Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine

Beretta, Simone; Sala, Gessica; Mattavelli, Laura; Ceresa, Chiara; Casciati, Arianna; Ferri, Alberto; Carrı̀, Maria Teresa; Ferrarese, Carlo

doi:10.1016/s0969-9961(03)00043-3

Cited by 74 publications

(53 citation statements)

References 46 publications

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“…Previous data support the idea that mitochondrial glutathione levels are related to mutSOD1 toxicity. The acetylated variant of the amino acid L-cysteine is able to restore viability and ATP production in human neuroblastoma cells expressing mut-SOD1 G93A (35) and to prolong survival of G93A transgenic mice (36). Therefore, this result is probably related not only to the well known antioxidant activity of the acetylated variant of the amino acid L-cysteine, but also to the fact that this drug is an excellent source of sulfhydryl groups and in vivo is converted into metabolites capable of stimulating glutathione synthesis.…”

Section: Discussionmentioning

confidence: 99%

Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

Ferri¹,

Cozzolino

Crosio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies suggest that the toxicity of familial amyotrophic lateral sclerosis mutant Cu, Zn superoxide dismutase (SOD1) arises from its selective recruitment to mitochondria. Here we demonstrate that each of 12 different familial ALS-mutant SOD1s with widely differing biophysical properties are associated with mitochondria of motoneuronal cells to a much greater extent than wild-type SOD1, and that this effect may depend on the oxidation of Cys residues. We demonstrate further that mutant SOD1 proteins associated with the mitochondria tend to form cross-linked oligomers and that their presence causes a shift in the redox state of these organelles and results in impairment of respiratory complexes. The observation that such a diverse set of mutant SOD1 proteins behave so similarly in mitochondria of motoneuronal cells and so differently from wild-type SOD1 suggests that this behavior may explain the toxicity of ALS-mutant SOD1 proteins, which causes motor neurons to die. motor neuron ͉ neurodegeneration ͉ amyotrophic lateral sclerosis I n the familial form of ALS (fALS), which is linked to mutations in the Cu, Zn superoxide dismutase (SOD1) gene, it is generally considered that the pathological phenotype is because of the acquisition by the mutant SOD1 protein of new properties that transform it from a highly stable, dimeric antioxidant enzyme into a protein with a propensity to form toxic aggregates and cause oxidative damage to neuronal tissue (1). More than 100 different ALS-causing mutations in the SOD1 gene have been reported to date, and the properties of many of the fALS-linked mutant SOD1 proteins (mutSOD1s) have been studied (2-8) in a concerted effort to identify properties common to the mutant proteins but not shared by wild-type SOD1 (wtSOD1), which might explain their toxicity. Instead of similarities, however, biochemical and biophysical studies of the mutSOD1s have revealed a wide range of differences; in fact, some of the mutSOD1s have been found to be very similar to wtSOD1 in all of the properties that have been measured (1). For example, mutSOD1s with substitutions at or near the metalbinding region have altered metal-binding properties and a tendency to crystallize in filamentous structures, but other mutSOD1s with substitutions remote from the metal-binding region are very similar to wtSOD1 in their crystal structures (9-11). Likewise, the global stabilities of some of the metal ion-free mutSOD1 apoproteins are severely compromised, but others have apoproteins that are nearly identical to or even more stable than apo-wtSOD1 (7). Therefore, other abnormal properties of the mutant proteins must be sought to explain the toxicity of all of the mutSOD1s.We reasoned that the common properties shared by the ALS-mutSOD1 proteins and not by wtSOD1 protein might only become apparent when the mutant proteins were studied within the cellular context and also, possibly, only within motoneuronal cells. We have therefore built a collection of inducible cell lines, derived from a mouse motoneuronal line...

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Section: Discussionmentioning

confidence: 99%

Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

Ferri¹,

Cozzolino

Crosio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

231

202

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“…Increased local production of superoxide results in a decrease in NO bioavailability (from the reaction of NO with superoxide) and the formation of peroxynitrite, a cytotoxic oxidant by its own, further worsening ischemia [31]. By interfering pathways of oxidative stress, NAC has been shown to be protective in models of gentamicin-mediated nephropathy [19], cisplatin [17]and ischemia/reperfusion renal injuries [14, 25].…”

Section: Discussionmentioning

confidence: 99%

N-Acetylcysteine Ameliorates Amphotericin-Induced Nephropathy in Rats

Feldman

Efrati²,

Dishy³

et al. 2004

Nephron Physiol

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Background: Amphotericin B may cause acute reduction in renal function. N-acetylcysteine (NAC) has a renoprotective activity in several nephrotoxic renal insults, but its effect on amphotericin-induced renal failure has not been investigated yet. Methods: Acute renal failure was induced in 30 Sprague-Dawley rats by a single intraperitoneal injection of amphotericin B (50 mg/kg). NAC (10 mg/kg) in isotonic saline or isotonic saline alone were administered daily for 4 days, starting 1 day before the amphotericin B injection. Glomerular filtration rate (GFR) was assessed using 99m-technetium diethylene triaminepentaacetic acid. Before and following amphotericin B administration, a 24-hour urine collection was performed for sodium, potassium and magnesium determination. The kidneys were preserved for pathologic examination. Results: Amphotericin B induced a significant decrease of GFR in both groups. Four days after amphotericin injection the GFR in the NAC-treated group was significantly higher than in the control group (0.62 ± 0.20 vs. 0.46 ± 0.14 ml/min, p = 0.042). Histologic signs of acute tubular necrosis were attenuated in the NAC-treated group. There were no significant differences between the groups in sodium, potassium and magnesium urine excretion after amphotericin injection. Conclusions: NAC treatment exerted a renoprotective effect on deterioration of GFR in a rat model of amphotericin-induced renal failure. No functional protection on tubular function, as obviated by similar polyuria and urine losses of potassium and magnesium in both groups, was observed.

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“…Second, ceftriaxone prolongs survival in ALS models, and this may be due to increases in the expression of either GLT-1 or xCT (Rothstein et al, 2005;. N-Acetylcysteine administration reduces oxidative stress and mitochondrial dysfunction in human neuroblastoma cells (SH-SY5Y) expressing the G93A-SOD1 mutation (Beretta et al, 2003). N-Acetylcysteine also delayed the onset of motor impairments and prolonged survival in G93A-SOD1 mice (Andreassen et al, 2000, although see Jaarsma et al, 1998).…”

Section: B Neurodegenerative Disordersmentioning

confidence: 99%

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System x_c⁻) to Normal and Pathological Glutamatergic Signaling

et al. 2012

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Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine

Cited by 74 publications

References 46 publications

Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

N-Acetylcysteine Ameliorates Amphotericin-Induced Nephropathy in Rats

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System x_c⁻) to Normal and Pathological Glutamatergic Signaling

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Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine

Cited by 74 publications

References 46 publications

Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials

N-Acetylcysteine Ameliorates Amphotericin-Induced Nephropathy in Rats

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

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Product

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About

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System x_c⁻) to Normal and Pathological Glutamatergic Signaling