Multifaceted deaths orchestrated by mitochondria in neurones

Abstract

Neurones undergo diverse forms of cell death depending on the nature and severity of the stress. These death outcomes are now classified into various types of programmed cell death, including apoptosis, autophagy and necrosis. Each of these pathways can run in parallel and all have mitochondria as a central feature. Recruitment of mitochondria into cell death signalling involves either (or both) induction of specific death responses through release of apoptogenic proteins into the cytosol, or perturbation in function leading to loss of mitochondrial energisation and ATP synthesis. Cross-talk between these signalling pathways, particularly downstream of mitochondria, determines the resultant pattern of cell death. The differential recruitment of specific death pathways depends on the timing of engagement of mitochondrial signalling. Other influences on programmed cell death pathways occur through stress of the endoplasmic reticulum and the associated ubiquitin-proteasome system normally handling potentially neurotoxic protein aggregates. Based upon contemporary evidence apoptosis is a relatively rare in the mature brain whereas the contribution of programmed necrosis to various neuropathologies has been underestimated. The death outcomes that neurones exhibit during acute or chronic injury or pathological conditions considered here (oxidative stress, hypoxic-ischaemic injury, amyotrophic lateral sclerosis, Parkinson's and Huntington's diseases) fall within a spectrum of the diverse death types across the apoptosis-necrosis continuum. Indeed, dying or dead neurones cells may simultaneously manifest characteristics of more than one of death pathway. Understanding neuronal death pathways and their cross-talk not only informs the detailed pathobiology but also suggests novel therapeutic strategies.

Repeated mild traumatic brain injury: potential mechanisms of damage

“…Injury-induced neuronal and glial cell death likely occurs along a continuum of necrotic (passive) and/or apoptotic (programmed) mechanisms, 134,135 resulting in removal of injured and dysfunctional cells, but also progressive neuronal degeneration and exacerbated functional deficits. 136,137 Necrotic cell death occurs under conditions of excitotoxicity and metabolic failure particularly prevalent at the site of impact immediately following focal TBI, while surviving cells spatially separated from the primary necrotic injury can undergo delayed and programmed cell death.…”

Novel Mitochondrial Targets for Neuroprotection

“…Mitochondria are principal mediators of cell death that occurs during both central nervous system injury and in chronic neurodegenerative disorders; see Nagley et al (2010) and Schon and Przedborski (2011) for comprehensive reviews. Mitochondria are therefore important targets for neuroprotective interventions.…”

Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons

“…Prominent sources of physiological intracellular ROS formation that may further be stimulated under conditions of cellular stress are, for example, lipoxygenases (LOXs), cyclooxygenases (COXs), NADPH-oxidases (NOXs) and the uncoupled mitochondrial respiratory chain. 7,8 After exposure to glutamate, dysfunctional mitochondria may generate toxic amounts of intracellular ROS, which may further severely perturb cellular redox balance. 9 In addition, these organelles host pro-apoptotic proteins, for example, apoptosis-inducing factor (AIF), cytochrome c or SMAC/ DIABLO (second mitochondria-derived activator of caspase/ direct IAP binding protein with low pI), which may trigger caspase-dependent or caspase-independent death when released into the cytosol.…”