The Journal of Neuroscience, December 15, 2002, 22(24):10761-10771
Changes in Mitochondrial Status Associated with Altered
Ca2+ Homeostasis in Aged Cerebellar Granule Neurons in
Brain Slices
Jie
Xiong1,
Alex
Verkhratsky2, and
Emil C.
Toescu1
1 Department of Physiology, Division of Medical
Sciences, University of Birmingham, Edgbaston B15 2TT, United
Kingdom, and 2 School of Biological Sciences, University of
Manchester, Manchester M13 9PT, United Kingdom
In the present work, we investigated the relationship between
mitochondrial function and Ca2+ homeostasis in brain
slices obtained from mice that aged normally. In acute preparations,
the cerebellar neurons had similar values for intracellular free
Ca2+
([Ca2+]i) regardless of their
age (range, 6 weeks to 24 months). However, compared with the young
slices, the aged neurons (20-24 months) showed an enhanced rate of
[Ca2+]i increases as a function of the
time the slices were maintained in vitro. When slices
were stimulated (KCl depolarization), there were significant
differences in the patterns of [Ca2+]i
signal displayed by the young and old cerebellar granule neurons. More
importantly, the aged neurons showed a significant delay in their
capacity to recover the resting
[Ca2+]i. The relationship between
[Ca2+]i and mitochondrial membrane
potential was assessed by recording both parameters simultaneously,
using fura-2 and rhodamine-123. In both young and aged neurons, the
cytosolic [Ca2+]i signal was
associated with a mitochondrial depolarization response. In the aged
neurons, the mitochondria had a significantly longer repolarization
response, and quantitative analysis showed a direct correlation between
the delays in mitochondrial repolarization and
[Ca2+]i recovery, indicating the
causal relationship between the two parameters. Thus, the present
results show that the reported changes in Ca2+
homeostasis associated with aging, which manifest principally in a
decreased capacity of maintaining a stable resting
[Ca2+]i or recovering the resting
[Ca2+]i values after stimulation, are
primarily attributable to a metabolic dysfunction in which the
mitochondrial impairment plays an important role.
Key words:
aging; Ca2+ homeostasis; mitochondrial
membrane potential; resting Ca2+ values; ATP
production; neuronal vulnerability; rhodamine-123; cerebellar granule
neurons; brain slices
Copyright © 2002 Society for Neuroscience 0270-6474/02/222410761-11$05.00/0
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