Academic Ageing Seminar - Accumulation of mitochondrial DNA deletions – a mechanism for impairment of tissue function during aging?

Location: Seminar Room, Wolfson Research Centre, Campus for Ageing and Vitality
Time/Date: 18th February 2010, 12:30 - 13:30

You are invited to attend the Academic Ageing Seminar on Thursday 18 February 2010 in the Wolfson Seminar Room, Institute for Ageing and Health. The seminar will take place at 12.30 pm with sandwiches available from 12 noon.

The speaker is Prof Dr Rudolf Wiesner, Institut für Vegetative Physiologie, der Universität zu Köln and the title of his talk is 'Accumulation of mitochondrial DNA deletions – a mechanism for impairment of tissue function during aging?'.

Abstract:

Deletions of mtDNA accumulate during normal aging in many tissues, but little is known about the mechanisms how they are generated, how and why they clonally expand over time and whether they are causally involved in tissue aging. One striking example are dopaminergic neurons in the Substantia nigra of humans, where an increase in deleted vs. wildtype molecules has been observed during normal aging as well as in Parkinsons disease, conditions in which these neurons are progressively lost.

We tested the hypotheses that

  • (i) accumulation of neuromelanin, the black pigment of the S. nigra, or
  • (ii) a high catecholamine turnover or
  • (iii) reactive oxygen species (ROS)

are involved.

Various mouse brain regions were analyzed: mtDNA deletions were not found in young mice (12 weeks), but were detectable at week 50 and further increased with age. Deletions were most prominent in S. nigra, followed by striatum, cerebellum and cortex, as in humans.

  • Since S. nigra of mice does not contain neuromelanin, (i) this intracellular protein-aggregate can be excluded as being causative.
  • In the adrenal gland, the percentage of deleted vs. wild-type mtDNA molecules was 5fold higher compared to S. nigra, supporting the hypothesis that (ii) a high turnover of catecholamines stimulates their generation and/or clonal expansion.
  • Mice overexpressing monoamine-oxidase B (MAO-B) in glial cells, thus producing highly reactive dopamine metabolites, showed the same amount of mtDNA deletions as controls. Thus, (iii) ROS must come from an intra-neuronal source, if they are involved at all.

Only a vulnerable subset of S. nigra neurons are prone to neurodegeneration, and dopaminergic neurons of other midbrain regions are spared, during aging as well as in Parkinsons disease. Differentiating between those different neuron types using electrophysiological techniques and gene expression signatures, we now try to explain the reasons for this differential vulnerability. 

Supported by: Center for Molecular Medicine Cologne (CMMC) & Cologne Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Köln, Germany

Published: 3rd February 2010