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.
Abbreviations: ER, endoplasmic reticulum; ETC, electron transport chain; IM, inner membrane; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition pore; OM, outer membrane.
Win S1, Than TA1, Min RW1, Aghajan M2, Kaplowitz N1.[expand title=”Show Affiliations”]
- USC Research Center for Liver Disease, Keck School of Medicine of USC, Los Angeles, California.
- IONIS Pharmaceuticals, Carlsbad, California. [/expand]
Sustained JNK activation has been implicated in many models of cell death and tissue injury. P-JNK interacts with the mitochondrial outer membrane protein, Sab (SH3BP5). Using knockdown or liver specific deletion of Sab we aimed to elucidate the consequences of this interaction on mitochondrial function in isolated mitochondria and liver injury models in vivo. Respiration in isolated mitochondria was directly inhibited by P-JNK+ATP. Knockdown or liver specific knockout of Sab abrogated this effect and markedly inhibited sustained JNK activation and liver injury from acetaminophen (APAP) or TNF/galactosamine. We then elucidated an intramitochondrial pathway in which interaction of JNK and Sab on the outside of the mitochondria released SHP1 (PTPN6) from Sab in the inside of the mitochondrial outer membrane leading to its activation and transfer to the inner membrane where it dephosphorylates P-Y419Src (active) which required a platform protein, DOK4, on the inner membrane. Knockdown of mitochondrial DOK4 or SHP1 inhibited the inactivation of mitochondrial P-Src and the effect of P-JNK on mitochondria. Conclusions; the binding to and phosphorylation of Sab by P-JNK on the outer mitochondrial membrane leads to SHP1 and DOK4 dependent inactivation of P-Src on the inner membrane. Inactivation of mitochondrial Src inhibits electron transport and increases ROS release, which sustains JNK activation and promotes cell death and organ injury.
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