CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations

Jaarsma, Dick; Rognoni, F; Duijn, Wim van; Verspaget, Hein W.; Haasdijk, Elize D.; Holstege, Jan C.

doi:10.1007/s004010100399

Cited by 247 publications

(123 citation statements)

References 34 publications

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“…In agreement, it might not be a coincidence that in ALS1, mutated SOD1 was shown to abnormally accumulate in the mitochondrial intermembrane space (Jaarsma et al, 2001; Liu et al, 2004), affecting mitochondrial function leading to disturbance of Ca 2+ homeostasis and ERMCC cycle (Jaiswal and Keller, 2009; Lautenschläger et al, 2013). Moreover, studies on cellular and animal ALS1 models have shown that Ca 2+ overload is linked with SOD1 aggregation (Tateno et al, 2004; Tradewell et al, 2011).…”

Section: Calcium Dysregulation In Als-affected Motor Neurons—the Factmentioning

confidence: 94%

Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability

Leal

Gomes

2015

Front. Cell. Neurosci.

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More than 20 distinct gene loci have so far been implicated in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by progressive neurodegeneration of motor neurons (MN) and death. Most of this distinct set of ALS-related proteins undergoes toxic deposition specifically in MN for reasons which remain unclear. Here we overview a recent body of evidence indicative that mutations in ALS-related proteins can disrupt fundamental Ca2+ signalling pathways in MN, and that Ca2+ itself impacts both directly or indirectly in many ALS critical proteins and cellular processes that result in MN neurodegeneration. We argue that the inherent vulnerability of MN to dysregulation of intracellular Ca2+ is deeply associated with discriminating pathogenicity and aberrant crosstalk of most of the critical proteins involved in ALS. Overall, Ca2+ deregulation in MN is at the cornerstone of different ALS processes and is likely one of the factors contributing to the selective susceptibility of these cells to this particular neurodegenerative disease.

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Section: Calcium Dysregulation In Als-affected Motor Neurons—the Factmentioning

confidence: 94%

Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability

Leal

Gomes

2015

Front. Cell. Neurosci.

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“…Alternatively, oxidative stress may be induced by mitochondrial dysfunction caused by abnormal recruitment of mutant SOD1 to the mitochondrial compartment . In the mutant SOD1 mouse, mitochondria undergo vacuolar degeneration in motor neurons (Jaarsma et al, 2001;Liu et al, 2004;Pasinelli et al, 2004). Misfolded mutant SOD1 has been found to bind to the outer mitochondrial membrane in a cell-and tissue-specific manner (Liu et al, 2004;Vande Velde et al, 2008).…”

Section: Lessons From Familial Alsmentioning

confidence: 99%

The neurobiology of amyotrophic lateral sclerosis

Bento‐Abreu

Damme

Bosch

et al. 2010

Eur J of Neuroscience

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Amyotrophic lateral sclerosis is a degenerative disease affecting the motor neurons. In spite of our growing insights into its biology, it remains a lethal condition. The identification of the cause of several of the familial forms of ALS allowed generation of models to study this disease both in vitro and in vivo. Here, we summarize what is known about the pathogenic mechanisms of ALS induced by hereditary mutations, and attempt to identify the relevance of these findings for understanding the pathogenic mechanisms of the sporadic form of this disease.

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“…4A, lanes 1-12) and under reducing conditions (Fig. 4A, lanes [13][14][15][16][17][18][19][20][21][22][23][24]. The levels of Sod1-C57S and Sod1-C57S, C146S were not affected by the lack of Ccs1 in mitochondria, similar to reduced wild-type Sod1 and in contrast to oxidized wild-type Sod1 (Fig.…”

Section: Mutant Variants Of Sod1 That Lack a Disulfide Bond Do Not Dementioning

confidence: 85%

“…Mitochondria are strongly implicated in both the function and pathology related to Sod1. Disease variants of Sod1 cause various mitochondrial dysfunctions [12,[15][16][17][18][19][20]. This is not surprising because Sod1 is localized not only in the cytosol but also in the intermembrane space (IMS) of mitochondria, the important source of reactive oxygen species in the cell [21,22].…”

Section: Introductionmentioning

confidence: 99%

Mia40 and MINOS act in parallel with Ccs1 in the biogenesis of mitochondrial Sod1

et al. 2013

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Superoxide dismutase 1 (Sod1) is a major superoxide-scavenging enzyme in the eukaryotic cell, and is localized in the cytosol and intermembrane space of mitochondria. Sod1 requires its specific chaperone Ccs1 and disulfide bond formation in order to be retained in the intermembrane space. Our study identified a pool of Sod1 that is present in the reduced state in mitochondria that lack Ccs1. We created yeast mutants with mutations in highly conserved amino acid residues corresponding to human mutations that cause amyotrophic lateral sclerosis, and found that some of the mutant proteins were present in the reduced state. These mutant variants of Sod1 were efficiently localized in mitochondria. Localization of the reduced, Ccs1-independent forms of Sod1 relied on Mia40, an essential component of the mitochondrial intermembrane space import and assembly pathway that is responsible for the biogenesis of intermembrane space proteins. Furthermore, the mitochondrial inner membrane organizing system (MINOS), which is responsible for mitochondrial membrane architecture, differentially modulated the presence of reduced Sod1 in mitochondria. Thus, we identified novel mitochondrial players that are possibly involved in pathological conditions caused by changes in the biogenesis of Sod1.

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CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations

Cited by 247 publications

References 34 publications

Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability

Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability

The neurobiology of amyotrophic lateral sclerosis

Mia40 and MINOS act in parallel with Ccs1 in the biogenesis of mitochondrial Sod1

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