Mitochondrial dynamics in the neonatal brain - a potential target following injury?

Abstract

The impact of birth asphyxia and its sequelae, hypoxic-ischaemic (HI) brain injury, is long-lasting and significant, both for the infant and for their family. Treatment options are limited to therapeutic hypothermia, which is not universally successful and is unavailable in low resource settings. The energy deficits that accompany neuronal death following interruption of blood flow to the brain implicate mitochondrial dysfunction. Such HI insults trigger mitochondrial outer membrane permeabilisation leading to release of pro-apoptotic proteins into the cytosol and cell death. More recently, key players in mitochondrial fission and fusion have been identified as targets following HI brain injury. This review aims to provide an introduction to the molecular players and pathways driving mitochondrial dynamics, the regulation of these pathways and how they are altered following HI insult. Finally, we review progress on repurposing or repositioning drugs already approved for other indications, which may target mitochondrial dynamics and provide promising avenues for intervention following brain injury. Such repurposing may provide a mechanism to fast-track, low-cost treatment options to the clinic.

Keywords: cell death; hypoxia; ischaemia-reperfusion injury; mitochondrial dynamics; neonatal.

Figure 1. Mitochondria morphology is highly regulated

Mitochondria cycle through fission and fusion with new mitochondria being generated through biogenesis and mitochondrial quality control managed by mitophagy. The GTPases OPA1 and mitofusins (MFNs) 1 and 2 regulate IMM and OMM fusion respectively. The GTPase DRP1 migrates from the cytosol to bind to one of a number of proteins (FIS1, MFF) located at the OMM to instigate fission. Midpoint fission generates small mitochondria for biogenesis and asymmetrical fission segregates damaged mitochondria for recycling via mitophagy. Abbreviations: IMM, inner mitochondrial membrane.

Figure 2. Secondary energy failure following birth asphyxia results in mitochondrial impairment

The primary phase of injury lasts over the time of the asphyxia and results in initial ATP depletion and necrosis. A latent phase lasting from 1 to 12 h following injury occurs in which ATP levels recover to baseline and where therapeutic interventions are initiated. A secondary injury phase is characterised by multiple cellular processes impairing mitochondrial function leading to BAX-mediated mitochondrial outer membrane permeabilisation (MOMP), mitochondrial fission and culminates in cell death.