UK Parkinson's Disease Consortium

UK Parkinson's Disease Consortium - UKPDC

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  • Cell Physiology
    • Michael Duchen
    • Laura Osellame
    • Zhi Yao
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  • Clinical Neuroscience
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  • Mitochondria
  • Molecular Biology and Biochemistry
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  • Protein Phosphorylation
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Cell Physiology Group

We are fascinated by the intimate dialogue between mitochondrial biology and cell signaling systems. How do cell signaling pathways impact on and regulate mitochondrial physiology? How do subtle changes in mitochondrial function affect the physiology of the cell? How are mitochondria in different cell types specialized to match the specialized differentiated function of the cells they inhabit? We are especially concerned to characterise the contributions of mitochondrial dysfunction to cell injury and cell death - by necrosis or apoptosis – that takes place in situations such as ischaemia, reperfusion injury and in the neurotoxicity mediated by glutamate or beta-amyloid. Another core theme again involving a complex dialogue is the mitochondrion as both a site and a target of oxidative stress and damage in disease models. 

Most of our work involves live cell fluorescence microscopy and imaging, including confocal, multiphoton and fast read-out cooled CCD instruments. All approaches have been adapted to allow the simultaneous or near simultaneous measurement of multiple variables - cytosolic calcium and mitochondrial potential, cytosolic calcium and mitochondrial calcium, NADH autofluorescence and cytosolic calcium or cytosolic magnesium and so on. We have a broad general interest in functional cellular imaging and in the development of new approaches to imaging aspects of cell function using targeted probes, GFP tagged proteins, FRET, FLIM and so on.

Interests of the lab extend through a wide range of biological problems in which mitochondria are involved - in ischaemia reperfusion injury in the heart, in the role of mitochondrial function in fertility in the mammalian egg (with John Carroll), in mitochondrial function and septic shock syndrome in liver, kidney and muscle, in mitochondrial biogenesis following exercise and training in muscle, and in mitochondrial dysfunction in beta cells in diabetes. This rather unusual breadth has had a positive influence on all our work, as resolving problems in one system invariably seems to illuminate problems with others. We have been astonished at the frequency with which a small number of basic principles are recapitulated in a wide and disparate array of models.

There is mounting evidence that PD involves mitochondrial dysfunction, both a bioenergetic deficit especially affecting complex I and a defect in quality control, with defects in autophagy. We are interested to understand the links between these, the possible roles of mitochondrial biogenesis as a protective strategy. We are also interested in the possible roles of lysosomes as a part of the autophagic machinery, as there are strong associations between lysosomal storage diseases and PD. This latter project involves collaborations with Sandip Patel and Tony Schapira (RFH).

In this movie, mitochondrial membrane potential was measured in a field of living astrocytes in culture using confocal microscopy. Cells were loaded with rhodamine 123 and potential measured as dequench (an increase in signal means mitochondrial depolarisation). Amyloid β 1-42 was applied shortly after the start of the time series. After a delay, we see a gradual progressive depolarisation of mitochondria on which are superimposed large transient depolarisations that may recover completely.

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