Search

Small inorganic compounds able to prevent the mitochondrial permeability transition, the master player in apoptosis and necrosis, are increasingly considered as beneficial tools in cytoprotection. Nitrite, a known cellular nitric oxide reservoir, has a recognized role in cardioprotection, but the molecular mechanisms of its action are not thoroughly understood. Mitochondrial permeability changes are known to constitute the molecular bases of human cardiac diseases and pathologies related to mitochondrial dysfunctions. In turn oxidative stress and mitochondrial damage are related issues in degenerative and cardiovascular diseases. Assumed that the mitochondrial F1FO complex is structurally or functionally involved in the mitochondrial permeability transition pore (MPTP), which triggers the mitochondrial permeability transition, nitrite effects on the enzyme complex may be exploited to shut the MPTP. Many clues suggest that nitrite may prevent or limit cell death by modulating the F1FO complex. Accordingly, nitrite decreases the ATPase activity stimulated by Ca2+, it is ineffective on the Mg-ATPase up to 2 mM and the enzyme inhibition is apparently enhanced under oxidative stress conditions. Through the inhibition of the calcium-activated F1FO complex, nitrite would shut the MPTP, which is likely to be related to the calcium-dependent functioning mode of the F1FO complex, and limit mitochondrial impairment and cell death under physio-pathological conditions.

The undifferentiated porcine Aortic Vascular Precursor cells (pAVPCs) are stem cells endowed with self-renewal capability and with the ability to differentiate in all cell types involved in vessel structure [1]. In general, the rapid proliferative potential in stem cells supports anabolism to synthesize the building blocks for macromolecules and biostructures, whereas differentiating cells switch to catabolism to support the bioenergetic demand [2]. After the 1st and 2nd cell passages the pAVPCs associate glycolysis with cellular respiration to mitochondrial ATP synthesis. Conversely, the pAVPCs from 3rd to 8th passages do not show any mitochondrial ATP turnover. Interestingly, when the 1st passage cells are exposed to lipopolysaccharides (LPS) at 0.1 or 10 μg/mL for 4h, ATP turnover is countered, although cells retain their spare respiratory capacity. Moreover, the inhibition of glycolytic efficiency decreases the glycolytic reserve. In contrast, pAVPCs at the 5th passage exposed to 10 μg/mL LPS for 4h increase the synthesis of mitochondrial ATP. The whole of data indicate that pAVPCs adapt their metabolism according to lineage features and assay conditions.

The mitochondrial F1FO-ATPase is a reversible and biologically unique energy-transducing mechanism with coupled capabilities of H+ translocation across the hydrophobic FO domain and ATP synthesis/hydrolysis by the hydrophilic F1 domain. When the Ca2+ replaces the natural cofactor Mg2+ in the catalytic site [1], most of the enzyme features are preserved, namely the inhibition by the FO blockers DCCD and oligomycin, the oligomycin desensitization by thiol oxidation and the dependence on the electrochemical gradient. The two differently activated F-ATPases share the basic structure and function mechanism of H+ translocation. However, the mixed type inhibition of the Ca-F1FO-ATPase by ADP and azide suggests that, while the overall F1 catalysis is apparently divalent ion-independent, the intimate molecular mechanism of catalysis can be altered by the replacement of Mg2+ with Ca2+, probably due to the higher steric hindrance of Ca2+ with respect to Mg2+ in the cofactor binding sites [2]. Apparently, the two F-ATPases are two distinct functioning modes of the same F1FO complex. The putative involvement of enzyme in membrane permeability changes [3] hints that the Ca-dependent F1FO-ATPase modulation may open/close the permeability transition pore.