IAH Seminar - Student led session
Location: Great Gable Meeting Room, Clinical Ageing Research Unit, CAV
Time/Date: 16th February 2012, 12:15 - 13:00
You are invited to the IAH research seminar which will take place on Thursday 16 February 2012 which will be held in the Great Gable meeting room of the Clinical Ageing Research Unit. The meeting will start at 12.15 and will be followed at approximately 13.00 by a sandwich lunch.
The presentation today will be given by three of our PhD students - Georgia Campbell (3rd year), James Wordsworth (2nd year) and Emma Burvill (1st year).
Abstracts:
Clonal expansion of mtDNA deletions in mitochondrial disease and aging
Georgia Campbell, 3rd year PhD student, IAH
The accumulation of mitochondrial DNA deletions by a process known as ‘clonal expansion’ is important in determining clinical severity in many cases of inherited and sporadic mitochondrial disease, as well as contributing to focal respiratory chain deficiency in both ageing and neurodegenerative disorders. The mechanism involved in clonal expansion of mtDNA deletions is currently unknown, although 3 main hypotheses have been proposed.
Our study was designed to test the 'advantage of the smallest' hypothesis - which proposes that smaller mitochondrial genomes accumulate due to a replicative advantage - by determining whether mtDNA molecules harbouring the largest deletions spread further by clonal expansion through muscle fibres than larger mtDNA molecules.
We characterised mtDNA deletion sizes in sets of long and short COX-deficient skeletal muscle fibres from patients with mtDNA maintenance disorders, expecting to observe the largest mtDNA deletions in the longest COX-negative fibre areas if the 'advantage of the smallest' hypothesis is true.
Senescent Cells and the Bystander Effect
James Wordsworth (2nd year PhD student, IAH)
If cell division continues under stress it can lead to the formation of life threatening tumours in vivo. Therefore the cell activates a permanent growth arrest, known as cellular senescence. In order to ensure the cell does not re-enter the cell cycle it initiates several positive feedback loops including the production of reactive oxygen species (ROS) and inflammatory cytokines, which continually stimulate the pathways leading to growth arrest. However neither ROS nor inflammatory cytokines are restricted to autonomous effects. They are secreted or pass through gap junctions stimulating the stress response, and resulting in DNA damage, in the surrounding bystander cells.
In this study confocal microscopy was used to observe the localisation of a fluorescent DNA damage response protein (53BP1-GFP) in bystander cells, co-cultured with senescent cells. DNA damage was found to significantly increase in bystander cells, and extracellular antioxidants added to the medium reduced damage to control level. The addition of medium from senescent cells also induced a small bystander effect indicating that long lived factors such as inflammatory cytokines could also play a role. Senescence activated β-galactosidase staining revealed that bystander cells could also be induced to become senescent.
These results indicate that senescent cells, which arise naturally in the body, could cause widespread damage in the surrounding tissue; and implicates ROS and senescence as key players in organismal decline.
The Role of UCHL1 (PARK5) in Mitochondrial Dynamics and Function
Emma Burvill (1st year PhD student, IAH)
UCHL1 is a deubiquitinating enzyme that stabilises levels of monomeric ubiquitin within the cell.
Since a global disruption of the ubiquitin system greatly impairs mitochondrial dynamics, we hypothesise that depletion of ubiquitin pools caused by UCHL1 inhibition or knockout will perturb mitochondrial dynamics, and cause poorly functioning mitochondria to build up.
Mitochondrial dynamics will be studied in primary neurons isolated from UCHL1 knockout mice, and the consequences of UCHL1 ablation on mitochondrial integrity will be studied in mouse brains in situ
Published: 3rd February 2012
