Targeting mitochondrial fusion to alleviate brain injury in infants

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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.