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Mitochondrial Optic Atrophy (OPA) 1 Processing Is Altered in Response to Neonatal Hypoxic-Ischemic Brain Injury
Ana A Baburamani1, Chloe Hurling2, Helen Stolp3
1Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, St. Thomas' Hospital, SE1 7EH London, UK. ana.baburamani@kcl.ac.uk.
Insights
Mitochondrial dysfunction and altered OPA1 protein cleavage are early events in neonatal hypoxic-ischemic (HI) injury. Targeting these changes may lead to new therapies for birth asphyxia complications.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neonatal hypoxic-ischemic (HI) injury disrupts mitochondrial function and triggers cell death.
- Mitoprotective therapies are crucial for mitigating lifelong disabilities from birth asphyxia.
Purpose of the Study:
- To investigate alterations in mitochondrial protein homeostasis following neonatal HI injury.
- To identify key proteins involved in mitochondrial morphology and function changes during HI.
Main Methods:
- Utilized primary neurons and a mouse model of HI.
- Analyzed mitochondrial morphology and function after oxygen-glucose deprivation.
- Examined the expression and cleavage of mitochondrial proteins, including OPA1, Yme1L, and Oma1.
Main Results:
- HI injury altered mitochondrial morphology and impaired function.
- Aberrant cleavage of the OPA1 protein into shorter forms was observed.
- Reduced Yme1L protein expression, but not Oma1, occurred in HI conditions.
Conclusions:
- Alterations in mitochondria-shaping proteins, particularly OPA1 and Yme1L, are early pathological events in neonatal HI injury.
- Understanding these molecular changes provides targets for developing novel therapeutic interventions.
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.
