Methylmalonate toxicity in primary neuronal cultures

McLaughlin, BethAnn; Nelson, David S.; Silver, Ian A.; Erecińska, Maria; Chesselet, M.-F.

doi:10.1016/s0306-4522(97)00594-0

Cited by 99 publications

(76 citation statements)

References 57 publications

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“…Thus, it seemed reasonable to suggest MMA as an endogenous toxic metabolite inducing neurodegenerative changes via impairment of energy metabolism (7,12). In fact, administration of MMA in vitro and in vivo induced neuronal cell damage involving ionotropic glutamate receptors and oxidative stress (13)(14)(15)(16)(17). Although two previous studies from the same group demonstrated inhibition of complex II activity by MMA (10, 11), we could not confirm this finding in a recent study (15).…”

Section: Discussionmentioning

confidence: 66%

“…It has been hypothesized that MMA induced inhibition of complex II (synonym, succinate:ubiquinone oxidoreductase), a multiprotein assembly imparted in the tricarboxylic acid cycle and the mitochondrial respiratory chain, has become a focus of interest (12). MMA induced cell damage in different neuronal culture systems (13)(14)(15) and evokes rotational behavior, seizures, and striatal lesions in rats after intrastriatal administration (16,17). MMA-induced changes were prevented by succinate, antagonists of ionotropic glutamate receptors, and antioxidants (15,16,18).…”

mentioning

confidence: 99%

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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: 66%

mentioning

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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“…This was highlighted in the mid-1990s with the discovery of the first SDHA mutation linked to LS (Bourgeron et al, 1995). This observation was corroborated by various studies showing the proapoptotic effects of specific complex II inhibitors, notably 3-nitropropionate (irreversible inhibitor) and methylmalonate (competitive inhibitor) in neuronal cells (Pang and Geddes, 1997;McLaughlin et al, 1998). Both reagents target the SDHA succinate-binding site and equally inhibit the SDH and SQR activities (Brusque et al, 2002;Lemarie et al, 2011).…”

Section: Role Of Complex II In Apoptosismentioning

confidence: 83%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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“…Forebrain neuronal-enriched cultures were prepared from embryonic day 17 rat fetuses as previously described (McLaughlin et al, 1998). Dissociated cells were plated on poly-Lornithine-treated tissue culture plates in a growth medium composed of 80% DM EM (high glucose with L-glutamine and without sodium pyruvate), 10% Ham's F12-Nutrients (Sigma), 10% bovine calf serum (heatinactivated) with antimycotic -antibiotic mixture (with amphotericin B and streptomycin sulfate).…”

Section: Methodsmentioning

confidence: 99%

p38 Activation Is Required Upstream of Potassium Current Enhancement and Caspase Cleavage in Thiol Oxidant-Induced Neuronal Apoptosis

et al. 2001

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Oxidant-induced neuronal apoptosis has been shown to involve potassium and zinc dysregulation, energetic dysfunction, activation of stress-related kinases, and caspase cleavage. The temporal ordering and interdependence of these events was investigated in primary neuronal cultures exposed to the sulfhydryl oxidizing agent 2,2Ј-dithiodipyridine (DTDP), a compound that induces the intracellular release of zinc. We previously observed that tetraethylammonium (TEA), high extracellular potassium, or cysteine protease inhibitors block apoptosis induced by DTDP. We now report that both p38 and extracellular signal-regulated kinase phosphorylation are evident in neuronal cultures within 2 hr of a brief exposure to 100 M DTDP. However, only p38 inhibition is capable of blocking oxidant-induced toxicity. Cyclohexamide or actinomycin D does not attenuate DTDPinduced cell death, suggesting that posttranslational modification of existing targets, rather than transcriptional activation, is responsible for the deleterious effects of p38. Indeed, an early robust increase in TEA-sensitive potassium channel currents induced by DTDP is attenuated by p38 inhibition but not by caspase inhibition. Moreover, we found that activation of p38 is required for caspase 3 and 9 cleavage, suggesting that potassium currents enhancement is required for caspase activation. Finally, we observed that DTDP toxicity could be blocked with niacinamide or benzamide, inhibitors of poly (ADP-ribose) synthetase. Based on these findings, we conclude that oxidation of sulfhydryl groups on intracellular targets results in intracellular zinc release, p38 phosphorylation, enhancement of potassium currents, caspase cleavage, energetic dysfunction, and translationally independent apoptotic cell death.

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Methylmalonate toxicity in primary neuronal cultures

Cited by 99 publications

References 57 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

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

p38 Activation Is Required Upstream of Potassium Current Enhancement and Caspase Cleavage in Thiol Oxidant-Induced Neuronal Apoptosis

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