Complex I specific increase in superoxide formation and respiration rate by PrP-null mouse brain mitochondria

• Published in: Journal of neurochemistry 2008-04, Vol.105 (1), p.177-191
• Main Authors: Paterson, Andrew W.J, Curtis, John C, MacLeod, Nikki K
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Biochemistry; Biochemistry and metabolism; Biological and medical sciences; Brain; Brain - ultrastructure; Cell Respiration - physiology; Central nervous system; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; electron microscopy; electron paramagnetic resonance; electron paramagnetic resonance spectroscopy; Electron Spin Resonance Spectroscopy - methods; Electron Transport Complex I - metabolism; Free radicals; Free Radicals - metabolism; Fundamental and applied biological sciences. Psychology; Medical sciences; Mice; Mice, Knockout; Microscopy, Electron, Transmission - methods; mitochondria; Mitochondria - physiology; neurodegeneration; Neurology; Oxidation; Oxygen Consumption - physiology; Prions - genetics; PrP; respiration; Rodents; submitochondrial particles; Submitochondrial Particles - metabolism; superoxide; superoxide dismutase; Superoxides - metabolism; tempone; Vertebrates: nervous system and sense organs; Voltage-Dependent Anion Channel 1 - metabolism
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.05123.x

An imbalance in free radical production and removal is considered by many to be an important factor in the etiology of many degenerative diseases. Since mitochondria are a major source of free radicals, we have examined mitochondrial free radical production in relation to oxidative phosphorylation in PrP-null mice. Quantitative electron paramagnetic resonance spectroscopy revealed up to a 70% increase in superoxide production from Complex I of submitochondrial particles prepared from PrP-null mice. This was accompanied by elevated respiratory capacity through Complex I without any discernible alteration in respiratory efficiency. These differences are associated with changes in superoxide dismutase levels and defects in mitochondrial morphology, confirming previously reported results. Our results demonstrate a clear difference in free radical production and oxygen consumption by mitochondrial Complex I between PrP-null mice and wild-type controls, pointing to Complex I as a potential target for pathological change, suggesting similarities between prion-related and other neurodegenerative diseases.