Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irreversible damage to Friend's erythroleukemia cells was caused by induction of endogenous heme biosynthesis with the differentiating agent N,N'-hexamethylene bisacetamide followed by a 30-min exposure to 0.25 mM H2O2. Early irreversible ATP depletion was observed concomitant with oxidative inactivation of the mitochondrial ATP synthase. Cell proliferative capacity was also impaired within 2 h of the treatment, and progressive delayed cell lethality, starting 2 h after the insults, was also found. Based on the prevention provided by specific antioxidants and on the absence of malodialdehyde production, all the effects were ascribed to the oxidant action of .OH radicals, or closely related species, generated through iron-catalyzed reactions of H2O2, which apparently caused site-directed oxidative modifications of iron-binding proteins, in particular mitochondrial ATP synthase, rather than peroxidation of membrane lipids. Similar effects were mimicked even in the parental cell line when oligomycin was used to inhibit selectively mitochondrial ATP synthase activity, thereby lowering the enzyme activity to a level similar to that found in H2O2-damaged differentiating cells. Hence, induction of erythroid differentiation makes the mitochondrial ATP synthase a major target of H2O2 by enhancing the availability of redox-active iron in the local environment of the enzyme. Subsequent oxidative inactivation of the mitochondrial ATP synthase, resulting in severe energy impairment, leads to loss of cell growth capacity. Erythroleukemia cells may serve as a model system for the combination of two selective properties: (1) the capacity for carrying out efficient heme synthesis and/or for undergoing iron overload-like state; and (2) subsequent enhanced sensitivity to reactive oxygen species generators. Early severe mitochondrial dysfunction and energy impairment may be a major part of the mechanism of the sensitivity.
 ...
PMID:Severe energy impairment consequent to inactivation of mitochondrial ATP synthase as an early event in cell death: a mechanism for the selective sensitivity to H2O2 of differentiating erythroleukemia cells. 960 2

The objective of the present study was to identify mitochondrial components associated with the damage caused by iron to the rat heart. Decreased cell viability was assessed by increased presence of lactate dehydrogenase (LDH) in serum. To assess the functional integrity of mitochondria, Reactive Oxygen Species (ROS), the Respiratory Control Ratio (RCR), ATP and chelatable iron content were measured in the heart. Chelatable iron increased 15-fold in the mitochondria and ROS increased by 59%. Deterioration of mitochondrial function in the presence of iron was demonstrated by low RCR (46% decrease) and low ATP content (96% decrease). Using two dimensional gel electrophoresis (2DE), we identified alterations in 21 mitochondrial proteins triggered by iron overload. Significantly, expression of the alpha, beta, and d subunits of F(1)F(o) ATP synthase increased along with the loss of ATP. This suggests that the F(1)F(o) ATP synthase participates in iron metabolism.
 ...
PMID:Increased expression of the F(1)F(o) ATP synthase in response to iron in heart mitochondria. 1831 52