Model of the pathway for the interplay of JNK and mitochondria in cell death. JNK is initially activated by the MAPK cascade either extrinsically by receptor signaling or intrinsically by organelle stress emanating from mitochondria, endoplasmic reticulum, or nucleus. Activated JNK translocates to the mitochondria, where it binds and phosphorylates Sab on the cytoplasmic side of the outer membrane. This leads to release of inactive SHP1 sequestered by Sab, which then is activated by p-Src and mediates inactivation of P-Y419Src, facilitated by the inner membrane DOK4 platform. Active Src maintains electron transport, whereas inactivation leads to impaired electron transport which promotes increased ROS release. The ROS release continues to activate upstream MAPK, leading to JNK activation in a self-sustaining loop, which accounts for JNK activation being sustained. In APAP toxicity, the amplified mitochondrial ROS from damaged mitochondria due to this loop promotes mitochondrial permeability pore opening and necrosis, whereas in TNF-induced apoptosis the sustained JNK activation is known to lead to enhanced activity of proapoptotic Bcl proteins and impairment of antiapoptotic Bcl proteins; the result is mitochondrial outer membrane permeabilization, which permits release of cytochrome c and other mitochondrial proteins, followed by caspase activation and apoptosis. The key feature is that the Sab-dependent effect of p-JNK on mitochondria through an intramitochondrial signaling pathway is the mechanism for sustained activation of p-JNK in the cytoplasm, which is necessary for cell death.
[/et_pb_text][et_pb_team_member admin_label=”Person” name=”Professor Neil Kaplowitz” image_url=”https://medicineinnovates.com/wp-content/uploads/2016/09/Professor-Neil-Kaplowitz-medicine-innovates.jpg” animation=”off” background_layout=”light” use_border_color=”off” border_color=”#ffffff” border_style=”solid”]
Holder of USC Associates/Thomas H. Brem Chair in Medicine and Budnick Chair in Liver Disease Professor of Medicine and Chief, Division of Gastrointestinal and Liver Diseases, and Professor of Physiology and Biophysics, Keck School of Medicine of USC Professor of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy Director, USC Research Center for Liver Disease[/et_pb_team_member][et_pb_text admin_label=”Text” background_layout=”light” text_orientation=”left” use_border_color=”off” border_color=”#ffffff” border_style=”solid”]
JNK mediates mouse liver injury through a novel Sab (SH3BP5) dependent pathway leading to inactivation of intramitochondrial Src. Win S, Than TA, Min RW, Aghajan M, Kaplowitz N. Hepatology. Volume 63, Issue 6 June 2016 Pages 1987–2003
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