Mitochondrial Regulation of Cell Death

Although required for life, paradoxically, mitochondria are often essential for initiating apoptotic cell death. Mitochondria regulate caspase activation and cell death through an event termed mitochondrial outer membrane permeabilization (MOMP); this leads to the release of various mitochondrial intermembrane space proteins that activate caspases, resulting in apoptosis. MOMP is often considered a point of no return because it typically leads to cell death, even in the absence of caspase activity. Because of this pivotal role in deciding cell fate, deregulation of MOMP impacts on many diseases and represents a fruitful site for therapeutic intervention. Here we discuss the mechanisms underlying mitochondrial permeabilization and how this key event leads to cell death through caspase-dependent and -independent means. We then proceed to explore how the release of mitochondrial proteins may be regulated following MOMP. Finally, we discuss mechanisms that enable cells sometimes to survive MOMP, allowing them, in essence, to return from the point of no return.In most organisms, mitochondria play an essential role in activating caspase proteases through a pathway termed the mitochondrial or intrinsic pathway of apoptosis. Mitochondria regulate caspase activation by a process called mitochondrial outer membrane permeabilization (MOMP). Selective permeabilization of the mitochondrial outer membrane releases intermembrane space (IMS) proteins that drive robust caspase activity leading to rapid cell death. However, even in the absence of caspase activity, MOMP typically commits a cell to death and is therefore considered a point of no return (Fig. 1). Because of this pivotal role in dictating cell fate, MOMP is highly regulated, mainly through interactions between pro- and antiapoptotic members of the Bcl-2 family. In this article, we begin by discussing how mitochondria may have evolved to become central players in apoptotic cell death. We then provide an overview of current models addressing the mechanics of MOMP, outlining how this crucial event leads to cell death through both caspase-dependent or -independent mechanisms. Finally, we discuss how caspase activity may be regulated post-MOMP and define other processes that allow cells to survive MOMP and, in effect, return from the point of no return.Open in a separate windowFigure 1.Mitochondrial regulation of cell death. Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP) can lead to caspase-dependent apoptosis (left) or caspase-independent cell death (right). Following MOMP, soluble proteins are released from the mitochondrial intermembrane space into the cytoplasm. Cytochrome c binds to monomeric Apaf-1 leading to its conformational change and oligomerization. Procaspase-9 is recruited to heptameric Apaf-1 complexes forming the apoptosome. This leads to activation of caspase-9 and, through caspase-9-mediated cleavage, activation of the executioner caspases-3 and -7. Release of Smac and Omi from the mitochondrial intermembrane space facilitates caspase activation by neutralizing the caspase inhibitor XIAP. MOMP can also lead to nonapoptotic cell death through a gradual loss of mitochondrial function and/or release of mitochondrial proteins that kill the cell in a caspase-independent manner.