The mitochondrial death pathway: A promising therapeutic target in diseases

Abstract

Introduction Mitochondria and cell death Mitochondrial outer membrane permeabilization (MOMP): point of no return MOMP by BCL-2 family proteins MOMP by permeability transition pore Regulation of MOMP: many ways to skin the cat Role of calcium in MOMP ROS-induced MOMP Role of caspases in MOMP Other regulators of MOMP Mitochondrial IMS: poison cabinet Mitochondrial pathway of cell death and disease pathogenesis Ischemia/reperfusion Neurodegenerative disorders Cancer Mitochondrial encephalomyopathies Others Therapeutic strategies that promote MOMP and cell death Targeting the BCL-2 family BCL-2 antisense-based strategies BAX-delivery vector BH3 mimetic peptides Natural and synthetic BH3 mimetic drugs Targeting mitochondria directly: mitochondriotoxic compounds inducing mitochondrial membrane permeabilization Peptide derivatives Small molecules Cationic lipophilic agents Bypassing the mitochondria: mitochondrial pro-apoptotic factors as chemotherapeutic agents Therapeutic strategies that inhibit MOMP and cell death Cyclosporin A and the inhibition of MPT Novel CsA analogues and other inhibitors of the pore Preconditioning of the heart protects by sparing mitochondria Pharmacological IPC mimetics Minocycline Inhibitors of PARP and the prevention of DNA damage-mediated mitochondrial damage Conclusion and future directions Abstract The mitochondrial pathway to apoptosis is a major pathway of physiological cell death in vertebrates. The mitochondrial cell death pathway commences when apoptogenic molecules present between the outer and inner mitochondrial membranes are released into the cytosol by mitochondrial outer membrane permeabilization (MOMP). BCL-2 family members are the sentinels of MOMP in the mitochondrial apoptotic pathway; the pro-apoptotic B cell lymphoma (BCL)-2 proteins, BCL-2 associated x protein and BCL-2 antagonist killer 1 induce MOMP whereas the anti-apoptotic BCL-2 proteins, BCL-2, BCL-xl and myeloid cell leukaemia 1 prevent MOMP from occurring. The release of pro-apoptotic factors such as cytochrome c from mitochondria leads to formation of a multimeric complex known as the apoptosome and initiates caspase activation cascades. These pathways are important for normal cellular homeostasis and play key roles in the pathogenesis of many diseases. In this review, we will provide a brief overview of the mitochondrial death pathway and focus on a selection of diseases whose pathogenesis involves the mitochondrial death pathway and we will examine the various pharmacological approaches that target this pathway. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.