Targeting mitochondrial fusion to alleviate brain injury in infants

在英国，每1000个婴儿中就有2-3个婴儿出生时出现大脑血流量/氧气受限，根据严重程度，可能导致永久性、终身脑损伤，包括脑瘫。儿童及其家庭的情感、社会和经济负担是相当大的，我们的工作重点是开发治疗方法，以改善这种毁灭性伤害的后果。在出生时受到初始损伤后，在大多数脑细胞死亡发生之前有几个小时的延迟，这一延迟为临床医生提供了宝贵的治疗窗口。目前唯一可行的治疗方法是治疗性低温，也就是将婴儿的体温降低三天。如果在出生后迅速进行低温治疗，可以使没有脑损伤的存活机会增加一倍。不幸的是，只有七分之一的新生儿成功，但它证明了我们可以在受伤后干预治疗，仍然产生有效的结果。这是至关重要的，因为到目前为止，我们还不能提前预测哪些婴儿会遭受脑损伤。线粒体存在于身体的所有细胞中（红细胞除外），其功能是产生生存所需的细胞能量。当细胞能量降至极低水平时，就会发生脑损伤和脑细胞死亡。因此，尽管许多事件是在侮辱之后触发的，但我们认为线粒体是所有这些事件汇聚的枢纽。在最初的损伤之后，线粒体外膜开始渗漏，将线粒体内容物释放到细胞中，从而导致细胞死亡。与此同时，线粒体内膜被破坏，释放出通常安全地保存在内膜褶皱中的促死亡分子。OPA1是一种线粒体蛋白，起着“分子钉”的作用，将线粒体内膜的褶皱连接在一起。我们的动物模型数据显示，不幸的是，出生损伤后，OPA1会退化。我们预测，如果我们保护了OPA1的完整性，我们将为线粒体提供额外的防御，以抵抗释放促死亡分子，并继续为细胞提供维持生命所需的能量。我们将在动物模型和各种培养的脑细胞中进行研究，以评估OPA1变性对脑损伤的影响。我们还将确定可能有助于OPA1降解的新机制，从而为未来的药物开发提供新的靶点。最后，我们有机会利用线粒体生物学来开发一种新的、非侵入性的早期检测方法，以确定婴儿大脑损伤的严重程度。通过采用这种方法的组合，我们的目标不仅是增加我们对OPA1生物学的了解，而且还利用它来开发药物和新工具，以改善有患终身神经损伤风险的婴儿的预后。

Restricted blood flow/oxygen to the brain occurs during the birth of 2-3 babies per 1000 in the UK and depending on the severity, can result in permanent, life-long brain injury including cerebral palsy. The emotional, social and financial burdens to the children and their families is considerable and our work focuses on developing therapies to ameliorate the consequences of this devastating injury. Following initial injury during birth, there is a delay of a few hours before the majority of brain cell death occurs and this delay provides clinicians with a valuable treatment window. Currently the only available treatment is therapeutic hypothermia, in which the body temperature of the baby lowered for three days. When hypothermia is initiated rapidly after birth, it can double the chances of survival without brain injury. Unfortunately, it is only successful for 1 in 7 neonates, but it proves that we can intervene with therapy following injury and still produce an effective outcome. This is critical because as yet we cannot predict in advance which babies will suffer brain injury. Mitochondria reside inside all cells in the body (except red blood cells), and function to generate cellular energy needed for survival. Brain injury and brain cell death occurs when cellular energy falls to extremely low levels. Therefore, although many events are triggered after the insult, we believe that mitochondria act as a hub where all these events converge. Following the initial insult, the outer mitochondrial membrane becomes leaky, releasing mitochondrial contents into the cell and in doing so, committing the cell to death. At the same time, the inner mitochondrial membrane becomes disrupted, freeing pro-death molecules normally held securely within the folds of the inner membrane. OPA1 is a mitochondrial protein which acts as a "molecular staple" holding together the folds of the inner mitochondrial membrane. Data from our animal model shows that unfortunately, OPA1 becomes degraded after the birth injury. We predict that if we protect the integrity of OPA1, we will provide mitochondria with additional defences to resist releasing pro-death molecules, and continue to feed the cell with the energy it needs to stay alive. We will perform research in our animal model and in a variety of cultured brain cells to evaluate the impact of OPA1 degeneration on brain injury. We will also identify new mechanisms which might contribute to the degradation of OPA1, thus providing novel targets for future drug development. Finally we have the opportunity to use mitochondrial biology to develop a new, non-invasive and early detection method to identify how severely an infant's brain has been injured. By taking this combination of approaches, we aim not only to increase our knowledge of OPA1 biology, but also to use it to our advantage in developing drugs and new tools to improve the outcome of babies at risk of developing lifelong neurological impairment.