Mitochondrial dysfunction in the development of neonatal hypoxic-ischaemic brain injury
Birth asphyxia resulting in the development of Hypoxic-ischaemic (HI) encephalopathy affects 2-3 in every 1000 term infants and, depending on severity, brings about life-changing neurological consequences or death. HI injury results in initial neuronal energy depletion followed, with a delay, by a secondary energy failure during which the majority of brain injury occurs. HI initiates multiple signalling events culminating in neuronal cell death through Bax-mediated apoptosis/necroptosis mechanisms. Currently, therapeutic hypothermia is the only available treatment and offers neuroprotection in a small subset of babies. Therefore additional therapies are urgently required, but therapeutic hypothermia acts as proof-of-concept that intervention post injury can be efficacious.
Mitochondrial dysfunction acts as a focal point in the development of the injury. Not only do mitochondria become permeabilised, but we find that mitochondrial dynamics (fission, fusion, mitophagy) are perturbed after HI injury. We find that as well as the characteristic impaired ATP production and elevated ROS, mitochondrial fission is rapidly induced, which correlates with degradation of the pro-fusion protein OPA1. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI, we find that YmelL is degraded, whereas we observe very little change in Oma1 expression. Recapitulating this Yme1L reduction in vitro using siRNA results in similar degradation of OPA1 and evidence of mitochondrial fission. As OPA1 degradation and increased fission can act as precursors for mitophagy, we are currently investigating mitophagic markers in our model. Taken together, our current data reinforce our belief that mitoprotective therapies offer a new avenue of intervention for babies who suffer life-long disabilities as a result of birth asphyxia.
Date: 18 July 2017, 13:00 (Tuesday, 13th week, Trinity 2017)
Venue: John Radcliffe Women's Centre, Headington OX3 9DU
Venue Details: Level 3 Anne Anderson Lecture Theatre
Speaker: Dr Claire Thorton (King’s College London.)
Organising department: Nuffield Department of Women's and Reproductive Health
Organiser contact email address: susie.barber@obs-gyn.ox.ac.uk
Topics:
Booking required?: Not required
Audience: Members of the University only
Editor: Susie Barber