ReviewPharmacological inhibition of mitochondrial membrane permeabilization for neuroprotection
Introduction
Many neurons die from necrosis and apoptosis through various mechanisms such as ischemia, mechanical stress, or degeneration. Therapeutic targeting of apoptosis (rather than necrosis) appears feasible because apoptosis is a delayed event and an energy-dependent, regulated process. Mitochondria are considered to be the central regulators of apoptotic cell death. In various paradigms of cell death, mitochondrial membrane permeabilization (MMP) delimits the frontier between life and death (Fig. 1). Mitochondria control the intrinsic pathway of apoptosis, in which MMP ignites the activation of caspases and other catabolic enzymes, and mitochondria participate in the extrinsic pathway of apoptosis, in which they amplify the self-destructive process (Green and Reed, 1998, Hengartner, 2000, Kroemer et al., 1997). Irrespective of its initiation at the inner or outer mitochondrial membrane, MMP culminates in the functional and structural collapse of mitochondria. The functional loss of mitochondria is accompanied by the dissipation of the mitochondrial membrane potential, shutdown of ATP synthesis, and a redox imbalance. The structural disruption of mitochondria leads to the reorganization of cristae and to the release of toxic intermembrane space proteins into the cytosol. MMP has a profound impact on cellular metabolism, activates caspase-dependent and -independent executioner mechanisms, and finally results in the demise of the cell (Ferri and Kroemer, 2001, Galluzzi et al., 2008). The lethal consequences of MMP relate to the critical position occupied by mitochondria in cellular bioenergetics and the release of proapoptotic proteins into the cytosol and the nucleus. Proapoptotic proteins liberated as a consequence of MMP include activators of the caspase cascade (e.g. cytochrome c), as well as caspase-independent death effectors (e.g. apoptosis-inducing factor (AIF) and endonuclease G) (Garrido et al., 2006, Li et al., 2001). Indeed, mitochondrial membrane permeabilization (MMP) is the main checkpoint of programmed cell death, and lethal pathways of signal transduction are often activated in neurodegenerative diseases. Hence, pharmacological agents that target mitochondria to subvert MMP are being evaluated as therapeutic approaches for the avoidance or treatment or neurodegenerative disorders. Here, we summarize the checkpoints of mitochondrion-dependent apoptosis and review current concepts on pharmacological targeting of mitochondria for neuroprotection.
Section snippets
Mitochondrial outer membrane permeabilization
MMP may affect the outer membrane through at least two distinct mechanisms. First, the activation of proapoptotic proteins of the Bcl-2 family (e.g., Bax, Bak) can lead to the generation of multimeric channels, allowing for the release of intermembrane space proteins (Zamzami and Kroemer, 2001), or alternatively to the formation of lipidic pores due to the interaction between proapoptotic Bcl-2 family members (e.g., Bax, truncated Bid) and lipids contained in mitochondrial membranes (Galluzzi
Mitochondrial inner membrane permeabilization
Mitochondrial membrane permeabilization may also start at the inner membrane. In contrast to the outer membrane, the inner membrane from healthy cells is nearly impermeable to small solutes and ions. When inner membrane impermeability is lost, for instance following the opening of the so-called permeability transition pore complex (PTPC), solutes enter the mitochondrial matrix, accompanied by a net influx of water. This process is known as mitochondrial permeability transition and can be
Importance of caspase-dependent pathways on neurodegenerative disease
Cystein aspartate-specific proteases or caspases are the central molecules involved in initiation and execution of apoptosis (Riedl and Shi, 2004). Caspases are processed through proteolytic cleavage at the sites containing aspartate residue. Mitochondria contain the entire cellular pool of cytochrome c, as well as a fraction of caspase-9, in the intermembrane space and both cytochrome c and caspase-9 are liberated into the cytoplasm after apoptotic insults. Cytochrome c triggers the formation
Importance of AIF in caspase-independent pathways on neurodegenerative disease
AIF is a 67 kDa protein flavoprotein that is highly conserved among mammalian species (> 95% amino acid identity between mouse and human) and bears a highly significant homology with flavoprotein oxidoreductases from all eukaryotic and prokaryotic kingdoms in its C-terminal portion (Lorenzo et al., 1999, Susin et al., 1999). AIF is normally confined to the mitochondrial intermembrane space. However, AIF translocates to the cytosol and to the nucleus after apoptotic insults (Susin et al., 1999,
Pharmacological targeting of mitochondria for preventing release of proapoptotic molecules via MMP inhibition
Mitochondrial outer membrane permeabilization (MOMP) is a critical event during apoptosis, representing the “point of no return” of the lethal process. Cytochrome c is released from mitochondria upon MOMP and binds to cytosolic apoptotic protease activating factor-1 (Apaf-1) to induce its dimerization and a conformational change (Bao et al., 2005). Apaf-1 then oligomerizes into apoptosomes that recruit and activate caspase-9 followed by serial activation of caspase-3 and other
Conclusions
MMP is a pivotal event in the pathogenesis of acute and chronic neurodegenerative disorders. Thus, various neurodegenerative disorders that involve apoptosis could be amenable to drug- and gene-based therapies that target MMP. Multiple redundant cell death pathways with overlapping and cross-talking molecular mechanisms can come into action, suggesting that neuroprotective agents should optimally be directed at multiple and/or comprehensive targets. In our studies, neither the Hq/Y genotype (a
Acknowledgments
GK is supported by the Ligue Nationale contre le Cancer (Equipe labellisée), European Commission (Active p53, Apo-Sys, RIGHT, TransDeath, ChemoRes, DeathTrain), Cancéropôle Ile-de-France, Fondation de France, and Fondation pour la Recherche Médicale.
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