Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS

Israelson, Adrian; Arbel, Nir; Cruz, Sandrine Da; Ilieva, Hristelina; Yamanaka, Koji; Shoshan‐Barmatz, Varda; Cleveland, Don W.

doi:10.1016/j.neuron.2010.07.019

Cited by 266 publications

(268 citation statements)

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“…Ca 2+ -induced mitochondrial Ca 2+ uptake in permeabilized cells, which does not rely on ER Ca 2+ release or the intimate coupling between mitochondria and ER, was not affected in mutant SOD1 G37R cells. This finding is also consistent with the observation that mutant SOD1 does not affect VDAC1-mediated Ca 2+ transfer (Israelson et al 2010). Cytosolic ATP levels were also significantly decreased in mutant SOD1 G37R cells resulting in compromised ER Ca 2+ uptake in intact cells while ER Ca 2+ uptake in permeabilized cells provided with sufficient amounts of ATP was not affected.…”

Section: Mutant Sod1 May Affect Er-mitochondrial Couplingsupporting

confidence: 90%

“…Mutant SOD1 has been shown to associate with Lysyl-tRNA synthetase (Kawamata et al 2008), an enzyme required for mitDNAencoded protein translation, members of the Bcl-2 family of proteins and the voltage-dependent anion channel VDAC1 (Israelson et al 2010). The binding of mutant SOD1 to VDAC1 deserves further attention.…”

Section: Mutant Sod1 May Affect Er-mitochondrial Couplingmentioning

confidence: 99%

“…For the same reasons, ER-mitochondrial uncoupling would limit the generation of [ATP] hot spots. In addition, the recent finding that mutant SOD1 binding to VDAC1 reduces VDAC1-mediated ADP transport across the outer mitochondrial membrane (Israelson et al 2010) will further limit ATP synthesis. In all these cases, ATP generation may thus be seriously hampered that it actually falls short of cytosolic ATP demand during on-going cellular activity.…”

Section: Mutant Sod1 May Affect Er-mitochondrial Couplingmentioning

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: Mutant Sod1 May Affect Er-mitochondrial Couplingsupporting

confidence: 90%

Section: Mutant Sod1 May Affect Er-mitochondrial Couplingmentioning

confidence: 99%

Section: Mutant Sod1 May Affect Er-mitochondrial Couplingmentioning

confidence: 99%

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Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Faes¹,

Callewaert²

2011

J Bioenerg Biomembr

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“…Mitochondrial abnormalities have been identified in postmortem tissue derived from ALS patients, 24 with ALS-linked SOD1 mutations shown to associate with mitochondria and disturb their bioenergetic capacity through an interaction with VDAC1. 25 In vivo autoradiography studies in SOD1 mice have also demonstrated that glucose utilization is impaired in motor tracts before any pathologic alterations and that this is accompanied by ATP depletion. 26 Metabolic alterations favouring lactacidosis may also be triggered directly as a consequence of Ca 2 þ -mediated excitotoxicity and glutamate excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition with no cure. Mitochondrial dysfunction, Ca 2 þ overloading and local hypoxic/ischemic environments have been implicated in the pathophysiology of ALS and are conditions that may initiate metabolic acidosis in the affected tissue. We tested the hypothesis that acidotoxicity and acid-sensing ion channels (ASICs) are involved in the pathophysiology of ALS. We found that motoneurons were selectively vulnerable to acidotoxicity in vitro, and that acidotoxicity was partially reduced in asic1a-deficient motoneuron cultures. Cross-breeding of SOD1 G93A ALS mice with asic1a-deficient mice delayed the onset and progression of motor dysfunction in SOD1 mice. Interestingly, we also noted a strong increase in ASIC2 expression in motoneurons of SOD1 mice and sporadic ALS patients during disease progression. Pharmacological pan-inhibition of ASIC channels with the lipophilic amiloride derivative, 5-(N,N-dimethyl)-amiloride hydrochloride, potently protected cultured motoneurons against acidotoxicity, and, given post-symptom onset, significantly improved lifespan, motor performance and motoneuron survival in SOD1 mice. Together, our data provide strong evidence for the involvement of acidotoxicity and ASIC channels in motoneuron degeneration, and highlight the potential of ASIC inhibitors as a new treatment approach for ALS. Cell Death and Differentiation (2013) 20, 589-598; doi:10.1038/cdd.2012.158; published online 11 January 2013Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition where motoneurons in the spinal cord and brain stem die, resulting in paralysis and eventual death. Despite the significant recent advances in understanding the pathophysiology and genetics of ALS, 1 there is no cure for this condition. Currently, the only FDA-approved, disease-modifying drug used for the treatment of ALS is riluzole, which inhibits neuronal glutamate, releases and stimulates glutamate uptake into astrocytes. 2 The use of riluzole is based on the hypothesis that overactivation of Ca 2 þ -permeable AMPA receptors in motoneurons results in excitotoxicity, and that this process contributes to motoneuron death in ALS. 3 Nevertheless, the disease-modifying effects of riluzole therapy are moderate and vary among patients. 4 Acid-sensing ion channels (ASICs) represent a group of ion channels activated by protons. They belong to the epithelial sodium (Na þ ) family of amiloride-sensitive cation channels, and allow for Na þ and Ca 2 þ entry into neurons. Of the six ASIC subunits cloned, ASIC1a, ASIC2a and ASIC2b are expressed in the brain and spinal cord neurons. 5 ASIC1a and ASIC2s are found in the brain regions with high synaptic density and facilitate excitatory synaptic transmission. 6,7 ASIC1a in particular is involved in nociception and fear behavior triggered by hypercapnia. 8,9 ASICs have also been investigated as new targets for the treatment of ischemic stroke and cerebral hypoxia 10 on the premise that activation of ASIC1a during ischemia ...

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“…In SOD1 G93A mice, a mouse model of familial ALS, mutant SOD1 protein accumulates in mitochondria early during disease (Luo et al 2013, Deng et al 2006, Higgins et al 2002. This build up of mutant protein is suggested to impair mitochondrial function (Song et al 2013, Israelson et al 2010, Pasinelli et al 2004. In line with these findings, mitochondria had a metabolic switch from oxidative phosphorylation to glycolysis in transgenic SOD1 G93A mice, NSC34 cells (motor neuron-like cell line) and fibroblasts transfected with mutant SOD1 compared to controls (Mattiazzi et al 2002, Richardson et al 2013, Allen et al 2013.…”

Section: Introductionmentioning

confidence: 92%