Calcium mitochondrial influx

Fas ligand and interleukin-ip), the neurotransmitter glutamate and thrombin. Like tumor necrosis factor (TNF) receptors, Fas is coupled to downstream death effector proteins that ultimately induce caspase activation (Ch. 22). Fas and TNF receptors recruit proteins called FADD and TRADD respectively FADD and TRADD then activate caspase-8, which, in turn, activates caspase-3 (Fig. 35-4). Calcium ion influx mediates neuronal apoptosis induced by glutamate receptor activation calcium induces mitochondrial membrane permeability transition pore opening, release of cytochrome c and caspase activation. Interestingly, in the absence of neurotrophic factors some neurotrophic factor receptors can activate apoptotic cascades, the low-affinity NGF receptor being one example of such a death receptor mechanism [23],... 

Akerman, K.E., 1978, Changes in membrane potential during calcium ion influx and efflux across the mitochondrial membrane, Biochim. Biophys. Acta 502, pp. 359-366... 

Inhibition of macromolecrrlar synthesis and of the mitochondrial energy metabolism, reduction of DNA synthesis, and direct interaction with the cell membrane have aU been imphcated in the organotin-induced cytotoxicity. Interaction of the tributyltin compormds with the cell membrane was reported to cause the ion charmels to open. This is followed by an influx of extracelMar Ca ion giving an increased cytosohc calcium concentration. This extraceUrrlar calcium ion influx has been indicated in tributyltin-induced apotosis in mouse thymocytes. ... 

NO may react with superoxide to yield the highly reactive peroxynitrite, ONOO-. Superoxide may also be converted into H202 and the reactive hydroxyl radical, OH. In this way excessive activation of glutamate receptors leads to oxidative damage. The calcium influx has a major effect on mitochondria and causes them to depolarize and swell. This leads to a pore being formed in the outer mitochondrial membrane, which allows the escape of cytochrome c and procaspases from the mitochondria into the cytosol. Cytochrome c activates the caspase cascade, which leads to apoptotic cell death (Ch. 35). 

Calcium levels are believed to be controlled in part at least by the uptake and release of Ca2+ from mitochondria.172"174 The capacity of mitochondria for Ca2+ seems to be more than sufficient to allow the buffering of Ca2+ at low cytosol levels. Mitochondria take up Ca2+ by an energy-dependent process either by respiration or ATP hydrolysis. It is now agreed that Ca2+ enters in response to the negative-inside membrane potential developed across the inner membrane of the mitochondrion during respiration. The uptake of Ca2+ is compensated for by extrusion of two H+ from the matrix, and is mediated by a transport protein. Previous suggestions for a Ca2+-phosphate symport are now discounted. The possible alkalization of the mitochondrial matrix is normally prevented by the influx of H+ coupled to the influx of phosphate on the H - PCV symporter (Figure 10). This explains why uptake of Ca2+ is stimulated by phosphate. Other cations can also be taken up by the same mechanism. 

Rigoni M, Caccin P, Gschmeissner S, Koster G, Postle AD et al. (2005) Equivalent effects of snake pla2 neurotoxins and lysophospholipid-fatty acid mixtures. Science 310 1678-80 Rigoni M, Pizzo P, Schiavo G, Weston AE, Zatti G et al. (2007) Calcium influx and mitochondrial alterations at synapses exposed to snake neurotoxins or their phospholipid hydrolysis products. JBiolChem 282 11238-45... 

The inner mitochondrial membrane may function primarily as a calcium sink, taking up excess calcium in the cytosol that results from hormonal activation of the cell. At cytosolic Ca + concentrations greater than 0.6 /rmol/L, the mitochondrial calcium pump is activated and stores calcium in the mitochondrial matrix as a nonionic, rapidly exchangeable, phosphate salt. At low cytosolic calcium concentrations, the inner mitochondrial membrane allows Ca + to leak into the cytosol. The capacity of the active influx pathway (the pump) is much greater than that of the passive efflux route (the leak). The mitochondrial pump-leak system may serve to fine-tune the cytosolic calcium concentration while the plasma membrane is the principal safeguard against entry of toxic amounts of calcium into the cell. 

The information discussed earlier suggests a working hypothesis. That is, distinct populations of vesicles and/or release sites respond to an intracellular pool of calcium, which is under mitochondrial control. Thus, the frequency of spontaneous transmitter release responds to the metabolic state of the nerve terminal. Discharge of spontaneously released vesicles activates postsynaptic Ach receptors, which mediate a highly localized calcium influx (Villarroel and Sakmann, 1996). Because calcium-activated NOS colocalizes with the muscle endplate Ach receptor (Luck et al., 2000 Blottner and Luck, 2001), each spontaneously... 

The mechanism of cell loss involves excitotoxicity provoked by intense neuronal firing (Grisar, 1986). There is excessive excitatory neurotransmitter release by activation of N-methyl-D-aspartate (NMDA) receptors and voltage-activated calcium channels which enables intracellular calcium influx in the neurons and glia. This calcium influx leads to a cascade of biochemical processes that ultimately lead to cell death mitochondrial dysfunction with uncoupling of oxidative phosphorylation, generation of reactive oxygen species, and activation of many proteolytic and catabolic enzymes that adversely affect cell function. 

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