Molecules in focus
Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease

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Abstract

Mitochondria plays a complex multi-factorial role in the cell. In addition to their primary role in ATP generation, the organelles sequester calcium and both generate and detoxify reactive oxygen species. All these functions are intimately inter-linked through the central bioenergetic parameter of the proton electrochemical gradient across the inner mitochondrial membrane. Subtle changes in respiratory chain capacity, substrate supply, glutathione levels, cytoplasmic calcium and membrane potential occur in aging and in conditions predisposing towards neurodegenerative disease. These interactions are incompletely understood and in this review I present an overview of some of the current research in this area, and its possible relevance to aging and aging-related disease.

Introduction

The bioenergetic properties of mitochondria in situ within neurons are critical determinants of the susceptibility of the cells to acute or chronic neurodegenerative stress [1], [2], [3]. Mitochondria play multi-factorial roles within the cell. In addition to their central bioenergetic task of ATP regeneration, the organelles are the main source both of reactive oxygen species and of the cell’s anti-oxidant defenses [4], while the properties of the Ca2+ transport pathways in the inner mitochondrial membrane are such that the organelles can avidly accumulate the cations under conditions of elevated local cytoplasmic Ca2+ [5]. In recent years, a revolution has occurred within the field of mitochondrial physiology, due not only to utilization of the organelle’s cytochrome c by the apoptotic pathway [6], but also to the realization that, rather than operating reliably in the background, the mitochondrion is highly tuned and prone to malfunction in response to even moderate additional stresses. In this short review, I shall summarize many of the bioenergetic loci whose malfunction may underlie the aging-related component to neurodegenerative and other diseases.

Section snippets

The bioenergetic network

Fig. 1 shows the major bioenergetic pathways that influence neuronal survival. The central parameter is the proton electrochemical potential gradient across the inner mitochondrial membrane, termed the protonmotive force, Δp, when expressed in voltage units. The three proton pumps of the respiratory chain operate in series with respect to the electron flow from NADH to O2 and in parallel with respect to the proton circuit, pumping about nine protons per two electrons and generating a maximal Δp

Respiratory chain capacity

The isolated nerve terminal, or synaptosome, preparation provides the simplest model for studying mitochondrial bioenergetics in a neural context. The mitochondria within a resting nerve terminal utilize <25% of their maximal in situ respiratory capacity (defined as the maximal respiration rate observed in the presence of a protonophore to relieve respiratory control) [12]. This basal respiration has two components: that required to regenerate ATP (8%) and that required to compensate for the

Complex I inhibition

Complex I has emerged in recent years as an additional site of O2radical dot generation within the respiratory chain [17], [18] in addition to the more well-defined site in complex III (see later). Complex I activity is readily restricted by oxidative damage [19], [20], [21]. Its extreme structural complexity, with 43 peptides and at least five detectable redox centers means that the precise locus of oxidative inhibition within the complex remains to be identified. However, the inhibitor rotenone appears

Inhibition of the tricarboxylic acid cycle and complex II

Since neurons utilize glucose as their primary energy source, it follows that the effective functioning of the tricarboxylic acid cycle is essential. Impaired functioning of three enzymes in the cycle, aconitase, α-ketoglutarate dehydrogenase and succinate dehydrogenase, have been described in models of aging-related mitochondrial dysfunction. Aconitase possesses an iron–sulfur cluster that is exquisitely sensitive to damage by superoxide [41]. A decrease in the activity of the α-ketoglutarate

Complex III

The ‘Q-cycle’ within complex III allows a two-electron carrier, UQH2, to feed the one-electron redox carriers (three cytochrome hemes and a FeS center) [7]. UQH2 binds to the outer Q-binding site and transfers one electron to the Rieske iron–sulfur protein and thus to cytochrome c1 and c. This is a relative low potential transfer with a redox potential of about +200 mV, however, the loss of the second electron from the resulting semiquinone anion UQradical dot to form the fully oxidized UQ is much more

Matrix glutathione levels

The glutathione pool in the mitochondrial matrix plays a major role in the maintenance of reduced protein thiols and in the detoxification of H2O2 via glutathione peroxidase, which is exclusively localized in the mitochondrial matrix [4]. Even partial depletion of this pool, for example by inhibiting γ-glutamylcysteine synthetase, has profound effects on the ability of mitochondria to withstand oxidative stress [50]. This is due to an interesting combination of thermodynamic and kinetic

The significance of the mitochondrial membrane potential

The membrane potential, Δψm, is the dominant component of Δp and therefore influences ATP synthesis and matrix Ca2+ accumulation as well as O2radical dot generation. An active area of current discussion is whether subtle modulation of Δψm could decrease this last parameter without adversely affecting the synthesis of ATP. In theory, it would be possible to decrease Δψm without affecting Δp by increasing the ΔpH component of the protonmotive force; however, while this may be accomplished with isolated

The significance of mitochondrial Ca2+ accumulation

In situ mitochondria become net accumulators of matrix Ca2+ whenever the free Ca2+ concentration in their environment rises above a critical value, termed the ‘set-point’, at which the activity of the Ca2+ uniport transporting Ca2+ into the matrix exceeds that of the independent Na+/Ca2+ exchanger responsible for Ca2+ efflux from the matrix [54]. Studies with both isolated brain mitochondria and cultured neurons suggest that this set-point lies at about 0.5 μM [55], [56], [57]. This level is

The permeability transition

Conditions of mitochondrial Ca overload and/or oxidative stress can result in the opening of a non-selective pore in the inner membrane allowing the passage of species up to 1.3 kDa [60]. This permeability transition pore (PTP) appears to be the consequence of a changed conformation of the adenine nucleotide translocator following its association with matrix cyclophilin D, while there is controversy as to whether the outer membrane porin VDAC is an integral component of the complex. This

Conclusion

In this brief review, it has been possible only to touch upon some of the many bioenergetic factors that influence the health and survival of mitochondria and the cells that they populate. Virtually, all these factors mutually interact, and the challenge for bioenergetic physiology is to obtain further insights into the nature and extent of these interactions in order to understand the consequences of bioenergetic alteration occurring with age or disease and to suggest strategies whereby the

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