MiP2005: Session 11Mitochondrial Physiology Network 10.9: 128-129 (2005) - download pdf
Mitochondrial dysfunction in brain neurodegenerative disorders: ageing and chronic cerebral hypoperfusion.
Jaromir Horecky1, S Kasparova2, O Vancova3, S Wimmerova1
Centrum of Surgical Pathophysiology and Tissue Engineering, Slovak Medical University1; NMR Laboratory, Slovak University of Technology2; Pharmacobiochemical Laboratory, Comenius University School of Medicine3, Bratislava, Slovak Republic. – jaromir.horecky@szu.sk
Decreases in mitochondrial respiratory chain complex activities have been implicated in neurodegenerative disorders such as Alzheimer`s disease. There are two basic factors for the development of neurodegeneration – advanced aging and chronic cerebral hypoperfusion [1]. The objective of our study was to evaluate brain energy metabolism in the aged (15-16 months old) Wistar rat model of chronic cerebral hypoperfusion accomplished by the occlusion of the brachiocephalic trunk and left common carotid artery (three-vessel occlusion, 3-VO) [2]. The forward rate constant of creatine kinase (kfor) was studied in vivo by saturation transfer 31P magnetic resonance spectroscopy on SISCO 4.7 T imaging spectrometer [3]. Oxygen consumption of isolated brain mitochondria was measured with a Gilson 5/6 oxygraph using a Clark oxygen electrode and sodium glutamate as substrate. Dynamic measurements of 31P MRS saturation transfer showed statistically significant decrease in forward rate constant of creatine kinase measured 10 weeks after 3-VO as compared to the control group of aged rats (TAB 1). There were no significant changes in basal (QO2S4) and ADP-stimulated (QO2S3) mitochondrial oxygen uptake, however, calculated ATP production (OPR) and coefficient of oxidative phosphorylation (ADP:O) were significantly decreased 10 weeks after 3-VO. Our experiments revealed that significant reduction of in vivo measured forward rate constant of creatine kinase correlates with the significant decrease of the coefficient (ADP:O) and the rate (OPR) of the oxidative phosphorylation measured in isolated brain mitochondria. Thus, 31P MRS technique can be used as preventive noninvasive measure for the detection of mitochondrial bioenergetics in the aged and hypoperfused brain.
TABLE 1. Forward rate constant, kfor [PCr=>ATP] and parameters of oxidative phosphorylation before (control) and 10 weeks after three-vessel occlusion (3-VO) in the brain of aged rats. *P<0.05, **P<0.01
Units<o:p></o:p> | Control (n=8)<o:p></o:p> | 3-VO (n=6)<o:p></o:p> |
<o:p> </o:p> | <o:p> </o:p> | <o:p> </o:p> |
Kfor [s-1]<o:p></o:p> | 0.30 ± 0.04<o:p></o:p> | 0.20 ± 0.01**<o:p></o:p> |
QO2S3 [nAtO.mg prot-1.min-1]<o:p></o:p> | 52.97 ± 2.40<o:p></o:p> | 51.35 ± 1.19<o:p></o:p> |
QO2S4 [nAtO.mg prot-1.min-1]<o:p></o:p> | 16.72 ± 0.85<o:p></o:p> | 17.13 ± 0.91<o:p></o:p> |
RCI [S3 S4]<o:p></o:p> | 3.32 ± 0.16<o:p></o:p> | 3.03 ± 0.15<o:p></o:p> |
ADP:O [nmol ADP.nAtO-1]<o:p></o:p> | 2.51 ± 0.08<o:p></o:p> | 2.21 ± 0.03**<o:p></o:p> |
OPR [nmol ATP.mg prot-1.min-1]<o:p></o:p> | 132.19 ± 6.48<o:p></o:p> | 113.35 ± 4.14*<o:p></o:p> |
1. de la Torre JC, Fortin T (1994) A chronic physiological model of dementia. Behav. Brain Res. 63: 35-40.
2. Kasparova S, Brezova V, Valko M, Horecky J, Mlynarik V, Liptaj T, Vancova O, Ulicna O, Dobrota D (2005) Study of the oxidative stress in a rat model of chronic brain hypoperfusion. Neurochemistry International 46: 601-611.
3. Clark JF, Harris GI, Dillon PF (1991) Multisite saturation transfer using DANTE and continuous wave. Magnet. Reson. Med.17: 274-278.
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