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Sten Orrenius

Publications and source records attributed to Sten Orrenius.

At least 19 recordsLinked to original sources
PubMed2007

Mitochondrial oxidative stress: implications for cell death.

In addition to the established role of the mitochondria in energy metabolism, regulation of cell death has emerged as a second major function of these organelles. This seems to be intimately linked to their generation of reactive oxygen species (ROS), which have been implicated in mtDNA mutations, aging, and cell death. Mitochondrial regulation of apoptosis occurs by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins into the cytoplasm. Cytochrome c release is initiated by the dissociation of the hemoprotein from its binding to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and increases the level of soluble cytochrome c in the intermembrane space. Subsequent release of the hemoprotein occurs by pore formation mediated by pro-apoptotic Bcl-2 family proteins, or by Ca(2+) and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.

Apoptosis↗
PubMed2006

Mitochondrial regulation of apoptotic cell death.

Mitochondria play a decisive role in the regulation of both apoptotic and necrotic cell death. Permeabilization of the outer mitochondrial membrane and subsequent release of intermembrane space proteins are important features of both models of cell death. The mechanisms by which these proteins are released depend presumably on cell type and the nature of stimuli. Of the mechanisms involved, mitochondrial permeability transition appears to be associated mainly with necrosis, whereas the release of caspase activating proteins during early apoptosis is regulated primarily by the Bcl-2 family of proteins. However, there is increasing evidence for interaction and co-operation between these two mechanisms. The multiple mechanisms of mitochondrial permeabilization may explain diversities in the response of mitochondria to numerous apoptotic stimuli in different types of cells.

Animals↗
PubMed2006

Multiple pathways of cytochrome c release from mitochondria in apoptosis.

Release of cytochrome c from mitochondria is a key initiative step in the apoptotic process, although the mechanisms regulating permeabilization of the outer mitochondrial membrane and the release of intermembrane space proteins remain controversial. Here, we discuss possible scenarios of the outer membrane permeabilization. The mechanisms by which the intermembrane space proteins are released from mitochondria depend presumably on cell type and on the nature of the apoptotic stimulus. The variety of mechanisms that can lead to outer membrane permeabilization might explain diversities in the response of mitochondria to numerous apoptotic stimuli in different types of cells.

Animals↗
PubMed2006

Carcinogenesis and apoptosis: paradigms and paradoxes.

Apoptosis is a physiological process of cell elimination, which is important for both maintenance of cellular homeostasis, and cell proliferation and differentiation. Disturbances in the cell death process might lead to uncontrolled cell growth and to tumor formation. In addition, proper function of the apoptotic machinery is critical for tumor susceptibility to treatment. Many pro-apoptotic and anti-apoptotic genes have been cloned and their significance for the proper function of the apoptotic pathways carefully investigated. However, the precise role of these genes and their products in cancer development is less clear. Here, we will discuss some of the current paradigms and paradoxes concerning the involvement of apoptotic genes in carcinogenesis.

Animals↗
PubMed2005

Arsenic stimulates release of cytochrome c from isolated mitochondria via induction of mitochondrial permeability transition.

Arsenic trioxide, As(III), is a known environmental toxicant, co-carcinogen, and potent chemotherapeutic agent. In model experiments with isolated rat liver mitochondria, As(III) stimulated a dose-dependent, cyclosporin A-sensitive release of cytochrome c via induction of mitochondrial permeability transition and subsequent swelling of mitochondria. Mitochondrial GSH does not seem to be a target for As(III) which, however, appears to cause oxidative modification of thiol groups of pore forming proteins, notably adenine nucleotide translocase. In mouse embryonic fibroblasts, 10 microM As(III) stimulated cytochrome c release and apoptosis via a Bax/Bak-dependent mechanism. At high concentrations (125 microM and higher), cells died by Bax/Bak-independent necrosis; at this concentration range As(III) targets mitochondria directly, particularly complex I of the mitochondrial respiratory chain. Since pyruvate, a substrate of complex I, is a predominant mitochondrial substrate in the cell, inhibition of complex I will cause mitochondrial instability and a decrease of Delta psi that facilitates permeability transition and necrotic cell death.

Animals↗
PubMed2005

Caspase-2 function in response to DNA damage.

