Tretter 2012 Free Radic Biol Med
| Tretter L, Adam-Vizi V. (2012) High Ca2+ load promotes hydrogen peroxide generation via activation of Ξ±-glycerophosphate dehydrogenase in brain mitochondria.. Free Radic Biol Med 53(11):2119-30. |
Β» [1]
Tretter L, Adam-Vizi V. (2012) Free Radic Biol Med
Abstract: H(2)O(2) generation associated with Ξ±-glycerophosphate (Ξ±-GP) oxidation was addressed in guinea pig brain mitochondria challenged with high Ca(2+) load (10 ΞΌM). Exposure to 10 ΞΌM Ca(2+) induced an abrupt 2.5-fold increase in H(2)O(2) release compared to that measured in the presence of a physiological cytosolic Ca(2+) concentration (100 nM) from mitochondria respiring on 5 mM Ξ±-GP in the presence of ADP (2 mM). The Ca(2+)-induced stimulation of H(2)O(2) generation was reversible and unaltered by the uniporter blocker Ru 360, indicating that it did not require Ca(2+) uptake into mitochondria. Enhanced H(2)O(2) generation by Ca(2+) was also observed in the absence of ADP when mitochondria exhibited permeability transition pore opening with a decrease in the NAD(P)H level, dissipation of membrane potential, and mitochondrial swelling. Furthermore, mitochondria treated with the pore-forming peptide alamethicin also responded with an elevated H(2)O(2) generation to a challenge with 10 ΞΌM Ca(2+). Ca(2+)-induced promotion of H(2)O(2) formation was further enhanced by the complex III inhibitor myxothiazol. With 20 mM Ξ±-GP concentration, stimulation of H(2)O(2) formation by Ca(2+) was detected only in the presence, not in the absence, of ADP. It is concluded that Ξ±-glycerophosphate dehydrogenase, which is accessible to and could be activated by a rise in the level of cytosolic Ca(2+), makes a major contribution to Ca(2+)-stimulated H(2)O(2) generation. This work highlights a unique high-Ca(2+)-stimulated reactive oxygen species-forming mechanism in association with oxidation of Ξ±-GP, which is largely independent of the bioenergetic state and can proceed even in damaged, functionally incompetent mitochondria. β’ Keywords: Mitochondria; Reactive oxygen species; Calcium; Hydrogen peroxide; Ξ±-Glycerophosphate dehydrogenase; Reverse electron transport; Permeability transition pore; Myxothiazol; Ξ±-Glycerophosphate shuttle; Free radicals
β’ O2k-Network Lab: HU_Budapest_Tretter L, HU Budapest Semmelweis Univ
Labels:
HRR: Oxygraph-2k
