Mitochondrial regulation of apoptotic cell death

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Abstract

Although it has long been known that impairment of mitochondrial function may lead to ATP depletion and necrotic cell death, recent work has revealed that these organelles also play an important role in the regulation of apoptotic cell death by mechanisms which have been conserved through evolution. Thus, it seems that a number of toxicants target the mitochondria and promote their release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and other parts of the apoptotic process. Cytochrome c release is governed by the Bcl-2 family of proteins, whereas subsequent caspase activation is modulated by other proteins, including inhibitor of apoptosis proteins (IAPs) and heat shock proteins. Recent findings indicate that cytochrome c extrusion occurs by a two-step process, which is initiated by a disruption of the association of the hemoprotein with cardiolipin, the phospholipid that anchors it to the outer surface of the inner mitochondrial membrane. Release of the solubilized pool of cytochrome c into the cytosol may then occur by permeabilization of the outer mitochondrial membrane mediated by pro-apoptotic Bcl-2 family proteins, notably Bax and Bak, or by Ca2+-triggered mitochondrial permeability transition. Taken together, these findings have placed the mitochondria in the focus of apoptosis research and further underlined the important function of these organelles in cell life and death.

Introduction

Apoptosis and necrosis are two modes of cell death with distinct morphological and biochemical features. Apoptosis is an active process characterized by cell shrinkage, nuclear and cytoplasmic condensation, chromatin fragmentation and phagocytosis. In contrast, necrosis is a passive form of cell death associated with inflammation, resulting from cellular and organelle swelling, rupture of the plasma membrane and spilling of cellular contents into the extracellular milieu. Lethal levels of different toxicants may trigger either apoptotic or necrotic cell death, depending on the cell type and severity of insult. Further, effectuation of the apoptotic death program requires maintenance of a sufficient intracellular energy level and of a redox state compatible with caspase activation. Thus, ATP depletion or severe oxidative stress may re-direct otherwise apoptotic cell death to necrosis.

Section snippets

Mitochondrial participation

Extensive evidence indicates that during apoptosis the outer mitochondrial membrane (OMM) becomes permeable to intermembrane space proteins, including cytochrome c (Green and Reed, 1998) (Fig. 1). Once released, cytochrome c promotes the activation of pro-caspase-9 directly within the apoptosome complex (Li et al., 1997). Permeabilization of the OMM is modulated by members of the Bcl-2 family of proteins. Anti-apoptotic members, such as Bcl-2 and Bcl-XL, inhibit protein release, whereas

Caspases

Since the discovery of interleukin-1β-converting enzyme (ICE or caspase-1), about a dozen additional caspases have been identified (Robertson and Orrenius, 2000). All caspases are present constitutively in precursor forms (30–50 kDa) that must be proteolytically cleaved in order to be activated. Each pro-caspase consists of a pro-domain, a large (∼20 kDa) and a small (∼10 kDa) subunit. Cleavage and subsequent hetero-dimerization of the larger and smaller subunits result in caspase activation, and

Environmental toxicants and cell death

In recent years this laboratory and others have focused on the ability of a variety of environmental toxicants to influence apoptosis. While toxicologists have traditionally associated cell death with necrosis, it is becoming increasingly evident that different noxious stimuli can trigger apoptotic cell death. This can be seen in the case of tributyltin (TBT), an organotin compound, and pyrrolidine dithiocarbamate (PDTC). In the case of TBT toxicity, the key determinant controlling the mode of

Concluding remarks

Various paradigms integrating cytotoxic chemicals and cell death are evolving as pathways become better characterized. Depending upon the severity of the insult, toxicants can stimulate either apoptotic or necrotic cell death. A central theme among different forms of apoptosis induced by chemicals is the involvement of mitochondria. Specifically, it seems that the release of cytochrome c, if not a universal event, occurs in many toxicant-mediated apoptotic models. Once released, cytochrome c is

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