Increased Vulnerability of Brain Mitochondria in Diabetic (Goto-Kakizaki) Rats With Aging and Amyloid-β Exposure
- 1Center for Neuroscience of Coimbra, Department of Zoology, University of Coimbra, Coimbra, Portugal
- 2Faculty of Medicine, University of Coimbra, Coimbra, Portugal
This study evaluated the respiratory indexes (respiratory control ratio [RCR] and ADP/O ratio), mitochondrial transmembrane potential (ΔΨm), repolarization lag phase, repolarization level, ATP/ADP ratio, and induction of the permeability transition pore of brain mitochondria isolated from normal Wistar and GK diabetic rats of different ages (1.5, 12, and 24 months of age). The effect of amyloid β-peptides, 50 μmol/l Aβ25–35 or 2 μmol/l Aβ1–40, on mitochondrial function was also analyzed. Aging of diabetic mice induced a decrease in brain mitochondrial RCR, ADP/O, and ATP/ADP ratios but induced an increase in the repolarization lag phase. Brain mitochondria from older diabetic rats were more prone to the induction of the permeability transition pore, i.e., mitochondria from 24-month-old diabetic rats accumulated much less Ca2+ (20 μmol/l) than those isolated from 12-month-old rats (50 μmol/l) or 1.5-month-old rats (100 μmol/l). In the presence of 50 μmol/l Aβ25–35 or 2 μmol/l Aβ1–40, age-related mitochondrial effects were potentiated. These results indicate that diabetes-related mitochondrial dysfunction is exacerbated by aging and/or by the presence of neurotoxic agents such as amyloid β-peptides, supporting the idea that diabetes and aging are risk factors for the neurodegeneration induced by these peptides.
Address correspondence and reprint requests to Catarina Resende de Oliveira, Center for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. E-mail:
Received for publication 14 November 2002 and accepted in revised form 24 February 2003.
ΔΨm, transmembrane potential; AD, Alzheimer’s disease; CNS, central nervous system; CsA, cyclosporin A; HNE, 4-hydroxynonenal; OXPHOS, oxidative phosphorylation; PTP, permeability transition pore; RCR, respiratory control ratio; TPP+, tetraphenylphosphonium.