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Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice
Marina Mattiazzi1, Marilena D'Aurelio, Carl D Gajewski
1Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
Abstract:
A growing body of evidence suggests that impaired mitochondrial energy production and increased oxidative radical damage to the mitochondria could be causally involved in motor neuron death in amyotrophic lateral sclerosis (ALS) and in familial ALS associated with mutations of Cu,Zn superoxide dismutase (SOD1). For example, morphologically abnormal mitochondria and impaired mitochondrial histoenzymatic respiratory chain activities have been described in motor neurons of patients with sporadic ALS. To investigate further the role of mitochondrial alterations in the pathogenesis of ALS, we studied mitochondria from transgenic mice expressing wild type and G93A mutated hSOD1. We found that a significant proportion of enzymatically active SOD1 was localized in the intermembrane space of mitochondria. Mitochondrial respiration, electron transfer chain, and ATP synthesis were severely defective in G93A mice at the time of onset of the disease. We also found evidence of oxidative damage to mitochondrial proteins and lipids. On the other hand, presymptomatic G93A transgenic mice and mice expressing the wild type form of hSOD1 did not show significant mitochondrial abnormalities. Our findings suggest that G93A-mutated hSOD1 in mitochondria may cause mitochondrial defects, which contribute to precipitating the neurodegenerative process in motor neurons.
Insights
Mitochondrial defects and oxidative damage in motor neurons are linked to amyotrophic lateral sclerosis (ALS). The G93A mutation in superoxide dismutase 1 (SOD1) causes these mitochondrial issues, contributing to motor neuron death in ALS.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration.
- Impaired mitochondrial function and oxidative stress are implicated in ALS pathogenesis.
- Mutations in Cu,Zn superoxide dismutase (SOD1) are linked to familial ALS.
Purpose of the Study:
- To investigate the role of mitochondrial alterations in ALS pathogenesis.
- To examine mitochondria in transgenic mice expressing wild type and G93A mutated human SOD1 (hSOD1).
Main Methods:
- Studied mitochondria from transgenic mice expressing wild type and G93A mutated hSOD1.
- Assessed mitochondrial respiration, electron transfer chain activity, and ATP synthesis.
- Examined mitochondrial protein and lipid oxidative damage.
Main Results:
- Enzymatically active SOD1 was found in the mitochondrial intermembrane space.
- G93A mice showed severe defects in mitochondrial respiration, electron transfer, and ATP synthesis at disease onset.
- Evidence of oxidative damage to mitochondrial proteins and lipids was observed in G93A mice.
- Presymptomatic G93A mice and wild-type hSOD1 mice showed no significant mitochondrial abnormalities.
Conclusions:
- G93A-mutated hSOD1 within mitochondria may induce mitochondrial dysfunction.
- These mitochondrial defects likely contribute to the neurodegenerative process in motor neurons in ALS.
- Mitochondrial dysfunction is a key factor in the pathogenesis of ALS caused by SOD1 mutations.