Caspase-2 is one of the best conserved caspases across species. This enzyme is unique among caspases in that it has features of both initiator and effector caspases. Caspase-2 appears to be necessary for the onset of apoptosis triggered by several insults, including DNA damage, administration of TNF, and different pathogens and viruses. In several experimental systems, a link has been shown between the p53 family proteins and caspase-2 activation leading to cell death. In this review, current knowledge concerning the structure of this protease and its function in cell physiology and cell death, particularly cell death triggered by DNA damage, is summarized and discussed.

Animals↗
PubMed2005

Indirect effects of Bax and Bak initiate the mitochondrial alterations that lead to cytochrome c release during arsenic trioxide-induced apoptosis.

Arsenic trioxide is a potent chemotherapeutic agent by virtue of its ability to selectively trigger apoptosis in tumor cells. Previous studies have demonstrated that arsenicals cause direct damage to mitochondria, but it is not clear that these effects initiate apoptosis. Here we used Bak-/- mouse liver mitochondria and virally immortalized Bax-/- Bak-/- mouse embryonic fibroblasts (MEFs) to investigate whether or not multidomain proapoptotic BCL-2 family proteins were required for arsenic-induced mitochondrial damage and cell death. At clinically achievable concentrations, arsenic stimulated cytochrome c release and apoptosis via a Bax/Bak-dependent mechanism. At higher concentrations (125 microM-1 mM), cells died via a Bax/Bak-independent mechanism mediated by oxidative stress that resulted in necrosis. Consistent with previous reports, arsenic directly inhibited complex I of the mitochondrial electron transport chain, which resulted in mitochondrial permeability transition (MPT), accompanying generation of reactive oxygen species (ROS), and thiol oxidation. However, these effects only occurred at concentrations of arsenic trioxide of 50 microM and higher, and the oxidative stress associated with these effects blocked caspase activation. Our data demonstrate for the first time that the cytochrome c release which initiates apoptosis in cells exposed to this classic mitochondrial poison occurs indirectly via the activation of Bax/Bak rather than via direct mitochondrial damage. Furthermore, the results implicate reactive oxygen species in a concentration-dependent mechanistic switch between apoptosis and necrosis.

Animals↗
PubMed2005

Overexpression of glutaredoxin 2 attenuates apoptosis by preventing cytochrome c release.

Human mitochondrial glutaredoxin 2 (Grx2) catalyzes glutathione-dependent dithiol reaction mechanisms, reducing protein disulfides, and monothiol reactions, reducing mixed disulfides between proteins and GSH (de-/glutathionylation). Here, we have overexpressed Grx2 in HeLa cells in its mitochondrial form (mGrx2-HeLa) as well as a truncated cytosolic form, lacking the mitochondrial translocation signal (tGrx2-HeLa). The resulting clones were less susceptible to apoptosis induced by 2-deoxy-d-glucose (2-DG) or doxorubicin (Dox). Overexpression of Grx2 inhibited cytochrome c release and caspase activation induced by both agents. In addition, Grx2 prevented 2-DG- and Dox-induced loss of cardiolipin, the phospholipid anchoring cytochrome c to the inner mitochondrial membrane. Overexpression of mGrx2 provided better protection than tGrx2 overexpression, especially after treatment with 2-DG. We propose that Grx2 facilitates the maintenance of cellular redox homeostasis upon treatment with apoptotic agents, thereby preventing cardiolipin oxidation and cytochrome c release.

Apoptosis↗
PubMed2005

Plasma membrane sequestration of apoptotic protease-activating factor-1 in human B-lymphoma cells: a novel mechanism of chemoresistance.

