Axonal Mitochondrial Clusters Containing Mutant SOD1 in Transgenic Models of ALS

Sotelo‐Silveira, José; Lepanto, Paola; Elizondo, Victoria; Horjales, Sofía; Palacios, Florencia; Martínez-Palma, Laura; Marı́n, Mónica; Beckman, Joseph S.; Barbeito, Luis

doi:10.1089/ars.2009.2614

Cited by 53 publications

(40 citation statements)

References 40 publications

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“…In addition, dense conglomerates of mitochondria in the anterior horn of lumbar spinal cord and proximal axons have been found in sporadic ALS patients [43,44]. Abnormal clustering of mitochondria was recently reported in motor axons in mutant SOD1 transgenic mice [45]. Extensive fragmentation of mitochondria was also reported in cultured NSC34 cells overexpressing mutant SOD1 [46,47].…”

Section: Abnormal Mitochondrial Morphology and Bioenergetics In Alsmentioning

confidence: 91%

“…Abnormal mitochondrial clustering and fragmentation [43,44,46,47,131] and altered mitochondrial transport [115,117,132] are highly suggestive that mitochondrial dynamics may be influenced in the presence of mutant SOD1. A recent study showed mitochondrial fragmentation, impaired mitochondrial dynamics, and decreased density of mitochondria along neurites in differentiated NSC34 cells expressing mutant SOD1 [117].…”

Section: S317mentioning

confidence: 99%

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Mitochondrial Dysfunction is a Converging Point of Multiple Pathological Pathways in Amyotrophic Lateral Sclerosis

Shi

Wei

Zhang

et al. 2010

JAD

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Abstract.A better understanding of the etiology of amyotrophic lateral sclerosis (ALS) is needed to develop effective therapies for the treatment of this fatal neurodegenerative disease. Extensive studies have produced a general agreement that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology, and aberrant RNA metabolism. Mitochondria have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules is disrupted in ALS. Furthermore, new evidence suggests that mitochondrial fission and fusion as well as mitophagy clearance may also be affected by mutant SOD1. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging "dying-back" axonopathy model of ALS. In this review, we will discuss findings supporting that mitochondrial dysfunction is likely to be a converging point of multiple pathways underlying the ALS pathogenesis and progression.

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Section: Abnormal Mitochondrial Morphology and Bioenergetics In Alsmentioning

confidence: 91%

Section: S317mentioning

confidence: 99%

Mitochondrial Dysfunction is a Converging Point of Multiple Pathological Pathways in Amyotrophic Lateral Sclerosis

Shi

Wei

Zhang

et al. 2010

JAD

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“…A number of potential scenarios exist. Of particular interest is the observation that mutant SOD1 preferentially accumulates at the cytoplasmic face of the outer membrane and in the intermembrane space of mitochondria (Cozzolino et al 2009;Ferri et al 2006;Higgins et al 2003;Sotelo-Silveira et al 2009). Therefore, it is possible that an aberrant association between mutant SOD1 and mitochondrial proteins may lead to impaired electron transport chain functioning, shortage of ATP, increased ROS formation and Ca 2+ dysregulation.…”

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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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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“…These trafficking abnormalities along with the observations of mitochondrial fragmentation and axonal clustering [188,189] are highly suggestive that mitochondrial dynamics modulated by mutSOD1 may play a critical role in ALS pathogenesis. However, as mutSOD1 only account for 3% of ALS cases the mitochondrial role in the pathogenesis of most common sporadic form of ALS has to be yet proved.…”

mentioning

confidence: 78%

Oxidative Stress and Altered Mitochondrial Function in Neurodegenerative Diseases: Lessons From Mouse Models

Fernández-Checa¹,

Fernández²,

Morales³

et al. 2010

CNSNDDT

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Oxidative stress has been consistently linked to ageing-related neurodegenerative diseases leading to the generation of lipid peroxides, carbonyl proteins and oxidative DNA damage in tissue samples from affected brains. Studies from mouse models that express diseasespecific mutant proteins associated to the major neurodegenerative processes have underscored a critical role of mitochondria in the pathogenesis of these diseases. There is strong evidence that mitochondrial dysfunction is an early event on neurodegeneration.Mitochondria are the main cellular source of ROS and key regulators of cell death.Moreover, mitochondria are highly dynamic organelles that divide, fuse and move along axons and dendrites to supply cellular energetic demands, and therefore, impairment of any of these processes would directly impact on neuronal viability. Most of the disease-specific pathogenic mutant proteins have been shown to target mitochondria promoting oxidative stress and the mitochondrial apoptotic pathway. In addition, disease-specific mutant proteins may also impair mitochondrial dynamics and recycling of damaged mitochondria via autophagy. Thus, all these data suggest that ROS-mediated defective mitochondria may accumulate during and contribute to disease progression, indicating that strategies aimed to improve mitochondrial function or ROS scavenging may be of potential clinical relevance.

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Axonal Mitochondrial Clusters Containing Mutant SOD1 in Transgenic Models of ALS

Cited by 53 publications

References 40 publications

Mitochondrial Dysfunction is a Converging Point of Multiple Pathological Pathways in Amyotrophic Lateral Sclerosis

Mitochondrial Dysfunction is a Converging Point of Multiple Pathological Pathways in Amyotrophic Lateral Sclerosis

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Oxidative Stress and Altered Mitochondrial Function in Neurodegenerative Diseases: Lessons From Mouse Models

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