Experimental evidence that maleic acid markedly compromises glutamate oxidation through inhibition of glutamate dehydrogenase and α-ketoglutarate dehydrogenase activities in kidney of developing rats

Abstract

Maleic acid (MA), which has been reported to be highly excreted in propionic acidemia (PAcidemia), was demonstrated to cause nephropathy by bioenergetics impairment and oxidative stress, but the effects on kidney mitochondrial respiration has not yet been properly investigated. Therefore, the present study investigated the effects of MA (0.05–5 mM), as well as of propionic (PA) and 3-hydroxypropionic (3OHPA) acids (5 mM) that accumulate in PAcidemia, on mitochondrial respiration supported by glutamate, glutamate plus malate or succinate in mitochondrial fractions and homogenates from rat kidney, as well as in permeabilized kidney cells. MA markedly decreased oxygen consumption in state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respiration in glutamate and glutamate plus malate-respiring mitochondria, with less prominent effects when using succinate. We also found that PA significantly decreased state 3 and uncoupled respiration in glutamate- and glutamate plus malate-supported mitochondria, whereas 3OHPA provoked milder or no changes. Furthermore, glutamate dehydrogenase and α-ketoglutarate dehydrogenase activities necessary for glutamate oxidation were significantly inhibited by MA in a dose-dependent and competitive fashion. The MA-induced decrease of state 3 and uncoupled respiration found in mitochondrial fractions were also observed in homogenates and permeabilized renal cells that better mimic the in vivo cellular milieu. Taken together, our data indicate that MA, and PA to a lesser extent, disturb mitochondrial-oxidative metabolism in the kidney with the involvement of critical enzymes for glutamate oxidation. It is postulated that our present findings may be possibly involved in the chronic renal failure observed in patients with PAcidemia.

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Abbreviations

ANOVA:

Analysis of variance

C-I:

Complex I

C-II:

Complex II

CAC:

Citric acid cycle

CCCP:

Carbonyl cyanide m-chloro phenyl hydrazone

CS:

Citrate synthase

DCIP:

Dichloroindophenol

ETS:

Electron transfer system

FS:

Fanconi syndrome

FAU:

Fluorescence arbitrary unity

GDH:

Glutamate dehydrogenase

HEK:

Human embryonic kidney

3OHPA:

3-Hydroxypropionic acid

α-KGDH:

α-Ketoglutarate dehydrogenase

MA:

Maleic acid

MDH:

Malate dehydrogenase

OXPHOS:

Oxidative phosphorylation

PA:

Propionic acid

PAcidemia:

Propionic acidemia

PMG:

Pyruvate plus malate plus glutamate

RCR:

Respiratory control ratio

SPSS:

Statistical Package for the Social Sciences

SUIT:

Substrate-uncoupler inhibitor titration

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Acknowledgements

This work was supported by Grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 404883/2013-3), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, 17/2551-0000/800-6), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Financiadora de Estudos e Projetos 01.06.0842-00 and Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção 573677/2008-5.

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Correspondence to Alexandre Umpierrez Amaral.

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All procedures performed in animals were in accordance with the “Principles of Laboratory Animal Care” (NIH publication no. 8023, revised 1996) and with the approval of Ethics Committee for Animal Research of the Universidade Federal do Rio Grande do Sul (no. 32076) and Universidade Regional Integrada do Alto Uruguai e das Missões (no. 35/2016). Furthermore, this article does not contain any studies with human participants performed by any of the authors.

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Roginski, A.C., Cecatto, C., Wajner, S.M. et al. Experimental evidence that maleic acid markedly compromises glutamate oxidation through inhibition of glutamate dehydrogenase and α-ketoglutarate dehydrogenase activities in kidney of developing rats. Mol Cell Biochem 458, 99–112 (2019). https://doi.org/10.1007/s11010-019-03534-7

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Keywords

  • Maleic acid
  • Propionic acid
  • Mitochondrial-oxidative metabolism
  • Propionic acidemia
  • Renal failure