Cytochemistry Of Succinic Dehydrogenase Activity In The Aging Brain

It is currently supported that the generation of reactive oxygen species (ROS) during the physiological process of cellular respiration is not properly controlled in old cells, and this may be responsible for significant damage to mitochondrial DNA (mtDNA) and membranes resulting, with increasing mtDNA mutation and membrane deterioration load, in alterations of mitochondrial morphology and in a progressive impairment of mitochondrial

Figure 40.8 Reactive plasticity of mitochondrial size at synaptic terminals in aging. The complement of oversized mitochondria was estimated by considering a Feretratio value threshold of <0.2. (Feretratio is obtained by dividing the shorter by the longer diameter of each mitochondrion). At the synaptic terminals of old rats, the percent of megamitochondria accounts for 20.6% vs. 8.6% and 5.3% found at the synaptic regions of young and adult animals, respectively.

Figure 40.8 Reactive plasticity of mitochondrial size at synaptic terminals in aging. The complement of oversized mitochondria was estimated by considering a Feretratio value threshold of <0.2. (Feretratio is obtained by dividing the shorter by the longer diameter of each mitochondrion). At the synaptic terminals of old rats, the percent of megamitochondria accounts for 20.6% vs. 8.6% and 5.3% found at the synaptic regions of young and adult animals, respectively.

Figure 40.9 SDH-positive mitochondria in the perykaryon of a CA1 pyramidal cell. The dark precipitate due to the reaction of copper ferrocyanide with the enzyme molecules is localized at the inner mitochondrial membrane. Bar: 0.5 jU.m.

functions. This concept has been concisely expressed and convincingly stressed in an important paper by Linnane et al. (1989) reporting that in aging the mitochondrial population present in a given cell (or cellular compartment) is composed of a mosaic of units with different metabolic competence because of the different mutation load accumulated with advancing age. This concept particularly applies to the old nerve cells that accumulate mtDNA mutations both as a consequence of ROS attacks during cellular respiration and because of the number of replications of their mtDNA. Namely, in the postmitotic nerve cells, considering that the half-life of neuronal mitochondria is about four weeks (Menzies and Gold 1971), mtDNA replicates at the rate of once a month, thus in 80 to 85 year-old human beings, mtDNA has undergone replication about 1000 times, at variance with the nuclear genome that does not replicate (Toescu et al., 2000). Considering the Linnane mitochondrial mosaic concept, it appears reasonable to hypothesize that the fraction of impaired or less functional mitochondria should increase with advancing age in postmitotic nerve cells, which can play an early significant role in the progressive decay in specific neuronal functional tasks (e.g., memory and learning capacities). In this context, the activity of succinic dehydrogenase (SDH) may represent a reliable parameter to verify the functional state of a given mitochondrial population. SDH, complex II of the oxidative phosphorylation (OXPHOS) process, constitutes a secondary entrance of the electron transport chain and has been reported to play a critical role when mitochondrial oxidative capacity is high. SDH is the only mitochondrial enzyme common both for electron and carbon fluxes, thus representing the unique molecule for cross control between cellular respiration and the Krebs cycle. Frequent burst of activity requiring adequate ATP amounts is an almost physiological condition of nerve cells; thus the activity of SDH reasonably may be considered as a reliable marker of the efficiency of ATP provision in neurons when energy demand is high. SDH activity can clearly be evidenced within single organelles by the preferential cytochemical reaction of copper ferrocyanide. As originally documented in the mid-1960s by Ogawa et al. (1968), the ferricyanide readily accepts electrons from the respiratory chain and is reduced to ferrocyanide that is captured by copper at the site of the enzyme activity. In turn, this molecule is trapped at mitochondrial cristae in the form of insoluble, electron opaque precipitate (see Figure 40.9).

SDH-positive mitochondria are easily identified at the electron microscope, and their ultrastructural features can be estimated reliably by conventional morphometric methods. In performing the preferential staining of SDH by the copper ferrocyanide method, only fresh samples can be used since the tissue must not be fixed to preserve SDH activity. Although this limits these studies to laboratory animals or human bioptic material, the data obtained may be considered as a reliable estimation of the actual oxidative capacity of the mitochondrial population analyzed. Studies conducted in old rats have shown that the volume density of SDH-positive mitochondria (i.e., the fraction of organelles/^m3 of cytoplasm or neuropil) is significantly decreased in the perykaria of large-sized neurons, such as cerebellar Purkinje cells and hippocampal CA1 pyramidal cells. In both these types of cells, this decrease is due to a significant numeric loss of the SDH-positive organelles, even though their average volume does not change significantly. Because of their large size, Purkinje and CA1 cells are reliable neuronal models to investigate cellular bioenergetics in aging since their extended dendritic trees and lengthy projections need high amounts of energy for normal maintenance and function, thus being particularly sensitive to any change in ATP supply. Considering the previously mentioned SDH functional features, these data support the idea that, in aging, neuronal mitochondria may not be able to match the energy needs for proper function when ATP demand is high.

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