Cytochrome c, release in apoptosis

Bossy-Wetzel E, Newmeyer D, Green D. Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 1997 17 37-49. 

Rodrigues CM, Ma X, Linehan-Stieers C, Fan G, Kren BT, Steer CJ (1999) Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation. Cell Death Differ 6, 842-54. 

As described earlier, superoxide is a well-proven participant in apoptosis, and its role is tightly connected with the release of cytochrome c. It has been proposed that a switch from the normal four-electron reduction of dioxygen through mitochondrial respiratory chain to the one-electron reduction of dioxygen to superoxide can be an initial event in apoptosis development. This proposal was supported by experimental data. Thus, Petrosillo et al. [104] have shown that mitochondrial-produced oxygen radicals induced the dissociation of cytochrome c from bovine heart submitochondrial particles supposedly via cardiolipin peroxidation. Similarly, it has been found [105] that superoxide elicited rapid cytochrome c release in permeabilized HepG2 cells. In contrast, it was also suggested [106] that it is the release of cytochrome c that inhibits mitochondrial respiration and stimulates superoxide production. 

Roberg, K., 2001, Relocalization ofcathepsin D and cytochrome c early in apoptosis revealed by immunoelectron microscopy. Lab. Invest. 81 149-158 Roberg, K., Johansson, U., and OUinger, K., 1999, Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress. Free Radio. Biol. Med. 27 1228-1237 Roberg, K. and OUinger, K., 1998, Oxidative stress causes relocation of the lysosomal... 

A systems biology assessment of bystander sunitinib targets points to AMPK and RSK inhibition as culprit for cardiotoxicity [12], Thus, RSK inhibition releases the pro-apoptotic factor BAD with activation of BAX and cytochrome c release, in turn promoting apoptosis and ATP depletion. The inhibition of AMPK... 

D.B. Ostrander, G.C. Sparagna, A.A. Amoscato, J.B. McMillan, and W. Dow-han. Decreased cardiolipin synthesis corresponds with cytochrome c release in palmitate-induced cardiomyocyte apoptosis, J. Biol. Chem., 2001, 276, 38061-38067. 

Shou Y, Li L, Prabhakaran K et al. (2003). p45 Mitogen-activated protein kinase contributes to Bax translocation and cytochrome c release in cyanide-induced apoptosis. Toxicol Sci, 75, 99-107. 

Arnoult D, Parone P, Martinou JC t al. Mitochondrial release of apoptosis-indudng factor occurs downstream of cytochrome c release in response to several proapoptotic stimuU. J Cell Biol 2002 159(6) 923-9. 

Lan, C. H., J. Q. Sheng, D. C. Fang et al. Involvement of VDACl and Bcl-2 family of proteins in VacA-induced cytochrome c release and apoptosis of gastric epithelial carcinoma cells../ Die Pic 11(1), 2010 43-9. 

Kim JY, Kim KM, Nan JX, Zhao YZ (2003) Induction of apoptosis by tanshinone I via cytochrome c release in activated hepatic stellate cells. Pharmacol Toxicol 92 195... 

CcR/CNT/PPy/Pt CcR/SAM-GNP/ PPy/Pt Cytochrome c CV 1-1000 nM 5-600nM Quantification of the mitochondrial cytochrome c released in cytosol of human lung carcinoma cells A549 upon induction of apoptosis with doxorubicin Pandiaraj et al. (2013)... 

Bcl-2 is a key apoptosis regnlatory protein of the mitochondrial death pathway whose function is dependent on its expression levels. NO prevented Bcl-2 cleavage and suppressed cytochrome c release in TNF-a and actinomycin D-treated adenocarcinoma (MCF-7) cells exposed to SNAP (Kim et al. 1998). This level is regulated by a ubiqutination-proteasome degradation system. There was inhibition of NO production by the NO scavenger. The NO donors DPTA/NONO and sodium nitro-prusside effectively upregulated Bcl-2 S-nitrosylation, decreased its ubiquitination, and inhibited apoptotic cell death induced by chromium. The effect of NO on Bcl-2 stability was shown to be independent of its dephosphorylation (Azad et al. 2006). 

