Schematic diagram of T cell activation, nitric oxide production, and mitochondrial hyperpolarization. Nitric oxide (NO) is produced in the cytosol, the mitochondrial membrane, and at the immunological synapse of T cells. Localized NO production has been linked to targeting of endothelial NO synthase (eNOS) to the outer mitochondrial membrane and to the T-cell synapse. NO regulates many steps of T cell activation, the production of cytokines, such as IL-2, and mitochondrial hyperpolarization and mitochondrial biogenesis. NO regulates mammalian target of rapamycin (mTOR) activity. NO dependent mTOR activation induces the loss of TCRζ in lupus T cells through HRES-1/Rab4. Mitochondrial hyperpolarization is associated with depletion of ATP, which predisposes T cells to necrosis. In turn, necrotic materials released from T cells activate monocytes and dendritic cells. Solid arrows indicate processes upregulated by NO, while broken lines indicate processes down-regulated by NO. APC, antigen-presenting cell; DAG, diacylglycerol; IP3, inositol-1,4,5-triphosphate; LAT, linker for activation of T cells; MHC, major histocompatibility complex; PIP2, phosphatidylinositol 4,5-biphosphate; PLC, phospholipase C.