Mutated Human SOD1 Causes Dysfunction of Oxidative Phosphorylation in Mitochondria of Transgenic Mice*
By Marina Mattiazzi, M. D'Aurelio, Carl D. Gajewski, K. Martushova, M. Kiaei, M. Beal, G. Manfredi. Journal of Biological Chemistry, 2002
631 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/20af433f2acc6a7ddcf4dc9391af2ac1a4a3fdfb
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
In Neurology
Citations in the corpus
- Mitochondria take center stage in aging and neurodegeneration (2005, background): “The proportion of SOD1 in mitochondria is estimated to be 2% of total SOD1, which may appear small, but given the limited volume of the intermembrane space actually represents a considerable load.(65) There is strong evidence that mitochondrial dysfunction may play a critical role in ALS pathogenesi”
- Molecular biology of amyotrophic lateral sclerosis: insights from genetics (2006, background): “It is evident that a fraction of SOD1 is localized in the mitochondrio”
- Mitochondria, oxidative stress and neurodegeneration. (2012, background): “SOD1 aggregates on the outer mitochondrial membrane may block protein importation and promote aberrant ROS production with consequent oxidative damage to mitochondrial proteins and lipids [89].”
- Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. (2010, background): “[121,122] and has been associated with increased oxidative damage, decreased respiratory activity of mitochondria [106], and the”
- Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases (2006, neutral): “Overexpressing the G93A Sod1 mutation in transgenic mice causes impaired mitochondrial energy metabolism in the brain and spinal cord at disease onse”
- Mitochondrial dysfunction as a cause of optic neuropathies. (2004, background): “These include mitochondrial inner membrane-embedded lipophilic co-factors, such as CoQ and alfa-tocopherol (vitamin E), mitochondrial intermembrane space-located proteins such as the Cu/ZnSOD (Mattiazzi et al., 2002) and the apoptosis-inducing factor (AIF) (Klein”
- Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond (2009, background): “Evidence in favor of both roles has emerged using irradiation and grafting (Kang and Rivest, 2007), but this outcome is likely the result of irradiation-induced disruption of the blood–brain barrier (Mildner et al., 2007).”