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 Mitochondrial IMS: poison cabinet Mitochondrial pathway of cell death and disease pathogenesis Therapeutic strategies that promote MOMP and cell death Therapeutic strategies that inhibit MOMP and cell death Conclusion and future directions 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.