Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities

Magrané, Jordi; Hervías, Isabel; Henning, Matthew S.; Damiano, Maria; Kawamata, Hibiki; Manfredi, Giovanni

doi:10.1093/hmg/ddp421

Cited by 141 publications

(123 citation statements)

References 46 publications

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“…2C). Consistent with the axonal transport defects observed in embryonic motor neurons and adult DRG neurons (10,11,16), axonal mitochondria in SOD1 G93A DRG neurons showed reduced mobility (13.54 Ϯ 0.38%, mean Ϯ S.E. ), anterograde transport (10.66 Ϯ 0.77%), and retrograde transport (2.88 Ϯ 0.46%) compared with agematched WT DRG neurons (total mobility: 21.35 Ϯ 1.08%, p Ͻ 0.001; anterograde: 14.74 Ϯ 1.05%, p Ͻ 0.001; retrograde: 6.61 Ϯ 0.78%, p Ͻ 0.001) (Fig.…”

Section: G93asupporting

confidence: 81%

“…Mitochondrial morphology and membrane dynamics, required for maintaining proper function, depend on proper mitochondrial mobility in neurons (50). Several studies have suggested that the onset of ALS symptoms is caused by alterations in mitochondrial transport induced by mutant SOD1 expression (10,11). In the SOD1 G93A mouse model, disease onset and motor neuron death is immediately preceded by the accumulation of dysfunctional mitochondria in the distal region of the axon near the neuromuscular junction.…”

Section: Discussionmentioning

confidence: 99%

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Increased Axonal Mitochondrial Mobility Does Not Slow Amyotrophic Lateral Sclerosis (ALS)-like Disease in Mutant SOD1 Mice

Zhu¹,

Sheng

2011

Journal of Biological Chemistry

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Reduced axonal mitochondrial transport has been observed in major neurodegenerative diseases, including fALS patients and SOD1 G93A mice. However, it is unclear whether this defect plays a critical role in axonal degeneration or simply reflects sequelae of general transport alteration. Using genetic mouse models combined with time-lapse imaging of live neurons, we previously discovered that axon-targeted syntaphilin (SNPH) acts as a docking receptor specific for axonal mitochondria. Deletion of the snph gene in mice results in a substantially higher proportion of axonal mitochondria in the mobile state without any effect on the transport of other axonal organelles. Here we address whether increased (rescued) axonal mitochondrial mobility changes the disease course by crossing fALSlinked transgenic SOD1G93A and snph ؊/؊ knock-out mice. We found that a 2-fold increase in axonal mitochondrial mobility in SOD1 G93A /snph ؊/؊ mice did not affect the onset of ALS-like symptoms. Both SOD1 G93A and SOD1 G93A /snph ؊/؊ mice exhibit similar weight loss, deterioration in motor function and motor neuron loss, significant gliosis, and a lifespan of 152-154 days. Thus, for the first time, our study provides genetic and pathological evidence that the impairment of mitochondrial transport seen in SOD1 G93A mice plays a minimal role in the rapid-onset of fALS-linked pathology.

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Section: G93asupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Increased Axonal Mitochondrial Mobility Does Not Slow Amyotrophic Lateral Sclerosis (ALS)-like Disease in Mutant SOD1 Mice

Zhu¹,

Sheng

2011

Journal of Biological Chemistry

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“…In our laboratory, we targeted mutant SOD1 to the IMS of NSC34 cells by using the cleavable yeast cytochrome b2 MTS. This resulted in mitochondrial fragmentation and alterations of mitochondrial dynamics in the neurites, as well as increased sensitivity to metabolic and oxidative stress conditions (38).…”

mentioning

confidence: 99%

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

Kawamata

Manfredi

2010

Antioxidants & Redox Signaling

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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“…Though SOD1 is primarily a cytosolic protein, its partial deposition in the mitochondrial intermembrane space was shown to lead to mitochondrial dysfunction in mutant SOD1 transgenic mice (Magrane et al, 2009). The presence of damaged mitochondria is a pathological common finding in ALS MNs that may be associated to impaired autophagy-lysosomal system.…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities

Cited by 141 publications

References 46 publications

Increased Axonal Mitochondrial Mobility Does Not Slow Amyotrophic Lateral Sclerosis (ALS)-like Disease in Mutant SOD1 Mice

Increased Axonal Mitochondrial Mobility Does Not Slow Amyotrophic Lateral Sclerosis (ALS)-like Disease in Mutant SOD1 Mice

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

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

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