Neural mitochondrial Ca<sup>2+</sup> capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn‐superoxide dismutase mutant mice

Damiano, Maria; Starkov, Anatoly A.; Petri, Susanne; Kipiani, Kathuna; Kiaei, Mahmoud; Mattiazzi, Marina; Beal, M. Flint; Manfredi, Giovanni

doi:10.1111/j.1471-4159.2006.03619.x

Cited by 214 publications

(175 citation statements)

References 63 publications

(114 reference statements)

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“…The first evidence of mitochondrial abnormalities came from ultrastructural studies showing aggregates of mitochondria in muscles and spinal cord motor neurons (Sasaki and Iwata 1996) and increased mitochondrial volume in motor nerve terminals of ALS patients (Siklos et al 1996). Consistent with these findings, observations of mitochondrial morphology in cell or animal models of familial ALS showed aggregated, swollen, vacuolated or fragmented mitochondria (Bendotti et al 2001;Coussee et al 2011;Damiano et al 2006;Jaarsma et al 2001;Jung et al 2002;Menzies et al 2002;Raimondi et al 2006;Xu et al 2004).…”

Section: Mitochondrial Morphological Abnormalities and Dysfunctions Isupporting

confidence: 56%

“…Impairment of intracellular Ca 2+ homeostasis has been reported in cells expressing mutant SOD1 G93A or SOD1 G37R (Carri et al 1997;Coussee et al 2011;Tradewell et al 2011) and in motor neurons from mutant SOD1 G93A transgenic mice Kruman et al 1999). Also isolated mitochondria from transgenic mutant SOD1 G93A and SOD1 G85R mice showed a significant decrease in Ca 2+ loading capacity (Damiano et al 2006;Nguyen et al 2009;Vila et al 2003). ATP deficit and Ca 2+ dysregulation may arise secondary to mutant SOD1-induced impairment of oxidative phosphorylation, or as a direct consequence of mutant SOD1 impeding on mitochondrial transport of ions and metabolites.…”

Section: Mitochondrial Morphological Abnormalities and Dysfunctions Imentioning

confidence: 99%

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Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Faes¹,

Callewaert²

2011

J Bioenerg Biomembr

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A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.

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Section: Mitochondrial Morphological Abnormalities and Dysfunctions Isupporting

confidence: 56%

Section: Mitochondrial Morphological Abnormalities and Dysfunctions Imentioning

confidence: 99%

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Faes¹,

Callewaert²

2011

J Bioenerg Biomembr

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“…Inhibition of mPT may also prove to be a beneficial therapy for neurodegenerative diseases. Mitochondria from the spinal cord of transgenic ALS mice have been shown to have an impaired Ca 2+ retention capacity, possibly contributing to neuronal degeneration (Damiano et al, 2006). Intrathecal administration of CsA to transgenic ALS mice (SOD1 G93A) extend the remaining life span at late stage disease (Keep et al, 2001) and delay onset of symptoms, prevent neuronal death and increase overall life span by presymptomatic treatment .…”

Section: Introductionmentioning

confidence: 99%

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Månsson¹,

Hansson²,

Morota³

et al. 2007

Neurobiology of Disease

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Minocycline has been shown to be neuroprotective in ischemic and neurodegenerative disease models and could potentially be relevant for clinical use. We revisited the hypothesis that minocycline acts through direct inhibition of calcium-induced mitochondrial permeability transition (mPT) resulting in reduced release of cytochrome c (cyt c). Minocycline, at high dosage, was found to prevent calcium-induced mitochondrial swelling under energized conditions similarly to the mPT inhibitor cyclosporin A (CsA) in rodent mitochondria derived from the CNS. In contrast to CsA, minocycline dose-dependently reduced mitochondrial calcium retention capacity (CRC) and respiratory control ratios and was ineffective in the de-energized mPT assay. Further, minocycline did not inhibit calcium-or tBid-induced cyt c release. We conclude that the neuroprotective mechanism of minocycline is likely not related to direct inhibition of mPT and propose that the mitochondrial effects of minocycline may contribute to toxicity rather than tissue protection at high dosing in animals and humans.

