Methylmalonate administration decreases Na+,K+-ATPase activity in cerebral cortex of rats

Wyse, Angela T. S.; Streck, Emílio L.; Barros, Sonja Verginia Tamborena; Brusque, Ana Maria; Zugno, Alexandra I.; Wajner, Moaçir

doi:10.1097/00001756-200007140-00052

Cited by 118 publications

(50 citation statements)

References 5 publications

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“…An effect on the malate carrier at higher concentrations might be theoretically interesting; however, it is questionable whether this effect has any relevance for the pathophysiology of methylmalonic acidurias. Apart from this, MMA was shown to inhibit pyruvate carboxylase (34) and Na ϩ /K ϩ -ATPases (35).…”

Section: Discussionmentioning

confidence: 99%

Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

Kölker¹,

Schwab²,

Hörster³

et al. 2003

Journal of Biological Chemistry

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Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonic acid and alternative metabolites. An impairment of energy metabolism plays a key role in the pathophysiology of this disease, resulting in neurodegeneration of the basal ganglia and renal failure. It has become the subject of intense debates whether methylmalonic acid is the major toxin, inhibiting respiratory chain complex II. To elucidate whether methylmalonic acid is a respiratory chain inhibitor, we used spectrophotometric analysis of complex II activity in submitochondrial particles from bovine heart, radiometric analysis of 14 C-labeled substrates (pyruvate, malate, succinate), and analysis of ATP production in muscle from mice. Methylmalonic acid revealed no direct effects on the respiratory chain function, i.e. on single electron transferring complexes I-IV, ATPase, and mitochondrial transporters. However, we identified a variety of variables that must be carefully controlled to avoid an artificial inhibition of complex II activity. In summary, the study verifies our hypothesis that methylmalonic acid is not the major toxic metabolite in methylmalonic acidurias. Inhibition of respiratory chain and tricarboxylic acid cycle is most likely induced by synergistically acting alternative metabolites, in particular 2-methylcitric acid, malonic acid, and propionyl-CoA.

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Section: Discussionmentioning

confidence: 99%

Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

Kölker¹,

Schwab²,

Hörster³

et al. 2003

Journal of Biological Chemistry

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“…It has been demonstrated that MMA loading decreases the ATP/ADP ratio in neuronal rat cultures and, concomitantly, the resting membrane potential (13). Furthermore, it has been shown that MMA decreases Na ϩ /K ϩ -ATPase activity (42). Consequently, membrane depolarization in general and the removal of the voltage-dependent Mg 2ϩ block of NMDA receptors in particular, results in an unimpeded influx of Ca 2ϩ and Na ϩ into neurons in general (43,44), and after MMA loading in particular (13).…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Okun¹,

Hörster²,

Farkas³

et al. 2002

Journal of Biological Chemistry

162

151

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Methylmalonic acidurias are biochemically characterized by an accumulation of methylmalonate (MMA) and alternative metabolites. There is growing evidence for basal ganglia degeneration in these patients. The pathomechanisms involved are still unknown, a contribution of toxic organic acids, in particular MMA, has been suggested. Here we report that MMA induces neuronal damage in cultures of embryonic rat striatal cells at a concentration range encountered in affected patients. MMA-induced cell damage was reduced by ionotropic glutamate receptor antagonists, antioxidants, and succinate. These results suggest the involvement of secondary excitotoxic mechanisms in MMA-induced cell damage. MMA has been implicated in inhibition of respiratory chain complex II. However, MMA failed to inhibit complex II activity in submitochondrial particles from bovine heart. To unravel the mechanism underlying neuronal MMA toxicity, we investigated the formation of intracellular metabolites in MMA-loaded striatal neurons. There was a time-dependent intracellular increase in malonate, an inhibitor of complex II, and 2-methylcitrate, a compound with multiple inhibitory effects on the tricarboxylic acid cycle, suggesting their putative implication in MMA neurotoxicity. We propose that neuropathogenesis of methylmalonic aciduria may involve an inhibition of complex II and the tricarboxylic acid cycle by accumulating toxic organic acids, and synergistic secondary excitotoxic mechanisms.

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“…MMA has been demonstrated to provoke behavioral alterations, seizures and striatal lesions in rats after intrastriatal administration through activation of glutamate receptors, energy depletion and oxidative damage (de Mello et al 1996;Wyse et al 2000;Fighera et al 2003;Malfatti et al 2003;Ribeiro et al 2005;Royes et al 2003Royes et al , 2005Royes et al , 2006Furian et al 2007). Other experimental studies confirmed that impairment of brain mitochondrial energy metabolism, alterations of the redox status and glutamatergic neurotransmission may represent important pathomechanisms of MMA neurotoxicity (Wajner and Coelho 1997;McLaughlin et al 1998;Fontella et al 2000;Kölker et al 2000;Brusque et al 2001Brusque et al , 2002Okun et al 2002;Malfatti et al 2003;Pettenuzzo et al 2006).…”

Section: Introductionmentioning

confidence: 98%

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

et al. 2011

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Methylmalonic acidemia and propionic acidemia are organic acidemias biochemically characterized by predominant tissue accumulation of methylmalonic acid (MMA) and propionic acid (PA), respectively. Affected patients present predominantly neurological symptoms, whose pathogenesis is not yet fully established. In the present study we investigated the in vitro effects of MMA and PA on important parameters of lipid and protein oxidative damage and on the production of reactive species in synaptosomes from cerebrum of developing rats. Synaptosomes correspond to nerve terminals that have been used to investigate toxic properties of compounds on neuronal cells. The in vivo effects of intrastriatal injection of MMA and PA on the same parameters and on enzymatic antioxidant defenses, were also studied. MMA-induced in vitro and in vivo lipid peroxidation and protein oxidative damage. Furthermore, the lipid oxidative damage was attenuated or prevented, pending on the doses utilized, by the free radical scavengers α-tocopherol, melatonin and by the NMDA glutamate receptor antagonist MK-801, implying the involvement of reactive species and glutamate receptor activation in these effects. In addition, 2',7'-dichlorofluorescein diacetate oxidation was significantly increased in synaptosomes by MMA, reinforcing that reactive species generation is elicited by this organic acid. We also verified that glutathione peroxidase activity was inhibited by intrastriatal MMA injection. In contrast, PA did not induce any significant effect on all parameters examined in vitro and in vivo, implying a selective action for MMA. The present data demonstrate that oxidative stress is induced by MMA in vitro in nerve terminals and in vivo in striatum, suggesting the participation of neuronal cells in MMA-elicited oxidative damage.

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Methylmalonate administration decreases Na+,K+-ATPase activity in cerebral cortex of rats

Cited by 118 publications

References 5 publications

Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

Methylmalonic Acid, a Biochemical Hallmark of Methylmalonic Acidurias but No Inhibitor of Mitochondrial Respiratory Chain

Neurodegeneration in Methylmalonic Aciduria Involves Inhibition of Complex II and the Tricarboxylic Acid Cycle, and Synergistically Acting Excitotoxicity

Experimental Evidence that Methylmalonic Acid Provokes Oxidative Damage and Compromises Antioxidant Defenses in Nerve Terminal and Striatum of Young Rats

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