Burkitt lymphoma (BL) is a highly aggressive B-cell neoplasm harboring chromosomal rearrangements of the c-myc oncogene. BL cells frequently resist apoptosis induction by chemotherapeutic agents; however, the mechanism of unresponsiveness has not been elucidated. Here, we show that cytochrome c fails to stimulate apoptosome formation and caspase activation in cytosolic extracts of human BL-derived cell lines, due to insufficient levels of apoptotic protease-activating factor-1 (Apaf-1). Enforced expression of Apaf-1 increased its concentration in the cytosolic compartment, restored cytochrome c-dependent caspase activation, and rendered the prototypic Raji BL cell line sensitive to etoposide- and staurosporine-induced apoptosis. Surprisingly, in nontransfected BL cells, the bulk of Apaf-1 was found to associate with discrete domains in the plasma membrane. Disruption of lipid raft domains or the actin cytoskeleton of Raji cells liberated Apaf-1 and restored sensitivity to cytochrome c-dependent apoptosis, indicating that constitutive Apaf-1 retained its ability to promote caspase activation. Moreover, disruption of lipid rafts sensitized BL cells to apoptosis induced by etoposide. Together, our findings suggest that ectopic (noncytosolic) localization of Apaf-1 may constitute a novel mechanism of chemoresistance in B lymphoma.

Apoptosis↗
PubMed2005

Role of mitochondria in toxic oxidative stress.

Oxidative stress and mitochondrial oxidative damage have been implicated in the etiology of numerous common diseases. The critical mitochondrial events responsible for oxidative stress-mediated cell death (toxic oxidative stress), however, have yet to be defined. Several oxidative events implicated in toxic oxidative stress include alterations in mitochondrial lipids (e.g., cardiolipin), mitochondrial DNA, and mitochondrial proteins (eg. aconitase and uncoupling protein 2). Furthermore, recent findings indicate the enrichment of mitochondrial membranes with vitamin E protects cells against the toxic effects of oxidative stress. This review briefly summarizes the role of these mitochondrial events in toxic oxidative stress, including: 1) the protective role of mitochondrial vitamin E in toxic oxidative stress, 2) the role of mitochondrial DNA in toxic oxidative stress, 3) the interaction between cardiolipin and cytochrome c in mitochondrial regulation of apoptosis, 4) the role of mitochondrial aconitase in oxidative neurodegeneration, and 5) the role of mitochondrial uncoupling protein 2 in the pathogenesis of type 2 diabetes.

Aconitate Hydratase↗
PubMed2004

Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids.

Caspases are cysteine proteases that play a central role in the execution of apoptosis. Recent evidence indicates that caspase-2 is activated early in response to genotoxic stress and can function as an upstream modulator of the mitochondrial apoptotic pathway. In particular, we have shown previously that fully processed caspase-2 can permeabilize the outer mitochondrial membrane and cause cytochrome c and Smac/DIABLO release from these organelles. Using permeabilized cells, isolated mitochondria, and protein-free liposomes, we now report that this effect is direct and depends neither on the presence or cleavage of other proteins nor on a specific phospholipid composition of the liposomal membrane. Interestingly, caspase-2 was also shown to disrupt the interaction of cytochrome c with anionic phospholipids, notably cardiolipin, and thereby enhance the release of the hemoprotein caused by treatment of mitochondria with digitonin or the proapoptotic protein Bax. Combined, our data suggest that caspase-2 possesses an unparalleled ability to engage the mitochondrial apoptotic pathway by permeabilizing the outer mitochondrial membrane and/or by breaching the association of cytochrome c with the inner mitochondrial membrane.

Caspase 2↗
PubMed2004

Processed caspase-2 can induce mitochondria-mediated apoptosis independently of its enzymatic activity.

The mechanism by which caspase-2 executes apoptosis remains obscure. Recent findings indicate that caspase-2 is activated early in response to DNA-damaging antineoplastic agents and may be important for the engagement of the mitochondrial apoptotic pathway. We demonstrate here that fully processed caspase-2 stimulates mitochondrial release of cytochrome c and Smac/DIABLO, but not apoptosis-inducing factor (AIF). This event occurs independently of several Bcl-2 family proteins, including Bax, Bak and Bcl-2, and inactivation experiments reveal that the proteolytic activity of caspase-2 is not required for the effect. Further, functional studies of mitochondria indicate that processed caspase-2 stimulates state 4 respiration and decreases the respiratory control ratio as a result of, in large part, an uncoupling effect. Combined, our data suggest that caspase-2 retains a unique ability to engage directly the mitochondrial apoptotic pathway, an effect that requires processing of the zymogen but not the associated catalytic activity.

Apoptosis↗
PubMed2004

Mitochondrial regulation of apoptotic cell death.

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.

Adenosine Triphosphate↗