Jones 2009 Exp Neurol

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Jones TT, Brewer GJ (2009) Critical age-related loss of cofactors of neuron cytochrome c oxidase reversed by estrogen. Exp Neurol 215:212-9.

» PMID: 18930048 Open Access

Jones TT, Brewer GJ (2009) Exp Neurol

Abstract: The mechanistic basis for the correlation between mitochondrial dysfunction and neurodegenerative disease is unclear, but evidence supports involvement of cytochrome c oxidase (CIV) deficits with age. Neurons isolated from the brains of 24 month and 9 month rats and cultured in common conditions provide a model of intrinsic neuronal aging. In situ CIV activity was decreased in 24 month neurons relative to 9 month neurons. Possible CIV-related deficits include holoenzyme activity, cofactor, and substrate. No difference was found between neurons from 24 month and 9 month rats in mitochondrial counts per neuron, CIV activity in submitochondrial particles, or basal respiration. Immunostaining for cytochrome c in individual mitochondria revealed an age-related deficit of this electron donor. 24 month neurons did not have adequate respiratory capacity to upregulate respiration after a glutamate stimulus, in spite of a two-fold upregulation of respiration seen in 9 month neurons. Respiration in 24 month neurons was inhibited by lower concentrations of potassium cyanide, suggesting a 50% deficit in functional enzyme in 24 month compared to 9 month neurons. In addition to cytochrome c, CIV requires cardiolipin to function. Staining with nonylacridine orange revealed an age-related deficit in cardiolipin. Treatment of 24 month neurons with 17-β-estradiol restored cardiolipin levels (10 ng/ml) and upregulated respiration under glutamate stress (1 pg/ml). Attempts to induce mitochondrial turnover by neuronal multiplication also rejuvenated CCO activity in 24 month neurons. These data suggest cytochrome c and cardiolipin levels are deficient in 24 month neurons, preventing normal upregulation of respiration needed for oxidative phosphorylation in response to stress. Furthermore, the data suggest this deficit can be corrected with estrogen treatment.

Keywords: Aging, Neuron culture, Cytochrome C oxidase, Mitochondria, Estrogen, Brain

O2k-Network Lab: US IL Springfield Brewer GJ


Stress:Mitochondrial disease  Organism: Rat  Tissue;cell: Nervous system  Preparation: Intact cells  Enzyme: Complex IV;cytochrome c oxidase 

Coupling state: OXPHOS 

HRR: Oxygraph-2k