrome via disturbance of renal energy homeostasis, though the underlying pathomechanism is still under debate. Our study aimed to examine the pathomechanism underlying maleic acid-induced nephrotoxicity. Methylmalonic acid (MMA) is structurally similar to MA and accumulates in patients affected with methymalonic aciduria, a defect in the degradation of branched-chain amino acids, odd-chain fatty acids and cholesterol, which is associated with ...[more]

PMID: 26086473

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Project description:ObjectiveSevere acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis.DesignAn initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7?-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified.ResultsOn admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 ?mol/L [8.6-47.7] compared to 1.9 ?mol/L [1.7-3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower.ConclusionSAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

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Maleic Acid--but Not Structurally Related Methylmalonic Acid--Interrupts Energy Metabolism by Impaired Calcium Homeostasis.

Publications

Maleic Acid--but Not Structurally Related Methylmalonic Acid--Interrupts Energy Metabolism by Impaired Calcium Homeostasis.

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