Mitochondrial ubiquitin dynamics and apoptotic cell death.

细胞进行自杀或凋亡的能力在健康身体的发育和维持以及疾病中起着非常重要的作用。这确保了感染或功能失调的细胞在造成太大破坏之前被清除。生与死的决定发生在线粒体。这些是细胞的发电站，是生命所需的能量货币ATP的主要来源。就像我们的核电站一样，这种活动也存在一定的风险，受损的线粒体会泄漏出称为活性氧簇（ROS）的有毒颗粒，对细胞有害。因此，存在一种故障安全机制，可以安全地将这些受损的线粒体包裹在双层膜中，并将它们转移到细胞的废物处理工厂-溶酶体，在那里它们可以被拆除。这个过程被称为Mitophagy，来自希腊语“phagos”，意思是吃。不能进行线粒体自噬被认为是在患有帕金森病（PD）的患者中观察到的神经元细胞死亡的原因之一。在某些形式的PD中丢失或突变的两种对该过程至关重要的蛋白质是Parkin和PINK1。它们一起用一个叫做泛素的小标签装饰受损线粒体的外表面，标记它们被破坏。我们感兴趣的是另一种蛋白质，它不断楔入线粒体表面，并具有去除泛素的能力。我们称这种蛋白质为去泛素化酶或DUB，这种特殊的蛋白质称为USP 30。从失去Parkin或PINK1的细胞中耗尽USP30可以恢复其清除受损线粒体的能力。这意味着针对USP30的抑制剂可能在帕金森病的治疗中具有价值。有趣的是，我们发现去除USP30也会使细胞敏感，从而更快地自杀，我们可以用一类称为BH3-mimetics的死亡诱导药物来触发。这些药物已经用于治疗癌症，以促进恶性肿瘤细胞的细胞死亡。然而，许多癌细胞对这些药物不敏感或耐药。我们认为，靶向USP30功能可能提供一种提高这些药物疗效的方法。在这项工作计划中，我们将研究USP30控制细胞死亡的方式，并重新审视其在线粒体自噬中的作用，为开发能够利用USP30在癌症和帕金森病中的双重功能的药物铺平道路。此外，我们还将研究另外两种DUB，称为USP9X和USP24，它们也被认为可以促进细胞死亡，因此可能为其他死亡诱导药物（如BH3模拟物）的组合疗法提供替代靶点。

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.