Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both natural (laurate) and artificial (m-chlorocarbonylcyanide phenylhydrazone; CCCP) uncouplers strongly inhibit O2.- and H2O2 formation by rat heart mitochondria oxidizing succinate. Carboxyatractylate, an ATP/ADP antiporter inhibitor, abolishes the laurate inhibition, the CCCP inhibition being unaffected. Atractylate partially releases the inhibition by laurate and decelerates the releasing effect of carboxyatractylate. GDP is much less effective than carboxyatractylate in releasing the laurate inhibition of reactive oxygen species (ROS) formation. Micromolar laurate concentrations arresting the ROS formation cause strong inhibition of reverse electron transfer from succinate to NAD+, whereas State 4 respiration and the transmembrane electric potential difference (delta psi) level are affected only slightly. It is suggested that (i) free fatty acids operate as natural 'mild uncouplers' preventing the transmembrane electrochemical H+ potential difference (delta muH+) from being above a threshold critical for ROS formation by complex I and, to a lesser degree, by complex III of the respiratory chain, and (ii) it is the ATP/ADP-antiporter, rather than uncoupling protein 2, that is mainly involved in this antioxidant mechanism of heart muscle mitochondria.
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PMID:Fatty acids as natural uncouplers preventing generation of O2.- and H2O2 by mitochondria in the resting state. 976 12

Mitochondrial uncoupling protein 3 (UCP(3))-mediated uncoupling has been postulated to depend on several factors, including superoxides, free fatty acids (FFAs), and fatty acid hydroperoxides and/or their derivatives. We investigated whether there is an interrelation between endogenous mitochondrial superoxides and fatty acids in inducing skeletal muscle mitochondrial uncoupling, and we speculated on the possible involvement of UCP(3) in this process. In the absence of FFAs, no differences in proton-leak kinetic were detected between succinate-energized mitochondria respiring in the absence or presence of rotenone, despite a large difference in complex I superoxide production. The addition of either arachidic acid or arachidonic acid induced an increase in proton-leak kinetic, with arachidonic acid having the more marked effect. The uncoupling effect of arachidic acid was independent of the presence of GDP, rotenone and vitamin E, while that of arachidonic acid was dependent on these factors. These data demonstrate that FFA and O(2-) play interrelated roles in inducing mitochondrial uncoupling, and we hypothesize that a likely formation of mitochondrial fatty acid hydroperoxides is a key event in the arachidonic acid-induced GDP-dependent inhibition of mitochondrial uncoupling.
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PMID:Interrelated influence of superoxides and free fatty acids over mitochondrial uncoupling in skeletal muscle. 1847 34

Coat protein complex I (COPI) vesicles play a central role in the recycling of proteins in the early secretory pathway and transport of proteins within the Golgi stack. Vesicle formation is initiated by the exchange of GDP for GTP on ARF1 (ADP-ribosylation factor 1), which, in turn, recruits the coat protein coatomer to the membrane for selection of cargo and membrane deformation. ARFGAP1 (ARF1 GTPase-activating protein 1) regulates the dynamic cycling of ARF1 on the membrane that results in both cargo concentration and uncoating for the generation of a fusion-competent vesicle. Two human orthologues of the yeast ARFGAP Glo3p, termed ARFGAP2 and ARFGAP3, have been demonstrated to be present on COPI vesicles generated in vitro in the presence of guanosine 5'-3-O-(thio)triphosphate. Here, we investigate the function of these two proteins in living cells and compare it with that of ARFGAP1. We find that ARFGAP2 and ARFGAP3 follow the dynamic behavior of coatomer upon stimulation of vesicle budding in vivo more closely than does ARFGAP1. Electron microscopy of ARFGAP2 and ARFGAP3 knockdowns indicated Golgi unstacking and cisternal shortening similarly to conditions where vesicle uncoating was blocked. Furthermore, the knockdown of both ARFGAP2 and ARFGAP3 prevents proper assembly of the COPI coat lattice for which ARFGAP1 does not seem to play a major role. This suggests that ARFGAP2 and ARFGAP3 are key components of the COPI coat lattice and are necessary for proper vesicle formation.
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PMID:ARFGAP2 and ARFGAP3 are essential for COPI coat assembly on the Golgi membrane of living cells. 2085 1

Protein trafficking through the secretory pathway plays a key role in epithelial organ development and function. The expansion of tracheal tubes in Drosophila depends on trafficking of coatomer protein complex I (COPI)-coated vesicles between the Golgi complex and the endoplasmic reticulum (ER). However, it is not clear how this pathway is regulated. Here we describe an essential function of the Sec7 domain guanine nucleotide exchange factor (GEF) gartenzwerg (garz) in epithelial tube morphogenesis and protein secretion. garz is essential for the recruitment of COPI components and for normal Golgi organization. A GFP-Garz fusion protein is distributed in the cytoplasm and accumulates at the cis-Golgi. Localization to the Golgi requires the C-terminal part of Garz. Conversely, blocking the GDP-GTP nucleotide exchange reaction leads to constitutive Golgi localization, suggesting that Garz cycles in a GEF-activity-dependent manner between cytoplasmic and Golgi-membrane-localized pools. The related human ARF-GEF protein GBF1 can substitute for garz function in Drosophila tracheal cells, indicating that the relevant functions of these proteins are conserved. We show that garz interacts genetically with the ARF1 homolog ARF79F and with the ARF1-GAP homolog Gap69C, thus placing garz in a regulatory circuit that controls COPI trafficking in Drosophila. Interestingly, overexpression of garz causes accumulation of secreted proteins in the ER, suggesting that excessive garz activity leads to increased retrograde trafficking. Thus, garz might regulate epithelial tube morphogenesis and secretion by controlling the rate of trafficking of COPI vesicles.
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PMID:The Drosophila Sec7 domain guanine nucleotide exchange factor protein Gartenzwerg localizes at the cis-Golgi and is essential for epithelial tube expansion. 2234 97