Mitochondrial ubiquitin dynamics and apoptotic cell death.

细胞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。这确保了在造成太大破坏之前，被感染或功能失调的细胞被消除。决定生死的是线粒体。这些是电池的发电站，是生命所需的能量货币三磷酸腺苷的主要来源之一。就像我们的核电站一样，这种活动也有一定的风险，受损的线粒体会泄漏被称为活性氧(ROS)的有毒颗粒，这种颗粒对细胞有害。因此，存在一种故障保护机制，它可以安全地将这种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厂--溶酶体，在那里它们可以被分解。这一过程被称为有丝分裂，源于希腊语“phagos”，意思是吃。未能进行有丝分裂被认为是帕金森病(PD)患者神经细胞死亡的原因之一。在某些形式的帕金森病中丢失或突变的两种对这一过程至关重要的蛋白质是Parkin和PINK1。它们一起用一种名为泛素的小标签装饰受损线粒体的外表面，将它们标记为要销毁的标记。我们对另一种蛋白质感兴趣，这种蛋白质不断嵌入线粒体表面，具有去除泛素的能力。我们称这种蛋白质为去泛素酶或DUBS，这种特殊的蛋白质被称为USP30。从遭受Parkin或PINK1缺失的细胞中耗尽USP30可以恢复它们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氏症的治疗中具有价值。有趣的是，我们发现去除USP30还会使细胞更快地自杀，我们可以用一种名为BH3-模拟物的致死药物来触发这种自杀。这些药物已经被用于癌症的治疗，以促进流氓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具有抗药性。我们认为，靶向USP30功能可能为提高这些药物的疗效提供了一种手段。在这项工作计划中，我们将研究USP30控制细胞死亡的方式，并重新探讨其在有丝分裂中的作用，为开发能够利用USP30在癌症和帕金森病中这一双重功能的药物铺平道路。此外，我们还将研究另外两个DUBS，称为USP9X和USP24，它们也被认为可以促进细胞死亡，因此可能为与其他诱导死亡药物的联合治疗提供替代靶点，如BH3-模拟物。

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.