Mitochondrial dysfunction and amyotrophic lateral sclerosis

Hervías, Isabel; Beal, M. Flint; Manfredi, Giovanni

doi:10.1002/mus.20489

Cited by 115 publications

(93 citation statements)

References 100 publications

(105 reference statements)

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“…23 Second, ALS has been increasingly linked to mitochondrial dysfunction and disturbances in bioenergetics. 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.…”

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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Section: Discussionmentioning

confidence: 99%

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

et al. 2013

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“…G37R mice A number of lines of evidence indicate mitochondrial abnormalities in the spinal cord in ALS and in transgenic mice expressing SOD1 mutants (Wong et al, 1995;Kong and Xu, 1998;Jaarsma et al, 2000;Bendotti et al, 2001;Hervias et al, 2006). Mutant SOD1 has been shown to preferentially associate with spinal cord mitochondria via tight association or cross-linking to the outer mitochondrial membrane (Liu et al, 2004).…”

Section: Increase In Mitochondrial Iron In Sod1mentioning

confidence: 99%

Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis

Jeong¹,

Rathore²,

Schulz³

et al. 2009

J. Neurosci.

150

169

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Amyotrophic lateral sclerosis (ALS), characterized by degeneration of spinal motor neurons, consists of sporadic and familial forms. One cause of familial ALS is missense mutations in the superoxide dismutase 1 (SOD1) gene. Iron accumulation occurs in the CNS of both forms of ALS; however, its contribution to the pathogenesis of ALS is not known. We examined the role of iron in a transgenic mouse line overexpressing the human SOD1 G37R mutant. We show that multiple mechanisms may underlie the iron accumulation in neurons and glia in SOD1 G37R transgenic mice. These include dysregulation of proteins involved in iron influx and sensing of intracellular iron; iron accumulation in ventral motor neurons secondary to blockage of anterograde axonal transport; and increased mitochondrial iron load in neurons and glia. We also show that treatment of SOD1 G37R mice with an iron chelator extends life span by 5 weeks, accompanied by increased survival of spinal motor neurons and improved locomotor function. These data suggest that iron chelator therapy might be useful for the treatment of ALS.

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“…A large body of evidence of mitochondrial abnormalities, morphologic and bioenergetic, are observed in human familial and sporadic ALS, as well as in many of the cell-culture and rodent models of SOD1-linked ALS (25,55). Like the wild-type protein, familial ALS-linked mutant SOD1 also accumulates in mitochondria, where it is thought to contribute directly to disease pathogenesis.…”

Section: Mutant Sod1 and Mitochondrial Dysfunction In Familial Alsmentioning

confidence: 99%

Import, Maturation, and Function of SOD1 and Its Copper Chaperone CCS in the Mitochondrial Intermembrane Space

Kawamata

Manfredi

2010

Antioxidants & Redox Signaling

Self Cite

127

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Cu,Zn, superoxide dismutase (SOD1) is a ubiquitous enzyme localized in multiple cellular compartments, including mitochondria, where it concentrates in the intermembrane space (IMS). Similar to other small IMS proteins, the import and retention of SOD1 in the IMS is linked to its folding and maturation, involving the formation of critical intra-and intermolecular disulfide bonds. Therefore, the cysteine residues of SOD1 play a fundamental role in its IMS localization. IMS import of SOD1 involves its copper chaperone, CCS, whose mitochondrial distribution is regulated by the Mia40=Erv1 disulfide relay system in a redox-dependent manner: CCS promotes SOD1 maturation and retention in the IMS. The function of SOD1 in the IMS is still unknown, but it is plausible that it serves to remove superoxide released from the mitochondrial respiratory chain. Mutations in SOD1 cause familial amyotrophic lateral sclerosis (ALS), whose pathologic features include mitochondrial bioenergetic dysfunction. Mutant SOD1 localization in the IMS is not dictated by oxygen concentration and the Mia40=Erv1 system, but is primarily dependent on aberrant protein folding and aggregation. Mutant SOD1 localization and aggregation in the IMS might cause the mitochondrial abnormalities observed in familial ALS and could play a significant role in disease pathogenesis. Antioxid. Redox Signal. 13, 1375-1384.

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Mitochondrial dysfunction and amyotrophic lateral sclerosis

Cited by 115 publications

References 100 publications

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration

Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis

Import, Maturation, and Function of SOD1 and Its Copper Chaperone CCS in the Mitochondrial Intermembrane Space

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