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...