Back to Search
Start Over
Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats
- Source :
- Diabetes
- Publication Year :
- 2010
- Publisher :
- American Diabetes Association, 2010.
-
Abstract
- OBJECTIVE Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. RESEARCH DESIGN AND METHODS Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). RESULTS Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. CONCLUSIONS Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.
- Subjects :
- Blood Glucose
Male
medicine.medical_specialty
Complications
Proteome
Sensory Receptor Cells
Ubiquinone
Endocrinology, Diabetes and Metabolism
Respiratory chain
Oxidative phosphorylation
Biology
Mitochondrion
Oxidative Phosphorylation
Diabetes Mellitus, Experimental
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Polyol pathway
Oxygen Consumption
Superoxides
Internal medicine
Internal Medicine
medicine
Cytochrome c oxidase
Animals
Hypoglycemic Agents
Insulin
Cells, Cultured
030304 developmental biology
chemistry.chemical_classification
Drug Implants
Glycated Hemoglobin
Neurons
0303 health sciences
Reactive oxygen species
Body Weight
Mitochondria
Rats
Citric acid cycle
Endocrinology
chemistry
Mitochondrial matrix
Mitochondrial Membranes
biology.protein
Reactive Oxygen Species
Methane
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 1939327X and 00121797
- Volume :
- 60
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....d869e234cbf044e1d63ee60814ecc2a0