Mitochondrial ubiquitin dynamics and apoptotic cell death.

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The ability of cells to undergo suicide or apoptosis plays a very important role in the development and maintenance of a healthy body as well as in disease. This ensures that infected or dysfunctional cells are eliminated before causing too much havoc. The decision over life and death is happening at the mitochondria. These are the power stations of the cell, one major source of the energy currency, ATP, that is needed for life. Just like our nuclear power stations, this activity comes with a certain risk and damaged mitochondria leak toxic particles called reactive oxygen species (ROS) that are harmful to the cell. Therefore a fail-safe mechanism exists that safely engulfs such damaged mitochondria in a double-membrane and moves them to the waste-disposal factory of the cell, the lysosome, where they can be dismantled. This process is called Mitophagy, derived from the greek "phagos", meaning eating. Failure to undergo mitophagy is believed to be one of the causes of neuronal cell death seen in patients suffering from Parkinson's disease (PD). Two proteins critical to this process, which are lost or mutated in some forms of PD are Parkin and PINK1. Together they decorate the outer surface of damaged mitochondria with a small tag called ubiquitin, that marks them out for destruction. We are interested in another protein that is constantly wedged into the surface of mitochondria and has the ability to remove ubiquitin. We call such proteins deubiquitylases or DUBs, and this particular one is called USP30. Depleting USP30 from cells that suffer from a loss of Parkin or PINK1 restores their ability to clear away damaged mitochondria. This means that inhibitors against USP30 may have value in the treatment of Parkinson's disease. Interestingly, we have found that removing USP30 also sensitises cells to undergo faster suicide, which we can trigger with a class of death-inducing drugs called BH3-mimetics. These drugs have already been used in the treatment of cancer to promote cell death of rogue tumour cells. However, many cancer cells are insensitive or resistant to these drugs. We believe that targeting USP30 function may provide a means to improve the efficacy of these drugs. In this programme of work we will study the way USP30 controls cell death and revisit its role in mitophagy, to pave the way for the development of drugs that can exploit this dual aspect of USP30 function in cancer and Parkinson's disease. In addition, we will also study two further DUBs, called USP9X and USP24, which have also been suggested to promote cell death and may therefore provide alternative targets for combinatorial therapies with other death inducing drugs, like the BH3-mimetics.