Abstract
Injury to the fragile immature brain is implicated in the manifestation of long-term neurological disorders, including childhood disability such as cerebral palsy, learning disability and behavioral disorders. Advancements in perinatal practice and improved care mean the majority of infants suffering from perinatal brain injury will survive, with many subtle clinical symptoms going undiagnosed until later in life. Hypoxic-ischemia is the dominant cause of perinatal brain injury, and constitutes a significant socioeconomic burden to both developed and developing countries. Therapeutic hypothermia is the sole validated clinical intervention to perinatal asphyxia; however it is not always neuroprotective and its utility is limited to developed countries. There is an urgent need to better understand the molecular pathways underlying hypoxic-ischemic injury to identify new therapeutic targets in such a small but critical therapeutic window. Mitochondria are highly implicated following ischemic injury due to their roles as the powerhouse and main energy generators of the cell, as well as cell death processes. While the link between impaired mitochondrial bioenergetics and secondary energy failure following loss of high-energy phosphates is well established after hypoxia-ischemia (HI), there is emerging evidence that the roles of mitochondria in disease extend far beyond this. Indeed, mitochondrial turnover, including processes such as mitochondrial biogenesis, fusion, fission and mitophagy, affect recovery of neurons after injury and mitochondria are involved in the regulation of the innate immune response to inflammation. This review article will explore these mitochondrial pathways, and finally will summarize past and current efforts in targeting these pathways after hypoxic-ischemic injury, as a means of identifying new avenues for clinical intervention.
Highlights
Perinatal brain injury remains a significant cause of long-term neurological and physical disability, and a significant socioeconomic burden in both developed and developing countries (Kruse et al, 2009; Lawn et al, 2011)
Mitochondrial permeabilization results in the release of mitochondrial apoptogenic factors into the cytosol including apoptosis-inducing factor (AIF), endonuclease g (Endo G), cyt c and Smac/Diablo. These proteins have a number of pro-apoptotic functions; cyt c interacts with Apaf-1 to form an active apoptosome, providing a platform for procaspase-9 cleavage; Smac/Diablo interacts with inhibitors of apoptosis (IAP) reducing their negative influence on the activity of caspases (Vila and Przedborski, 2003)
No therapies exist that target mitochondria and the stages of perinatal brain injury once they have manifested, critically the latent phases are responsible for later neurological impairment and disabilities such as cerebral palsy
Summary
Perinatal brain injury remains a significant cause of long-term neurological and physical disability, and a significant socioeconomic burden in both developed and developing countries (Kruse et al, 2009; Lawn et al, 2011). Mice with knockdown of the PGC-1α gene exhibit progressive neuropathology and abnormal behavior (Lin et al, 2004; Cheng et al, 2012) These data strongly suggest that mitochondrial biogenesis has an important regulatory role in synaptic and brain development. Cultured neurons deficient in DRP1 have decreased numbers of neurites and defective synapses (Ishihara et al, 2009); a dominant-negative mutation of the DRP1 gene was found in a newborn girl with microcephaly and abnormal brain development (Waterham et al, 2007) These results support that fission is an important means to increase the number of mitochondria to meet energy demands during neuronal plasticity. Mitochondrial fusion proteins may attenuate apoptosis by inhibiting the release of proapoptotic agents like cytochrome c (cyt c), while mitochondrial fission protein DRP1 promotes apoptosis through Bax, leading to mitochondrial outer membrane permeabilization and cell death (Cassidy-Stone et al, 2008)
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