page_title: Intermembrane space
section_title: Oxidative phosphorylation
hierarchical_section_title: Intermembrane space / Intermembrane space of mitochondria / Oxidative phosphorylation
caption_attribution_description: English: Reactions of peroxynitrite leading to either apoptotic or necrotic cell death. NO and RNS may potentially prevent hepatocyte apoptosis as well as promote either necrotic or apoptotic cell death. The following mechanisms have been proposed. With regard to NO, RNS and prevention of apoptosis, the main molecular mechanisms resulting in an anti-apoptotic effect, related to S-nitrosating species, include [237-239]: stimulation of guanylate cyclase, leading to increased cyclic guanine monophosphate levels; the evolutionarily conserved inhibition of caspases by potentially reversible S-nitrosation of a critical cysteine residue at the caspase active site; activation of the Ras/Erk1/2 pro-survival pathway, which may result in activation of mitogen and stress activated kinase 1 (MSK1) and pp90 ribosomal S6 kinase (RSK), which in turn may inactivate the pro-apoptotic protein Bad or up-regulate anti-apoptotic proteins of the Bcl-2 family [237]; RNS also possibly acting by inhibiting leukocyte adhesion through S-nitrosation of critical -SH groups exposed by activated neutrophils and macrophages [240]. NO and RNS may prevent or promote cell death in relation to intracellular and intramitochondrial (because of mitochondrial NOS) levels of GSH and the concomitant cellular levels of transition metal ions. Moreover, NO may also lead to up-regulation of heme oxygenase 1 (HO-1) in hepatocytes and this may serve as a cytoprotective event [237,238]. The dark (that is, damaging) side of NO and RNS: in the presence of higher levels of ROS, the right NO/superoxide ratio or levels of molecular oxygen, NO may lead again to generation of highly reactive RNS, such as N2O3 or ONOO- at levels that are able to induce more aggressive oxidation, nitrosation/S-nitrosation and nitration of different biological macromolecules, potentially leading either to necrotic or apoptotic cell death. If NO-dependent pro-apoptotic mechanisms are concerned, the following have been shown to have a major role, with some again depending on S-nitrosating species: RNS and so called NO+ -carriers (nitrosating species) may result in activation of JNK, which, as previously reported for ROS, may sustain induction of apoptosis; NO, if generated at high levels in mitochondria, may result in ubiquinol auto-oxidation with concomitant production of superoxide, hydrogen peroxide and ONOO-, species that may be responsible for irreversible damage to complexes I and II of the respiratory chain, inhibition of ATP synthesis and eventually cytochrome c release and induction of caspase-dependent apoptosis. It should also be noted that, in the presence of significant redox stress, NO can potentiate damaging effects, resulting in a scenario of necrotic cell death rather than apoptosis. This is likely to occur particularly when the redox state is significantly affected, as in conditions resulting in depletion of GSH or significant alterations of the GSH/GSSG ratio. Novo and Parola Fibrogenesis &amp; Tissue Repair 2008 1:5 doi:10.1186/1755-1536-1-5
context_page_description: The intermembrane space is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the inner membrane and the outer membrane of a mitochondrion or a chloroplast. It also refers to the space between the inner and outer nuclear membranes of the nuclear envelope, but is often called the perinuclear space. The IMS of mitochondria plays a crucial role in coordinating a variety of cellular activities, such as regulation of respiration and metabolic functions. Unlike the IMS of the mitochondria, the IMS of the chloroplast does not seem to have any obvious function.
context_section_description: The pyruvate generated by glycolysis and the fatty acids produced by breakdown of fats enter the mitochondrial IMS through the porins in the outer mitochondrial membrane. Then they are transported across the inner mitochondrial membrane into the matrix and converted into the acetyl CoA to enter the citric acid cycle.
  The respiratory chain in the inner mitochondrial membrane carries out oxidative phosphorylation. Three enzyme complexes are responsible for the electron transport: NADH-ubiquinone oxidoreductase complex (complex I), ubiquinone-cytochrome c oxidoreductase complex (complex III), and cytochrome c oxidase (complex IV). The protons are pumped from the mitochondrial matrix to the IMS by these respiratory complexes. As a result, an electrochemical gradient is generated, which is combined by forces due to a H⁺ gradient (pH gradient) and a voltage gradient (membrane potential). The pH in the IMS is about 0.7 unit lower than the one in the matrix and the membrane potential of the IMS side becomes more positively charged than the matrix side. This electrochemical gradient from the IMS to the matrix is used to drive the synthesis of ATP in the mitochondria.
caption: Apoptotic components released from the intermembrane space of a mitochondrion
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