Impairment Of Mitochondrial Structural Dynamics In Aging

In order to accomplish their peculiar task, consisting of the coupling of respiration to ATP synthesis, mitochondria have a unique and peculiar morphology: namely, an outer membrane surrounding an inner membrane (the cristae) that surrounds an internal matrix. The ordered architecture of this topologically closed bi-layered system represents a critical topographic arrangement for the mitochondrial mechanisms involved in the synthesis of adenosinetriphosphate (ATP) from adenosine diphosphate and inorganic phosphate via oxidative phosphorylation. During this process protons are pumped into the intermembrane space by the respiratory chain located at the inner mitochondrial membrane; therefore all the reactions of the oxidative phosphorylation process (OXPHOS) significantly rely on the structural features of the organelles. Mitochondrial morphology is known to be heterogeneous and may be quite different from cell to cell of the same organ or from one cellular compartment to another within the same cell. In addition, select mitochondrial pools are in a very dynamic condition and may undergo significant ultrastructural remodeling to tailor the cellular energy providing machinery to the functional energy requirements of the actual environmental conditions (Bertoni-Freddari et al., 1993; Bereiter-Hahn and Voth, 1994; Bertoni-Freddari et al., 2001). Quantitative estimations of these mitochondrial structural dynamics may be carried out, in semiautomatic mode, applying morphometric procedures by computer-assisted image analyzers. Namely, volume and numeric densities (i.e., the mitochondrial volume fraction and number/^m3 of tissue) as well as the average size and/or shape of the mitochondria are the ultrastructural parameters currently investigated and reported to be significantly modulated by actual energy demands. It has been documented that these parameters provide information on discrete aspects of mitochondrial ultrastructure; however, they are dependent on each other. Thus the overall quantitative estimation of their reciprocal changes may represent an index of the mitochondrial functional plasticity. The clear awareness that this function-driven dynamic condition of discrete pools of mitochondria is continuously challenged by any cellular activity requiring an adequate ATP supply has led to several investigations on the many factors potentially able to modulate the mitochondrial morphological features and, in turn, the bioenergetic competence in specific cellular compartments where the organelles are located.

In agreement with this knowledge on the plastic condition of the mitochondrial morphology, the aging process has been considered as a very critical, though physiological, condition able to exert a subtle and significant modulating action on the mitochondrial structural dynamics. Several studies conducted in different organs and types of cells from various animal species and human beings document the notion that a general trend can be clearly envisaged: in old organisms mitochondria decrease in number, but increase in size; the final outcome of these balanced changes is that the overall mitochondrial volume density (i.e., the mitochondrial fraction/^m3 of tissue) is constant during the individual's lifespan (Bertoni-Freddari et al., 1993; Solmi, 1994; Walter et al., 1999) (see Figure 40.7).

An impaired duplicative capacity, due to age, may account for mitochondrial numeric loss, whereas the enlargement in the average mitochondrial volume has been considered as a compensating reaction aimed at

Figure 40.7 Age-related ultrastructural alterations of rat synaptic mitochondria. The cytoplasmic volume fraction occupied by mitochondria (volume density: Vv) appears to be constant throughout the whole lifespan. With regard to the numeric density (Nv), the average mitochondrial volume (V), and the skeleton (Sk: an estimation of mitochondrial elongation), if the values of these parameters are considered 100%, in the adult rats the increase of Nv (+27%) is paired by a decrease of V (-37%) and Sk (-40%). In old rats opposite changes can be observed; that is, a 31% decrease of Nv is paired by an increase of V (+30%) and Sk (+34%).

Figure 40.7 Age-related ultrastructural alterations of rat synaptic mitochondria. The cytoplasmic volume fraction occupied by mitochondria (volume density: Vv) appears to be constant throughout the whole lifespan. With regard to the numeric density (Nv), the average mitochondrial volume (V), and the skeleton (Sk: an estimation of mitochondrial elongation), if the values of these parameters are considered 100%, in the adult rats the increase of Nv (+27%) is paired by a decrease of V (-37%) and Sk (-40%). In old rats opposite changes can be observed; that is, a 31% decrease of Nv is paired by an increase of V (+30%) and Sk (+34%).

increasing the mitochondrial area involved in cellular respiration (see Figure 40.8).

Specifically, at the synaptic terminals of old animals the percent of oversized organelles is reported to be markedly increased. Oversized organelles, also referred to as megamitochondria (MM), have been found in some adverse conditions, sometimes representing a serious threat for cell survival; therefore a positive interpretation of the consistent presence within the cell of MM is questioned. The conventional staining procedures adopted to carry out electron microscopic investigations, though enabling a better visualization of all the cellular constituents by increasing ubiquitously their contrast against the background, do not provide detailed information from a functional point of view. Thus, in order to obtain a better insight into the biological significance of any estimated ultrastructural change, specific cyto-chemical techniques have been developed to visualize arrays of molecules with well-defined and reliable functional meaning.

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