Apoptotic Cell Death Induced by Inhibitors of Energy Conservation

Abstract

Energy charge controls intermediary metabolism and cellular regulation. Here we show that inhibition of energy conservation at the level of glucose uptake, glycolysis, citric acid cycle, and oxidative phosphorylation induces cell death, leading to fragmentation of DNA into an oligonucleosomal ladder and morphological changes typical for apoptosis. Bcl-2, the prototype of oncogenes that suppress cell death, efficiently inhibits apoptosis induced by metabolic inhibitors. Bcl-2 does not antagonize the inhibitory potential of mitochondrial inhibitors, and cannot prevent or delay the decrease of the cellular ATP level subsequent to metabolic inhibition. Thus, we propose that Bcl-2 blocks apoptosis at a point downstream of the collapse of the cellular-energy homeostasis.Keywords : apoptosis ; ATP; energy conservation ; Bcl-2 ; metabolic regulation.Apoptosis, a common form of cell death, can be induced by mic reticulum (ER) membranes [15]. The mechanism of action of Bcl-2 is largely unknown. It has been shown that Bcl-2 a wide array of physiological and pathological stimuli [1,2]. This form of cell death is characterized by morphological retards diminution of the mitochondrial membrane potential (∆ψ) and reactive oxygen species (ROS) generation in T-cell changes of cellular structures, such as cell shrinkage, chromatin condensation, and membrane blebbing [1]. Molecular-biological hybridomas in response to dexamethasone and ceramide [10], protects against lipid peroxidation in IL-3Ϫdependent lymphoid studies on cell death have identified a number of genetic factors implicated in induction or suppression of apoptosis [2].progenitor cells [16] and regulates intracellular calcium repartitioning [17,18]. The biochemical mechanism of apoptosis remains elusive. The common theme emerging from most of the studies is mitoIn the present study we report that inhibition of energy conservation at the level of glycolysis, citric acid cycle or oxidachondrial dysfunction [3]. It has been shown that alterations in mitochondrial structure and function are early events in tive phosphorylation results in cell death showing oligonucleosomal DNA degradation, chromosomal condensation and apoptosis induced by tumor-necrosis factor [4,5], dexamethasone [6], oxygen radicals [7], nitric oxide [8] and activation of fragmentation, characteristics of apoptosis. Bcl-2 inhibited cell death induced by blockage of energy metabolism. However, exp53 [9]. The first signs of mitochondrial instability, reduced transmembrane potential and generation of reactive oxygen radi-pression of Bcl-2 neither blocks the activity of electron-transport-chain inhibitors, nor does it rescue cellular ATP levels. Apcals, both precede oligonucleosomal DNA fragmentation [10], a characteristic feature of apoptosis. Extensive DNA damage by parently, Bcl-2 orchestrates a protective response to depletion of cellular ATP. oxygen radicals induces activation of poly-(ADP-ribose) polymerase, leading to depletion of its substrate, NAD ϩ , and subsequently the cellular ATP pool [11]. An...

Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells

“…Consistent with recent findings indicating that inhibition of bioenergetic pathways may result in apoptosis (Richter et al, 1996;Marton et al, 1997), depletion of ATP content induced by Ro 40-8757 may be responsible for the proapoptotic effects exerted by the drug also in this cellular system. Since apoptosis is an active process that requires ATP (Richter et al, 1996), the recovery of ATP levels observed after 12 h of treatment probably constitutes a compensatory mechanism that provides the energy supply to successfully carry out the apoptotic process.…”

Characterization of MPP+-Induced Cell Death in a Dopaminergic Neuronal Cell Line: Role of Macromolecule Synthesis, Cytosolic Calcium, Caspase, and Bcl-2-Related Proteins

“…It remains to be determined how the proapoptotic protein, Bcl-2, blocks cell death independently of Bax expression, level of cytosolic calcium, and caspase activation. As we have proposed that the protective effect of Bcl-2 following MPP ϩ treatment is mediated by a reduced rate of glucose uptake (33), one of the potential sites of Bcl-2 action in MPP ϩ -induced cell death could be at a point downstream of the collapse of cellular energy homeostasis as previously suggested (24). Given findings that overexpression of Bcl-2 in MN9D cells or in neocortical neurons of transgenic mice partially blocks MPP ϩ -induced cell death (28), these data suggest that mechanisms independent of Bcl-2 may be involved in MPP ϩ -induced cell death.…”

Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase Suppresses Apoptosis Mediated by a Mitochondrial Death Pathway

“…3), and 2DG induced the depletion of intracellular ATP via an ATP-consuming reaction by which 2DG is actively metabolized to 2-deoxyglucose 6-phosphate (34). Marton et al (35) reported similarly that inhibitors of energy conservation, such as 2DG, rotenone and oligomycin, decrease levels of intracellular ATP in FL5.12 cells and induce apoptosis. By contrast, apoptosis induced by, for example, Fasspecific antibodies, a Ca 2ϩ ionophore, etoposide, dexamethasone and staurosporine, requires ATP (36 -38) and is abolished when levels of ATP are very low.…”