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Mitochondrial membrane permeabilization in neuronal injury

Key Points

  • Both cerebrovascular diseases and traumatic insults are associated with the irreversible loss of cells from the CNS. In the core of lesions, cell death proceeds in an uncontrollable fashion. By contrast, surrounding cells undergo programmed cell death, most frequently via the intrinsic (mitochondrial) pathway of apoptosis.

  • Several pro-apoptotic stimuli, including Ca2+ overload and oxidative stress (two conditions that are intimately connected with neuronal injury), can initiate mitochondrial apoptosis. The complex interplay among multiple pro- and anti-apoptotic signalling pathways determines the neuronal response to stress.

  • If pro-apoptotic signals prevail over anti-apoptotic ones, mitochondrial membrane permeabilization (MMP) occurs, thereby leading to the dissipation of the mitochondrial transmembrane potential and to the release of mitochondrial proteins from the intermembrane space (IMS) into the cytosol.

  • Members of the BCL-2 protein family regulate MMP in a multifaceted fashion. Multidomain proteins such as BAX and BCL-2 have prominent MMP-stimulatory and MMP-inhibitory functions, respectively. Moreover, BH3-only proteins promote MMP either by activating BAX or by subverting its BCL-2-mediated inhibition.

  • IMS proteins that are released by mitochondria following MMP include direct and indirect activators of caspases (such as cytochrome c and DIABLO (also known as SMAC), respectively) as well as proteins that promote cell death in a caspase-independent fashion, such as apoptosis-inducing factor and endonuclease G.

  • Many in vivo studies (performed in animal models of ischaemia and trauma) indicate that the inhibition of intrinsic apoptosis, upstream and/or downstream of MMP, can confer neuroprotection.

Abstract

Acute neurological conditions such as cerebrovascular diseases and trauma are associated with irreversible loss of neurons and glial cells. Severe or prolonged injury results in uncontrollable cell death within the core of lesions. Conversely, cells that are less severely damaged succumb in a relatively slow fashion, frequently via the intrinsic pathway of cell death, through the deterioration of mitochondrial functions. The permeabilization of mitochondrial membranes determines whether cells will succumb to or survive the injury, and represents a 'point of no return' in mitochondrial cell death. It is therefore an attractive target for the development of new neuroprotective interventions.

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Figure 1: The extrinsic and intrinsic (mitochondrial) pathways of apoptosis.
Figure 2: Pre-mitochondrial events that regulate mitochondrial membrane permeabilization in neurons.
Figure 3: Mechanisms of mitochondrial membrane permeabilization and the BCL-2 protein family.
Figure 4: Caspase-dependent and caspase-independent executioner mechanisms of cell death.
Figure 5: Mitochondrial membrane permeabilization and neuroprotection.

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Acknowledgements

We apologize to all colleagues whose articles we were unable to cite owing to space limitations. O. Kepp and C. Zhu are acknowledged for help in figure preparation. Electron microscopy pictures were kindly provided by F. Northington and L. Martin. G.K. is supported by Ligue Nationale contre le cancer (équipe labellisée), Agence National de Recherche, Cancéropôle Ile-de-France, Institut National du Cancer, Fondation pour la Recherche Médicale, and the European Community (Active p53, Apo-Sys, ChemoRes, DeathTrain, TransDeath, RIGHT). K.B. is supported by the Swedish Research Council and the Swedish Childhood Cancer Foundation.

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Examples of the neuroprotective potential of MMP inhibitors (PDF 450 kb)

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Examples of the neuroprotective potential of inhibitors of post-mitochondrial executioner mechanisms (PDF 385 kb)

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Glossary

Astrocyte–neuron lactate shuttle

The process in which astrocytes, which take up glucose more efficiently than neurons, convert glucose to lactate, which is then transported into the extracellular space and taken up by neurons. Lactate is thought to be one of the most prominent energy sources for neurons.

Mitochondrial membrane permeabilization

(MMP). The rupture of mitochondrial membranes that leads to the functional impairment of mitochondria and to the release of toxic mitochondrial intermembrane space proteins into the cytosol.

Apoptotic bodies

Double-membraned vacuoles that shed from dying cells during the late stages of apoptosis, which may include parts of the nucleus and/or apparently normal organelles.

Excitotoxicity

The pathological process by which neurons are damaged and die owing to the overactivation of receptors for excitatory neurotransmitters (for example, glutamate), which results in cytosolic Ca2+ overload and activation of multiple catabolic enzymes.

BH3-only proteins

A subset of proteins from the BCL-2 family that have significant homology only within the Bcl-2 homology 3 domain (BH3) and act as intracellular stress sensors.

Microsphere embolism

Microspheres with a diameter of approximately 50 μm are injected into the cerebral circulation, resulting in distal disseminated embolism.

Oxidative phosphorylation

Respiratory chain complexes embedded in the inner mitochondrial membrane catalyse a series of redox reactions that generate the electrochemical gradient that is required for mitochondrial ATP synthesis.

Mitochondrial permeability transition

(MPT). The abrupt increase in the inner mitochondrial membrane permeability to ions and low-molecular-mass solutes that results from long-lasting openings of the permeability transition pore complex, finally provoking osmotic swelling of the mitochondrial matrix and MMP.

NO donors

Pharmacological agents that can release NO, either spontaneously or following specific chemical reactions that occur within target cells.

Mitochondrial outer membrane permeabilization

(MOMP). The loss of the outer mitochondrial membrane impermeability to proteins that results from the pore-forming activity of pro-apoptotic BCL-2 family members, such as BAX and BAK.

Uraemic encephalopathy

A multi-symptom neurological disorder that may follow renal failure as a result of insufficient clearance of toxic metabolites, changes in volume and electrolyte composition of body fluids, and imbalances in the levels of various hormones.

Macroautophagy

An evolutionarily conserved mechanism of intracellular catabolism relying on newly formed vacuoles (autophagosomes) that engulf supernumerary, old or damaged intracellular organelles and/or portions of the cytoplasm.

Initiator caspases

Members of the caspase family (for example, caspase 2, 8, 9 and 10) that cleave and hence activate executioner caspases, thereby initiating the apoptotic cascade.

Executioner caspases

Members of the caspase family that execute apoptosis (for example, caspase 3, 6 and 7), by cleaving a number of substrates implicated in this morphological manifestation of cell death.

Apoptosome

A supramolecular complex that includes CYT C, APAF1 and dATP, and is required for the autocatalytic activation of procaspase-9.

Heat-shock proteins

(HSPs). A family of evolutionarily conserved proteins, the expression of which is increased in response to various types of stress. They support the proper folding of native polypeptides and prevent the aggregation of denatured proteins.

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Galluzzi, L., Blomgren, K. & Kroemer, G. Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 10, 481–494 (2009). https://doi.org/10.1038/nrn2665

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