A novel ageing-related pathway regulating ROS homeostasis

Oxygen is essential for life, however once inside our body, it can be converted to other forms called reactive oxygen species (ROS). These ROS are potentially dangerous for our cells as they can damage proteins, DNA and lipids. It is proposed that this damage contributes to the ageing of our cells, and hence our body, and it also contributes to age-related diseases such as cancer, heart disease and Alzheimers. It is important, therefore, to understand how the levels of ROS in our cells are regulated. ROS levels can increase due changes in the function of the mitochondria, which are the energy producing factories of the cell. It is important that, in response to increased ROS levels, the cell responds by altering the production of proteins, for example by increasing the expression of anti-oxidant enzymes. This will cause a reduction in the ROS levels and protect the cells from damage. We have uncovered a new pathway for regulating ROS in cells. We found that an enzyme that normally resides in the mitochondria and contributes to generating energy can be redirected to the nucleus when ROS levels in cells are increased. Within the nucleus, the enzyme can regulate the expression of genes encoding proteins that reduce the elevated ROS levels. This enzyme therefore acts to communicate the status of the mitochondria to the nucleus. The significance of the project is that a fuller understanding of how ROS levels are regulated will facilitate efforts to promote healthier living as well as the development of therapies that combat its detrimental effects.

Reactive oxygen species (ROS) are a major cellular stress that is increased when mitochondrial function is compromised. ROS can damage cell components including DNA, proteins, and lipids, and contribute to cellular ageing and ageing-related disorders such as cancer, heart disease and neurodegeneration. It is therefore crucial that mitochondria communicate with the nucleus to promote the reprogramming of gene expression to combat the increased oxidative stress. We have uncovered a novel nuclear function for Clk-1, a mitochondrial hydroxylase involved in the electron transport chain. Genetic studies have demonstrated that reduced function of Clk-1 increases lifespan in both mice and the nematode C.elegans, but the underlying mechanisms are poorly understood. Our data show that increased ROS levels can direct a pool of Clk-1 to the nucleus where it associates with chromatin and regulates gene expression. We have demonstrated that nuclear Clk-1 is required for maintaining ROS homeostasis and for protecting cells from oxidative stress. The project will focus on key questions that remain including how ROS control Clk-1 nuclear localization, how Clk-1 coordinates gene expression to regulate ROS-sensitive signalling pathways, and establishing the biological significance of nuclear Clk-1. We will use cultured cells to uncover the mechanisms underpinning Clk-1 action and the model organism C.elegans to determine the importance of nuclear Clk-1 in vivo for regulating development, oxidative stress responses and longevity. The diversity of mechanisms controlling ROS homeostasis are only beginning to be characterised, so our finding of a novel function for Clk-1 as a ROS-dependent mediator of mitochondrial-nuclear communication will advance our understanding of how cells manage ROS levels during development and ageing, and also in ROS-related diseases.

We plan to publish our research in high impact peer-reviewed journals with open access agreements to gain maximum visibility amongst other academics. We will also present our results through the University of Manchester web site as well as at seminars and conferences. There is also significant interest in this research area within Industry as it could be exploited in a number of areas including promoting healthy ageing, preventing and treating age-related diseases (such as cancers, heart disease and neurodegenerative diseases) and in the production of food and health products. Due to the basic nature of the project, it is unclear at this stage if there are likely to be commercially or medically exploitable results generated within the lifetime of the grant. If there are, the Faculty has a number of mechanisms we can engage with for promoting collaboration with Industry, including employing Research Business Managers, whose remit involves facilitating such collaborations, and an office dedicated to the commercialisation of research (Manchester Innovations). A further impact will be derived from our involvement in public engagement activities. To ensure that our research is disseminated to the public in an easily accessible form we will consult with the Faculty media relations officer, who has contacts with both local and national press. In addition, the co-applicants and the research staff employed on the grant will participate in University-hosted public engagement events and we will also provide summer lab experience for sixth-form and undergraduate students aimed at enthusing them to seriously consider careers in research. Finally, the grant will impact on the careers of the researchers employed through it. The Faculty provides an excellent training environment for its research staff and is strongly committed to their career development. They will build on their previous experience and acquire a valuable set of research based and transferable skills that will benefit their continued career in research.