Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects.
Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects.
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DOI：
10.1016/j.celrep.2014.04.037
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发表时间：
2014-06-12
期刊：
影响因子：
8.8
通讯作者：
DeBerardinis RJ
中科院分区：
文献类型：
--
作者：
Mullen AR;Hu Z;Shi X;Jiang L;Boroughs LK;Kovacs Z;Boriack R;Rakheja D;Sullivan LB;Linehan WM;Chandel NS;DeBerardinis RJ
哺乳动物细胞通过线粒体中的丙酮酸脱羧产生柠檬酸，以供应三羧酸（TCA）循环。相比之下，缺氧和其他线粒体功能损伤会诱导一条替代途径，通过 NADPH 依赖性异柠檬酸脱氢酶 (IDH) 还原羧化 α-酮戊二酸 (AKG)，从而产生柠檬酸。目前尚不清楚细胞如何产生在线粒体损伤的情况下提供还原羧化所需的还原当量。在这里，我们使用还原羧化确定了细胞中共有的代谢特征。矛盾的是，在 TCA 循环中，还原羧化伴随着 AKG 氧化。抑制 AKG 氧化会降低还原当量可用性并抑制还原羧化。通过烟酰胺核苷酸转氢酶阻断还原当量从 NADH 到 NADPH 的转移，增加了 NADH 丰度并降低了 NADPH 丰度，同时抑制了还原羧化。数据表明，还原羧化需要沿着氧化和还原途径双向 AKG 代谢，氧化途径产生用于反向操作 IDH 的还原当量。
Mammalian cells generate citrate by decarboxylating pyruvate in the mitochondria to supply the tricarboxylic acid (TCA) cycle. In contrast, hypoxia and other impairments of mitochondrial function induce an alternative pathway that produces citrate by reductively carboxylating α-ketoglutarate (AKG) via NADPH-dependent isocitrate dehydrogenase (IDH). It is unknown how cells generate reducing equivalents necessary to supply reductive carboxylation in the setting of mitochondrial impairment. Here we identified shared metabolic features in cells using reductive carboxylation. Paradoxically, reductive carboxylation was accompanied by concomitant AKG oxidation in the TCA cycle. Inhibiting AKG oxidation decreased reducing equivalent availability and suppressed reductive carboxylation. Interrupting transfer of reducing equivalents from NADH to NADPH by nicotinamide nucleotide transhydrogenase increased NADH abundance and decreased NADPH abundance while suppressing reductive carboxylation. The data demonstrate that reductive carboxylation requires bidirectional AKG metabolism along oxidative and reductive pathways, with the oxidative pathway producing reducing equivalents used to operate IDH in reverse.
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影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.8
作者：
Gameiro, Paulo A.;Laviolette, Laura A.;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
影响因子：
29
作者：
Marin-Valencia I;Yang C;Mashimo T;Cho S;Baek H;Yang XL;Rajagopalan KN;Maddie M;Vemireddy V;Zhao Z;Cai L;Good L;Tu BP;Hatanpaa KJ;Mickey BE;Matés JM;Pascual JM;Maher EA;Malloy CR;Deberardinis RJ;Bachoo RM
通讯作者：
Bachoo RM
影响因子：
3.2
作者：
Rakheja, Dinesh;Mitui, Midori;DeBerardinis, Ralph J.
通讯作者：
DeBerardinis, Ralph J.