Abstract
Perturbation of mitochondrial function and subsequent induction of cell death pathways are key hallmarks in neonatal hypoxic-ischemic (HI) injury, both in animal models and in term infants. Mitoprotective therapies therefore offer a new avenue for intervention for the babies who suffer life-long disabilities as a result of birth asphyxia. Here we show that after oxygen-glucose deprivation in primary neurons or in a mouse model of HI, mitochondrial protein homeostasis is altered, manifesting as a change in mitochondrial morphology and functional impairment. Furthermore we find that the mitochondrial fusion and cristae regulatory protein, OPA1, is aberrantly cleaved to shorter forms. OPA1 cleavage is normally regulated by a balanced action of the proteases Yme1L and Oma1. However, in primary neurons or after HI in vivo, protein expression of YmelL is also reduced, whereas no change is observed in Oma1 expression. Our data strongly suggest that alterations in mitochondria-shaping proteins are an early event in the pathogenesis of neonatal HI injury.
Highlights
Moderate to severe hypoxic-ischemic encephalopathy (HIE), caused by a lack of oxygen or blood flow to the brain around the time of birth, affects 1.5 in every 1000 live births in the UK and far more in the developing world [1,2,3]
After 90 min oxygen-glucose deprivation (OGD), we observed an increase in green monomeric JC-1 suggesting impaired membrane potential and altered morphology with both mitochondrial aggregates and rounded puncta (Figure 1a,b, OGD)
As there was a distinct alteration in mitochondrial morphology in response to OGD, we examined the expression of key genes involved in mitochondrial fission and fusion
Summary
Moderate to severe hypoxic-ischemic encephalopathy (HIE), caused by a lack of oxygen or blood flow to the brain around the time of birth, affects 1.5 in every 1000 live births in the UK and far more in the developing world [1,2,3]. It is well established that in animal models of neonatal HI, mitochondrial respiration and calcium homeostasis are impaired [17,18,19]. It was determined that mitochondrial outer membrane permeabilization (MOMP) mediated mitochondrial dysfunction in rodent neonatal HI models [20]. Once released AIF and cytochrome c initiate a cascade resulting in activation of caspases, degradation of DNA and cell death [21]. We present data analyzing the effect of in vitro oxygen-glucose deprivation (OGD) and in vivo HI on the processing of OPA1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
