Nitric oxide-associated protein 1 (NOA1) is necessary for oxygen-dependent regulation of mitochondrial respiratory complexes.

In eukaryotic cells, maintenance of cellular ATP stores depends mainly on mitochondrial oxidative phosphorylation (OXPHOS), which in turn requires sufficient cellular oxygenation. The crucial role of proper oxygenation for cellular viability is reflected by involvement of several mechanisms, which sense hypoxia and regulate activities of respiratory complexes according to available oxygen concentrations. Here, we focus on mouse nitric oxide-associated protein 1 (mNOA1), which has been identified as an important component of the machinery that adjusts OXPHOS activity to oxygen concentrations. mNOA1 is an evolutionary conserved GTP-binding protein that is involved in the regulation of mitochondrial protein translation and respiration. We found that mNOA1 is located mostly in the mitochondrial matrix from where it interacts with several high molecular mass complexes, most notably with the complex IV of the respiratory chain and the prohibitin complex. Knock-down of mNOA1 impaired enzyme activity I+III, resulting in oxidative stress and eventually cell death. mNOA1 is transcriptionally regulated in an oxygen-sensitive manner. We propose that oxygen-dependent regulation of mNOA1 is instrumental to adjusting OXPHOS activity to oxygen availability, thereby controlling mitochondrial metabolism.

Induction of smooth muscle cell migration during arteriogenesis is mediated by Rap2.

OBJECTIVE: Collateral artery growth or arteriogenesis is the primary means of the circulatory system to maintain blood flow in the face of major arterial occlusions. Arteriogenesis depends on activation of fibroblast growth factor (FGF) receptors, but relatively little is known about downstream mediators of FGF signaling. METHODS AND RESULTS: We screened for signaling components that are activated in response to administration of FGF-2 to cultured vascular smooth muscle cells (VSMCs) and detected a significant increase of Rap2 but not of other Ras family members, which corresponded to a strong upregulation of Rap2 and C-Raf in growing collaterals from rabbits with femoral artery occlusion. Small interfering RNAs directed against Rap2 did not affect FGF-2 induced proliferation of VSMC but strongly inhibited their migration. Inhibition of FGF receptor-1 (FGFR1) signaling by infusion of a sulfonic acid polymer or infection with a dominant-negative FGFR1 adenovirus inhibited Rap2 upregulation and collateral vessel growth. Similarly, expression of dominant-negative Rap2 blocked arteriogenesis, whereas constitutive active Rap2 enhanced collateral vessel growth. CONCLUSIONS: Rap2 is part of the arteriogenic program and acts downstream of the FGFR1 to stimulate VSMC migration. Specific modulation of Rap2 might be an attractive target to manipulate VSMC migration, which plays a role in numerous pathological processes.