Good ROS Versus Bad ROS

Science Signaling  20 Jul 2010:
Vol. 3, Issue 131, pp. ec218
DOI: 10.1126/scisignal.3131ec218

Oxidative stress in muscle is produced by high concentrations of circulating glucose and fatty acids associated with insulin resistance and diabetes. Increased production of reactive oxygen species (ROS) has been mechanistically linked to insulin resistance through a pathway in which cellular stress activates the JNK mitogen-activated protein kinase, which phosphorylates the insulin receptor substrate 1 (IRS1) protein, leading to its degradation and thus to decreased insulin signaling. Exercise-induced oxidative phosphorylation in mitochondria of muscle also increases production of ROS and activation of JNK, but it produces the opposite effect: Exercise increases insulin sensitivity. Berdichevsky et al. therefore evaluated the effects of chronic and acute oxidative stress on insulin resistance and JNK signaling in cultured mouse muscle cells. As expected, chronic stress (treatment of cells for 2 days with hydrogen peroxide) led to insulin resistance, but acute treatment enhanced insulin signaling (measured as phosphorylation of the protein kinase Akt) and also improved insulin signaling in cells made insulin resistant by long-term exposure to increased concentrations of glucose and insulin. Localization of JNK was monitored by immunofluorescence microscopy and revealed that, although chronic oxidative stress activated JNK in the cytoplasm and associated with intracellular membranes, acute stress led to activation of JNK in the nucleus. Insulin-resistant cells had large amounts of active JNK in the cytoplasm, similar to that of cells undergoing chronic oxidative stress. But when these insulin-resistant cells were exposed to acute stress, amounts of active JNK were increased in the nucleus and decreased in the cytoplasm. The total amount of JNK appeared to remain the same, indicating that cytoplasmic JNK was inactivated. Indeed, MAP kinase phosphatase 7 (MKP7), which specifically dephosphorylates and inactivates JNK, was excluded from the nucleus in insulin-resistant cells exposed to acute oxidative stress and accumulated in the cytoplasm. Furthermore, siRNA-mediated depletion of MKP7 prevented the effect of acute oxidative stress to restore insulin signaling in insulin-resistant cells. The authors thus conclude that the paradoxical opposite effects of acute and chronic oxidative stress on insulin signaling appear to be explained by distinct effects on the localized activation of JNK and MKP7.

A. Berdichevsky, L. Guarente, A. Bose, Acute oxidative stress can reverse insulin resistance by inactivation of cytoplasmic JNK. J. Biol. Chem. 285, 21581–21589 (2010). [Abstract] [Full Text]