It has been shown in many studies that protective effects of carotenoids can be observed only at small carotenoid concentrations, whereas at high concentrations carotenoids exert pro-oxidant effects via propagation of free radical damage (Chucair et al., 2007 Lowe et al., 1999 Palozza, 1998, 2001 Young and Lowe, 2001). For example, supplementation of rat retinal photoreceptors with small concentrations of lutein and zeaxanthin reduces apoptosis in photoreceptors, preserves mitochondrial potential, and prevents cytochrome c release from mitochondria subjected to oxidative stress induced by paraquat or hydrogen peroxide (Chucair et al., 2007). However, this protective effect has been observed only at low concentrations of xanthophylls, of 0.14 and 0.17 pM for lutein and zeaxanthin, respectively. Higher concentrations of carotenoids have led to deleterious effects (Chucair et al., 2007). 

Classic antioxidants, vitamin E, vitamin C, and others can suppress the activation of apoptosis. For example, ascorbic acid prevented cytochrome c release and caspase activation in human leukemia cells exposed to hydrogen peroxide [128], Pretreatment with A -acctylcystcinc, ascorbate, and vitamin E decreased homocysteine thiolactone-induced apoptosis in human promyelocytic leukemia HL-60 cells [129]. Resveratrol protected rat brain mitochondria from anoxia-reoxygenation damage by the inhibition of cytochrome c release and the reduction of superoxide production [130]. However, it should be mentioned that the proapoptotic effect of ascorbate, gallic acid, or epigallocatechin gallate has been shown in the same human promyelocytic leukemia cells [131]. 

Many of the morphological and biochemical changes that occur in cells that die by necrosis are very different from those that occur in apoptosis. During necrosis cells swell, mitochondria and endoplasmic reticulum lose their structure and become dysfunctional and the nuclear membrane becomes disrupted (Fig. 35-1). Necrotic death is independent of premitochondrial apoptotic proteins such as Bax, cytochrome c release and caspase activation. Necrosis is further distinguished from apoptosis by the fact that necrosis usually occurs as the result of a traumatic physical injury or stroke and cells die en masse, whereas apoptosis typically occurs in individual cells within a population of surviving neighbors. 

Miura, K., Aminova L., and MurayamaY. Fusarenon-X induced apoptosis in HL-60 cells depends on caspase activation and cytochrome c release. Toxicology 172, 103, 2002. 

Nitric oxide-induced apoptosis in human leukemic lines requires mitochondrial hpid degradation and cytochrome c release. Blood 93 2342-2352. 

It is now well estahlished that activation of the caspase cascade is an indispensable and sufficient process in the execution phase of apoptosis (Nunez et al, 1998). As for mitochondria-mediated apoptosis, cytochrome c released from the mitochondrial inner membrane is well known to play an important role in the activation of caspase 9, one of the upstream proteases in the cascade (Zou et al, 1997). For activation of caspase 9, cytochrome c or apoptotic protease activating factor 2 (Apaf 2) induces the formation of the complex between Apaf 1 and caspase 9. The resultant activated caspase 9 then activates caspase 3, which in turn leads to the genomic DNA fragmentation and apoptotic cell death. 

The toxic effect of 7-oxysterols, 25- and 27-hydroxycholesterols and their involvement in LDL cytotoxicity have been extensively studied on the different vascular cell types (Lizard et al, 1999 Aupeix et al, 1995 Clare et al, 1995 Ramasamy et al, 1992). 7a and 7p-hydroxycholesterols, 7-ketocholesterol, 25 and 27-hydroxycholesterol induce apoptosis (Brown and Jessup, 1999 Lizard et al, 1999, 1998 Zhang et al, 1997 Hughes et al, 1994). 7p-hydroperoxycholesterol is one of the most toxic Oxysterols present in oxidized LDL (Brown and Jessup, 1999 Colles et al, 1996). 25-hydroxycholesterol, though less active (Aupeix et al 1995), is able to trigger a cytochrome c release and subsequent caspase activation in CHO cells, but also calcium inaease in relation with apoptosis (Rusinol et al, 2000). 

CuvUlier, O., Nava, V.E., Murthy, S.K., Edsall, L.C., Levade, T, MUstien, S. and Spiegel, S., 2001, Sphingosine generation, cytochrome c release, and activation ofcaspase-7 in doxorubidn-induced apoptosis of MCF7 breast adenocarcinoma cells. Cell Death Differ 8 162-171. 

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