THE "REDOX TRIANGLE" - COMMUNICATION BETWEEN PEROXISOMES, THE ENDOPLASMIC RETICULUM AND MITOCHONDRIA IN HEALTH AND DISEASE

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In order to survive and thrive, social animals need to communicate and collaborate effectively so that when taken as a whole, a community of individuals is greater than the sum of its parts. "It is the long history of humankind (and animal kind, too) that those who learned to collaborate and improvise most effectively have prevailed" (Charles Darwin, 1809 - 1882). This general concept is also true for communication between different parts of the human cell. The "language" used may differ, instead of vocal calls between animals as a warning of danger, cellular compartments exchange chemical signals to indicate a change in environment, but the underlying premise is shared. My research aims to explore how different compartments inside cells communicate and what happens when this communication breaks down. Conceptually, the human cell can be sub-divided into separate compartments (organelles) which are a part of wider networks or production lines. Each organelle has its own particular job to perform but also relies extensively on other units within the network. For example, foods such as fats (lipids) are often partially processed in one organelle before being handed over to a different organelle for further processing. Such coordination is also required for the generation of energy, the production of lipids required to build nerve cell membranes, and the activation of the cells recycling systems. The idea that organelles need to come together to communicate and collaborate in cellular reactions is an emerging field in cell biology and we still know relatively little about the factors involved and when this communication takes place. However, a breakdown in organelle communication, due to defects in the machinery involved, has been implicated in diseases such as Alzheimer's and Parkinson's as well as metabolic disorders. Furthermore, as cells age their metabolic efficiency is reduced and the ability to coordinate detoxification of dangerous waste products is diminished, perhaps as a result of communication breakdown, resulting in progressive damage which contributes to the ageing process. In my research I will use mammalian cells to investigate how three organelles, the endoplasmic reticulum, peroxisomes and mitochondria communicate. These organelles are the major centres in the cell which are involved in both lipid exchange and the production and detoxification of waste products in the form of reactive oxygen species. I will assess how and when these organelles communicate and what components are involved. As the accumulation of reactive oxygen species is associated with ageing I will investigate how signal exchange between the organelles works to share the load and coordinate detoxification. I will uncover the metabolic switches which turn different pathways and systems on and off and generate new tools and systems which can also be used by other researchers in the field, accelerating research in this area. The first phase of the work will provide the underpinning knowledge and tools which will then be leveraged in the second phase to assess how defects in organelle interactions are linked to disease. I will investigate how interactions between organelles can change over time as a model for ageing and will also assess what happens to the lipid balance in cells when communication goes wrong. Finally, I aim to restore defective communication channels to determine if this can be a possible therapeutic approach. This novel and extremely exciting area of cell biology promises to deliver fundamental insights into organelle interactions events in cells and also establish how this fits into the broader cellular signalling network and how failure to communicate may be linked to disease.