Targeting mitochondrial fusion to alleviate brain injury in infants

针对线粒体融合减轻婴儿脑损伤

• 批准号: MR/T014725/1
• 负责人: Claire Thornton
• 金额: $ 88.93万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT014725%2F1
• 关键词: Targeting; mitochondrial; fusion; alleviate; brain

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.

在英国，每1000名婴儿中有2-3名婴儿出生时，大脑的血流/氧气受到限制，根据严重程度，可能导致永久性的终身脑损伤，包括脑瘫。儿童及其家庭的情感，社会和经济负担相当大，我们的工作重点是开发治疗方法，以减轻这种毁灭性伤害的后果。在出生时的初始损伤之后，在大多数脑细胞死亡发生之前有几个小时的延迟，这种延迟为临床医生提供了宝贵的治疗窗口。目前唯一可用的治疗方法是治疗性低温，即婴儿的体温降低三天。当出生后迅速开始低温时，它可以使没有脑损伤的生存机会增加一倍。不幸的是，只有1/7的新生儿成功，但它证明了我们可以在损伤后进行干预治疗，仍然可以产生有效的结果。这是至关重要的，因为我们还不能提前预测哪些婴儿会遭受脑损伤。线粒体存在于体内所有细胞（红细胞除外）中，并发挥作用以产生生存所需的细胞能量。当细胞能量福尔斯降到极低水平时，就会发生脑损伤和脑细胞死亡。因此，尽管许多事件是在损伤后触发的，但我们认为线粒体充当了所有这些事件汇聚的枢纽。在最初的损伤之后，线粒体外膜变得渗漏，将线粒体内容物释放到细胞中，并在这样做的过程中使细胞死亡。与此同时，线粒体内膜被破坏，释放出通常固定在内膜褶皱内的促死亡分子。OPA 1是一种线粒体蛋白，其充当将线粒体内膜的折叠保持在一起的“分子钉”。来自我们动物模型的数据显示，不幸的是，OPA 1在出生损伤后降解。我们预测，如果我们保护OPA 1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。我们将在我们的动物模型和各种培养的脑细胞中进行研究，以评估OPA 1变性对脑损伤的影响。我们还将确定可能有助于OPA 1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，以确定婴儿大脑受损的严重程度。通过采取这种方法的组合，我们的目标不仅是增加我们对OPA 1生物学的了解，而且还利用它来开发药物和新工具，以改善有终身神经损伤风险的婴儿的结局。

项目成果

Montelukast reduces grey matter abnormalities and functional deficits in a mouse model of inflammation-induced encephalopathy of prematurity.

• DOI: 10.1186/s12974-022-02625-5
• 发表时间: 2022-10-29
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3

Mitochondrial dynamics in the neonatal brain - a potential target following injury?

• DOI: 10.1042/bsr20211696
• 发表时间: 2022-03-31
• 期刊: Bioscience reports
• 影响因子: 4
• 作者: Jones A;Thornton C
• 通讯作者: Thornton C

Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia-Ischemia.

• DOI: 10.3390/cells11071193
• 发表时间: 2022-04-01
• 期刊: Cells
• 影响因子: 6
• 作者: Nair S;Leverin AL;Rocha-Ferreira E;Sobotka KS;Thornton C;Mallard C;Hagberg H
• 通讯作者: Hagberg H