Mitochondrial network disruption as a final common pathway in the age-related decline of multiple tissues

There is increasing evidence that ageing-related decline of multiple tissues is associated with a decline in mitochondrial function. This has been reported to occur in multiple tissues, such as muscle (skeletal and cardiac), neurons and in vision cells including RPE. The age-related declines in mitochondrial function include reduced capacity for energy generation, abnormal cell calcium handling, increased reactive oxygen species generation and increased apoptotic signalling. The causes of these changes are unknown, but there is increasing evidence that within cells mitochondrial form a complex network (or reticulum). This is particularly apparent in post-mitotic multi-nucleate tissues such as skeletal muscle The structure and distribution of mitochondria are highly dynamic and regulated by mitochondrial fission, fusion, and mitophagy. Under physiological conditions, mitochondrial fission and fusion events occur in a balanced frequency to maintain not only the size and shape of the mitochondrial network, but also its gross distribution. Fusion results in the elongation of mitochondria into interconnected, tubular networks enabling the mixing of their contents (i.e. metabolites, proteins and mtDNA) and redistribution of energy. Furthermore, a fused network is thought to prevent the local accumulation of dysfunctional mitochondria. In contrast, mitochondrial fission is a process that acts to fragment the network into smaller, discrete organelles. Fission appears to segregate network components, which may be damaged or dysfunctional, for removal by mitophagy. Together with mitochondrial biogenesis, these processes ensure restructuring of the reticulum in response to stimuli including nutrient availability, cellular stress, and other molecular signals. Increased mitochondrial ROS, low respiration rates, aberrant calcium handling and increased apoptosis are known to be consequences of the reorganisation of the mitochondrial reticulum via increased fission and reduced fusion.
This project will utilise newly developed electron microscopy techniques with 3-D rendering of images to examine the changes in mitochondrial distribution that occur in ageing cell culture models and tissues from in vivo studies. These will be compared with markers of fission, fusion and mitophagy with the overall objective of determining whether disruption of the cellular mitochondrial network is a prerequisite for the changes in degenerative mitochondrial signalling (Increased mitochondrial ROS, low respiration rates and increased apoptosis) that lead to tissue degeneration in ageing and hence may provide a target for potential ant-ageing interventions.
The student will learn a number of different imaging techniques (EM and confocal), biochemical approaches (measurements of ROS generation, mitochondrial bioenergetics and apoptotic signalling, cell culture and molecular techniques). The project will be hosted in the Muscle pathophysiology laboratories in the William Henry Duncan Building which is currently supported by external project grants examining skeletal muscle ageing and reactive oxygen species from the MRC, BBSRC, UK Space Agency and US National Institutes of Health (NIH).