Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

Shacka, J. J.; Sahawneh, M. A.; Gonzalez, J. D.; Ye, Y.-Z.; D'Alessandro, T. L.; Estévez, A. G.
September 2006
Cell Death & Differentiation;Sep2006, Vol. 13 Issue 9, p1506
Academic Journal
The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.Cell Death and Differentiation (2006) 13, 1506–1514. doi:10.1038/sj.cdd.4401831; published online 20 January 2006


Related Articles

  • Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis. Haga, Naomi; Fujita, Naoya; Tsuruo, Takashi // Oncogene;8/28/2003, Vol. 22 Issue 36, p5579 

    Mitochondria play a central role in apoptotic signaling pathways. Upon exposure to apoptotic stimuli, mitochondria release cytochrome c to the cytoplasm and activate caspase cascade leading to cell death. However, the events upstream of cytochrome c release are not fully understood. Here, we...

  • ADF/cofilin proteins translocate to mitochondria during apoptosis but are not generally required for cell death signaling. Rehklau, K; Gurniak, C B; Conrad, M; Friauf, E; Ott, M; Rust, M B // Cell Death & Differentiation;Jun2012, Vol. 19 Issue 6, p958 

    Non-muscle cofilin (n-cofilin) is a member of the ADF/cofilin family of actin depolymerizing proteins. Recent studies reported a mitochondrial translocation of n-cofilin during apoptosis. As these studies also revealed impaired cytochrome c release and a block in apoptosis upon small interfering...

  • The ‘harmless’ release of cytochrome c. Von Ahsen, O; Waterhouse, N J; Kuwana, T; Newmeyer, D D; Green, D R // Cell Death & Differentiation;Dec2000, Vol. 7 Issue 12, p1192 

    Release of cytochrome c from the mitochondria plays an integral role in apoptosis; however, the mechanism by which cytochrome c is released remains one of the conundrums that has occupied the field. Recently, evidence has emerged that the commitment to death may be regulated downstream of...

  • Mechanisms of mitochondrial membrane permeabilization. Reed, J C; Kroemer, G // Cell Death & Differentiation;Dec2000, Vol. 7 Issue 12, p1145 

    Editorial. Introduces the December 2000 issue of the journal 'Cell Death and Differentiation' which contains articles devoted to the topic and mitochondria and their role in apoptosis. Controversy over the precise mechanisms by which mitochondria control cell life and death decisions; Escape...

  • A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis. Pellegrini, L.; Scorrano, L. // Cell Death & Differentiation;Jul2007, Vol. 14 Issue 7, p1275 

    Mitochondria are crucial amplifiers of death signals. They release cytochrome c and other pro-apoptotic factors required to fully activate effector caspases. This release is accompanied by fragmentation of the mitochondrial reticulum and by remodelling of the internal structure of the organelle....

  • Cytochrome c signalosome in mitochondria. Díaz-Moreno, Irene; García-Heredia, José; Díaz-Quintana, Antonio; Rosa, Miguel // European Biophysics Journal;Dec2011, Vol. 40 Issue 12, p1301 

    Cytochrome c delicately tilts the balance between cell life (respiration) and cell death (apoptosis). Whereas cell life is governed by transient electron transfer interactions of cytochrome c inside the mitochondria, the cytoplasmic adducts of cytochrome c that lead to cell death are amazingly...

  • A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c. Mootha, Vamsi K.; Wei, Michael C.; Buttle, Karolyn F.; Scorrano, Luca; Panoutsakopoulou, Vily; Mannella, Carmen A.; Korsmeyer, Stanley J. // EMBO Journal;2/15/2001, Vol. 20 Issue 4, p661 

    Multiple apoptotic pathways release cytochrome c from the mitochondrial intermembrane space, resulting in the activation of downstream caspases. In vivo activation of Fas (CD95) resulted in increased permeability of the mitochondrial outer membrane and depletion of cytochrome c stores. Serial...

  • Sensitization for Anticancer Drug-Induced Apoptosis by Betulinic Acid. Fulda, Simone; Debatin, Klaus-Michael // Neoplasia;Feb2005, Vol. 7 Issue 2, p162 

    We previously described that betulinic acid (BetA), a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit...

  • Activation of Bax by joint action of tBid and mitochondrial outer membrane: Monte Carlo simulations. Veresov, Valery G.; Davidovskii, Alexander I. // European Biophysics Journal;Sep2009, Vol. 38 Issue 7, p941 

    The mitochondrial pathway of apoptosis proceeds when molecules, such as cytochrome c, sequestered between the outer and inner mitochondrial membranes are released to the cytosol by mitochondrial outer membrane (MOM) permeabilization. Bax, a member of the Bcl-2 protein family, plays a pivotal...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics