MEK Kinase 1 Induces Mitochondrial Permeability Transition Leading to Apoptosis Independent of Cytochrome cRelease

Abstract

Induction of apoptosis often converges on the mitochondria to induce permeability transition and release of apoptotic proteins into the cytoplasm resulting in the biochemical and morphological alteration of apoptosis. Activation of a serine threonine kinase MEK kinase 1 (MEKK1) is involved in the induction of apoptosis. Expression of a kinase-inactive MEKK1 blocks genotoxininduced apoptosis. Upon apoptotic stimulation, MEKK1 is cleaved into a 91-kDa kinase fragment that further induces an apoptotic response. Mutation of a consensus caspase 3 site in MEKK1 prevents its induction of apoptosis. The mechanism of MEKK1-induced apoptosis downstream of its cleavage, however, is unknown. Herein we demonstrate that full-length and cleaved MEKK1 leads to permeability transition in the mitochondria. This permeability transition occurs through opening of the permeability transition (PT) pore. Inhibiting PT pore opening and reactive oxygen species production effectively reduced MEKK1-induced apoptosis. Overexpression of MEKK1, however, failed to release cytochrome c from the mitochondria or activate caspase 9. Since Bcl2 regulates changes in mitochondria and blocks MEKK1-induced apoptosis, we determined that Bcl2 blocks MEKK1-induced apoptosis when targeted to the mitochondria. This occurs downstream of MEKK1 cleavage, since Bcl2 fails to block cleavage of MEKK1. In mouse embryonic fibroblast cells lacking caspase 3, the cleaved but not full-length MEKK1 induces apoptosis and permeability transition in the mitochondria. Overall, this suggests that cleaved MEKK1 leads to permeability transition contributing to MEKK1-induced apoptosis independent of cytochrome c release from the mitochondria.

Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation

“…This conclusion is consistent with previous studies suggesting that MPT pore opening is unlikely to occur under the low pH conditions of ischemia and is more likely to occur after reperfusion (18,20); indeed, we observed a fall in ⌬⌿ m during ischemia before reperfusion. However, other investigators have used higher (10,16) or lower (38) concentrations of cyclosporin A to inhibit the opening of that pore, so it is not clear whether protection would have been observed at different concentrations or with other inhibitors of the MPT pore.…”

Death receptor-4 (DR4) expression is regulated by transcription factor NF-κB in response to etoposide treatment

“…MEK kinase 1 (MEKK1) is a serine/threonine kinase that participates in the induction of apoptosis [14][15][16][17][18][19][20]. MEKK1 has been found present in the IKK complex and activates the NF-jB signalling pathway [20,21].…”

JNK-dependent Release of Mitochondrial Protein, Smac, during Apoptosis in Multiple Myeloma (MM) Cells

“…Exogenous JNK has been shown to phosphorylate many mitochondrial proteins during apoptosis (23); however, not all apoptotic agents trigger a sequential activation of JNK and mitochondrial pathways (25,26). Our prior studies showed that dexamethasone-induced apoptosis in MM.1S occurs independent of JNK activation, but is associated with Smac release (18).…”