Research reportReduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging
Introduction
Aging is characterized by a generalized physiological decline. It has been proposed that mitochondrial dysfunction may have a role in this process 1, 2, 3, especially in highly oxidative phosphorylation-dependent tissues such as brain where the toxic free radicals derived from the respiratory chain activity may damage the mitochondrial DNA (mtDNA) [4]. In the last few years, it has been hypothesized that the accumulation of somatic mutations in the mtDNA secondary to this toxic effect might contribute to the neurological impairment associated with aging 5, 6. However, since only a low proportion of mutated mtDNA molecules has been consistently found in aged individuals, other changes not related to the structure of mtDNA may play a role in aging. For example, studies in brain from rat have shown that concentrations of mitochondrial RNA (mtRNA) decline with age, which has been related to a reduced mitochondrial transcription rate [7]rather than to a drop in mtDNA levels [8]. To our knowledge such studies have not been performed in humans, where brain is one of the most clinically relevant targets in senescence. Herein, we report the effect of aging on the content of mtDNA and mtRNA in the frontal cortex of 13 human brains.
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Material and methods
Brain tissue from the cortical region of frontal lobe was obtained from autopsy of individuals without any clinical history suggestive of mitochondrial encephalomyopathy. Brain tissue was obtained within 12 h of death and was stored at −80°C until use. Frontal cortex consisted of cortex in front of the precentral gyrus and above the sylvian fissure. The families of all the individuals gave informed consent and the protocol was approved by the ethics committee of the hospital.
Total DNA was
Results
Frontal lobe brain tissue obtained from 13 control individuals aged between 21 and 84 years were included in this study. Patients suffered from bronchopneumonia (3), congestive heart failure (3), coronary artery disease (2) and multiple trauma (5). They were not taking psychoactive medications at the time of death. They were free of neurological disease and showed no neuropathological abnormalities on postmortem examination.
Southern blot analyses with digested and undigested mtDNA did not
Discussion
There is a great deal of evidence indicating that changes in mtDNA may have a role in aging. The aim of the present study was to address the effect of human aging on mtDNA content and on mtDNA transcription products from the frontal cortex, one the most metabolically active regions of the brain. In agreement with results previously reported in rats [11], we found a decrease of the steady-state levels of mtDNA transcripts. This fact could be due to qualitative or quantitative changes in mtDNA
Acknowledgements
The authors wish to thank Dra. Laia Villegas for her contribution in neuropathological examinations. Helena Kruyer is thanked for her help with the manuscript. This work was supported by grants DGICYT PM95-0105, CICYT SAF191-95, FIS94/1563, and CICYT SAF96-0027. XE and VN are supported by Servei Catala de la Salut from Generalitat de Catalunya. AB has now a postdoctoral position at the Department of Neurology D4-5 in the University of Miami.
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