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“…Accompanying mutant SOD1-mediated disease in some mice is evidence for altered mitochondrial calcium-buffering capacity (11) and changes in the activity of complexes of the electron transport chain (12). Deletion of the mitochondrial BCL-2-related proteins BAX and BAK delays disease onset in SOD1 G93A mice (13), perhaps by modulating effects of SOD1 conformational changes to BCL-2 (14).…”

mentioning

confidence: 99%

ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import

Velde²,

Israelson³

et al. 2010

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

151

131

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Mutations in superoxide dismutase 1 (SOD1) cause familial ALS. Mutant SOD1 preferentially associates with the cytoplasmic face of mitochondria from spinal cords of rats and mice expressing SOD1 mutations. Two-dimensional gels and multidimensional liquid chromatography, in combination with tandem mass spectrometry, revealed 33 proteins that were increased and 21 proteins that were decreased in SOD1G93A rat spinal cord mitochondria compared with SOD1WT spinal cord mitochondria. Analysis of this group of proteins revealed a higher-than-expected proportion involved in complex I and protein import pathways. Direct import assays revealed a 30% decrease in protein import only in spinal cord mitochondria, despite an increase in the mitochondrial import components TOM20, TOM22, and TOM40. Recombinant SOD1 G93A or SOD1 G85R, but not SOD1WT or a Parkinson's disease-causing, misfolded α-synuclein E46K mutant, decreased protein import by >50% in nontransgenic mitochondria from spinal cord, but not from liver. Thus, altered mitochondrial protein content accompanied by selective decreases in protein import into spinal cord mitochondria comprises part of the mitochondrial damage arising from mutant SOD1.motor neuron disease | proteomic | neurodegenerative disease | amyotrophic A myotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of the motor neurons within the spinal cord and dysfunction of the motor pathways in the cortex (1, 2). Most cases of ALS (90%) are sporadic. Of the 10% of cases that are inherited, about one-fifth are caused by mutation within the superoxide dismutase 1 (SOD1) gene. Rodents expressing mutant SOD1 develop an ALS-like disease (1, 2). A consensus has emerged that disease arises from acquisition by the mutant proteins of one or more toxic properties, rather than from loss of dismutase activity (3, 4). At least eight prominent mutant-derived toxicities have been proposed, including mitochondrial dysfunction, excitotoxicity, endoplasmic reticulum stress, toxic extracellular SOD1, superoxide production from microglia or astrocytes, and disruption of the blood-brain barrier (5). Furthermore, pathogenesis is noncell autonomous with disease progression driven by mutant synthesis in astrocytes (6-8) and microglia (3, 9).Dysfunction of mitochondria can clearly cause specific damage to neurons or muscle because deletion/mutation in mitochondrial genes causes specific nerve and muscle diseases (10). Accompanying mutant SOD1-mediated disease in some mice is evidence for altered mitochondrial calcium-buffering capacity (11) and changes in the activity of complexes of the electron transport chain (12). Deletion of the mitochondrial BCL-2-related proteins BAX and BAK delays disease onset in SOD1 G93A mice (13), perhaps by modulating effects of SOD1 conformational changes to BCL-2 (14). Apparent damage to mitochondria has been reported in autopsy material from ALS patients (15, 16).Although SOD1 is a primarily cytosolic enzyme, wild-type SOD1 is also found in the intermembrane ...

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Neural mitochondrial Ca²⁺ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn‐superoxide dismutase mutant mice

Abstract: Mitochondrial respiratory chain dysfunction, impaired intracellular Ca 2+

Cited by 214 publications

References 63 publications

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import

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Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn‐superoxide dismutase mutant mice

Abstract: Mitochondrial respiratory chain dysfunction, impaired intracellular Ca 2+

Cited by 214 publications

References 63 publications

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import

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Neural mitochondrial Ca²⁺ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn‐superoxide dismutase mutant mice