1. Mitochondrial Redox Control of the Cellular Metabolism
This project is based on the hypothesis that mitochondria dynamically decide whether to utilize available oxygen for ATP production or H2O2 generation. H2O2 egressing from mitochondria initiates redox signaling, generation of oxidants is controlled by sophisticated mechanisms of electron transfer in part controlled by the enzyme manganese superoxide dismutase MnSOD. In cancer, MnSOD is constitutively unregulated and as shown in our studies the levels of MnSOD upregulation parallels tumor stage. By maintaining a steady flow of H2O2 originating in mitochondria MnSOD sustains AMP-activated kinase (AMPK) activity that produces the glycolytic shift that induces tumor cell energetic viability.
?2. S-Nitrosation inhibits Suppressor of Cytokine Signaling-1 (SOCS-1) allowing NF-kB activation in response to TLR4 activation
This project is based on the observation that NOS1 activation in response to TLR4 activation is critical for initiation of NF-kB driven inflammation in macrophages. Our studies showed that NOS1 S-nitrosates, and thereby inhibits SOCS1. In its inhibited state SOCS1 cannot target the transcriptionally active NF-kB subunit p65 to proteasomal degradation allowing for the synthesis of pro inflammatory mediators. These studies indicate that the duration and intensity of signals originating from NOS1 define the course, locality and duration of inflammation.