dc.contributor.author |
Németh, Beáta |
|
dc.contributor.author |
Dóczi, Judit |
|
dc.contributor.author |
Csete, Dániel |
|
dc.contributor.author |
Kacsó, Gergely |
|
dc.contributor.author |
Ravasz, Dóra |
|
dc.contributor.author |
Daniel Adams |
|
dc.contributor.author |
Kiss, Gergely |
|
dc.contributor.author |
Nagy, Ádám Miklós |
|
dc.contributor.author |
Horváth, Gergő |
|
dc.contributor.author |
Tretter, László |
|
dc.contributor.author |
Mócsai, Attila |
|
dc.contributor.author |
Csépányi-Kömi, Roland |
|
dc.contributor.author |
Iordanov, Iordan |
|
dc.contributor.author |
Ádám, Veronika |
|
dc.contributor.author |
Chinopoulos, Christos |
|
dc.date.accessioned |
2016-10-13T10:03:47Z |
|
dc.date.available |
2016-10-13T10:03:47Z |
|
dc.date.issued |
2016 |
|
dc.identifier.citation |
pagination=286-300;
journalVolume=30;
journalIssueNumber=1;
journalTitle=The FASEB Journal; |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/2664 |
|
dc.identifier.uri |
doi:10.1096/fj.15-279398 |
|
dc.description.abstract |
Itaconate is a nonamino organic acid exhibiting antimicrobial effects. It has been recently identified in cells of macrophage lineage as a product of an enzyme encoded by immunoresponsive gene 1 (Irg1), acting on the citric acid cycle intermediate cis-aconitate. In mitochondria, itaconate can be converted by succinate-coenzyme A (CoA) ligase to itaconyl-CoA at the expense of ATP (or GTP), and is also a weak competitive inhibitor of complex II. Here, we investigated specific bioenergetic effects of increased itaconate production mediated by LPS-induced stimulation of Irg1 in murine bone marrow-derived macrophages (BMDM) and RAW-264.7 cells. In rotenone-treated macrophage cells, stimulation by LPS led to impairment in substrate-level phosphorylation (SLP) of in situ mitochondria, deduced by a reversal in the directionality of the adenine nucleotide translocase operation. In RAW-264.7 cells, the LPS-induced impairment in SLP was reversed by short-interfering RNA(siRNA)-but not scrambled siRNA-treatment directed against Irg1. LPS dose-dependently inhibited oxygen consumption rates (61-91%) and elevated glycolysis rates (>21%) in BMDM but not RAW-264.7 cells, studied under various metabolic conditions. In isolated mouse liver mitochondria treated with rotenone, itaconate dose-dependently (0.5-2 mM) reversed the operation of adenine nucleotide translocase, implying impairment in SLP, an effect that was partially mimicked by malonate. However, malonate yielded greater ADP-induced depolarizations (3-19%) than itaconate. We postulate that itaconate abolishes SLP due to 1) a "CoA trap" in the form of itaconyl-CoA that negatively affects the upstream supply of succinyl-CoA from the α-ketoglutarate dehydrogenase complex; 2) depletion of ATP (or GTP), which are required for the thioesterification by succinate-CoA ligase; and 3) inhibition of complex II leading to a buildup of succinate which shifts succinate-CoA ligase equilibrium toward ATP (or GTP) utilization. Our results support the notion that Irg1-expressing cells of macrophage lineage lose the capacity of mitochondrial SLP for producing itaconate during mounting of an immune defense.
© FASEB. |
|
dc.title |
Abolition of mitochondrial substrate-level phosphorylation by itaconic acid produced by LPS-induced Irg1 expression in cells of murine macrophage lineage |
|
dc.type |
Journal Article |
|
dc.date.updated |
2015-11-24T14:34:07Z |
|
dc.language.rfc3066 |
en |
|
dc.identifier.mtmt |
2940351 |
|
dc.contributor.department |
SE/AOK/I/Orvosi Biokémiai Intézet |
|
dc.contributor.department |
SE/AOK/I/OBI/MTA-SE Lendület Ioncsatorna Kutatócsoport |
|
dc.contributor.department |
SE/AOK/I/OBI/MTA-SE Lendület Neurobiokémiai Munkacsoport |
|
dc.contributor.department |
SE/AOK/I/OBI/MTA-SE Neurobiokémiai Kutatócsoport |
|
dc.contributor.department |
SE/AOK/I/Élettani Intézet |
|
dc.contributor.department |
SE/AOK/I/ÉI/MTA-SE Lendület Gyulladásélettani Kutatócsoport |
|
dc.contributor.institution |
Semmelweis Egyetem |
|