Mitochondrial respiratory chain activity in the human brain as a function of age

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Abstract

Age-associated changes in mitochondrial respiratory chain activity were investigated in human brain tissue collected at autopsy. Four brain regions, the frontal cortex, superior temporal cortex, cerebellum and putamen, were studied to map any regional variation. A significant decrease in cytochrome c oxidase activity was seen in all regions studied with increasing age (P<0.05). Although a small decrease in succinate dehydrogenase-cytochrome c oxidoreductase and NADH: ubiquinone oxidoreductase activities was observed, this was not statistically significant. This study has shown that the age-related fall in cytochrome c oxidase activity affects the frontal cortex, superior temporal cortex, cerebellum and putamen. The variation in the extent of age-related oxidative phosphorylation decline was striking. We hypothesize that individuals with more severe age-related decline may be predisposed to neuronal dysfunction, whereas individuals with well preserved oxidative phosphorylation may enjoy some degree of neuronal protection.

Introduction

Over 300 theories of ageing have been proposed to explain the events that lead to the death of an organism (Medvedev, 1990). The mitochondrial respiratory chain failure has been implicated as a factor in the ageing process (Miquel et al., 1980, Trounce et al., 1989), and it has been proposed that accumulation of mitochondrial mutations may underlie this phenomenon (Linnane et al., 1989, Wallace, 1992). Respiratory chain failure is likely to have a greater effect in tissues that have a high dependency on energy generated through oxidative phosphorylation (OXPHOS) and which lack a regenerative capacity. Theoretical considerations, therefore, indicate that the most vulnerable target cell population to respiratory chain failure, is the cerebral neuronal pool (Byrne et al., 1991). Mitochondrial DNA (mtDNA) mutations in disease state tend to coexist with wild-type mtDNA (heteroplasmy), and an uneven distribution of mutant and wild-type species between adjacent cells leads to energy mosaicism. In tissues which lack a complex tertiary structure and which retain a regenerative capacity, cells which develop an energy crisis related to OXPHOS failure can readily be replaced by divisions of cells which have preserved mitochondrial activity. In the cerebral neuronal pool, however, there is no opportunity for such replenishment to take place and this population is especially vulnerable both to inherited and acquired mtDNA mutations.

A decline in OXPHOS with ageing is well recognized in non-neuronal human tissues including skeletal muscle, liver and heart (Fleming et al., 1982, Trounce et al., 1989, Yen et al., 1989, Cooper et al., 1992), and animal central nervous system (CNS) tissues (Bowling et al., 1993, Nicoletti et al., 1996). It has been postulated that this process may contribute to neuronal apoptosis in normal ageing and also that it may play a role in neurodegenerative disease (Beal, 1995). There is some evidence that age-related changes in OXPHOS efficiency may relate, at least in part, to gradual accumulation of mutations in the mitochondrial genome (Linnane et al., 1989, Miquel, 1991, Wallace, 1992).

Although mitochondrial failure has been implicated in a number of ageing human tissues (Fleming et al., 1982, Trounce et al., 1989, Yen et al., 1989, Cooper et al., 1992), there have been no reports in human brain tissue. It is important to establish the extent and variability in OXPHOS failure in the normal ageing brain as a prerequisite to determine the significance of this process in neurodegenerative diseases. This study aims to determine the relationship between age and the respiratory chain activity of the human brain, in autopsy specimens from subjects of varying age; and to map regional variation. This will provide essential information as to whether a significant mitochondrial failure occurs with the ageing process and also whether if a failure is demonstrated, it has regional variations which may predispose to selective neuronal degeneration.

Section snippets

Subjects

Autopsy brains from 12 subjects (Table 1), average post-mortem intervals of 28±22 h, with no clinical history of neurodegenerative disease were examined macroscopically. Morphological examinations were carried out by a neuropathologist to exclude pathological changes associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Sections from frontal, insular, temporal and occipital cortex, hippocampus, basal ganglia, thalamus, cerebellum and brain stem were examined

Results

Cytochrome c oxidase, succinate dehydrogenase-cytochrome c oxidoreductase, NADH: ubiquinone oxidoreductase and citrate synthase activities were analyzed in human brain mitochondria from subjects of various ages. The results were presented with and without correction for citrate synthase activity which was used as a measure of mitochondrial number. There was no evidence to suggest that gender or agonal state could have affected the results. The possibility arises that medications the subjects

Discussion

Our findings in this study confirm that a fall in OXPHOS capacity, manifested by fall in cytochrome c oxidase activity with age, occurs in the four human brain regions studied. These findings could not be explained by variation in autopsy intervals.

The degree of impairment was variable amongst older subjects suggesting considerable variation in bioenergetic capacity in the ageing brain. Subjects who have marked inefficiency in the OXPHOS pathway, may be predisposed to the development of CNS

Acknowledgements

This study was supported by funding from The National Health and Medical Research Council of Australia. The first author was supported by the Australian Post-graduate Research Award, administered by the University of Melbourne. The study fulfilled the ethics criteria of St Vincent’s Hospital and The University of Melbourne.

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