Regulation of substrate utilization by the mitochondrial pyruvate carrier.
Regulation of substrate utilization by the mitochondrial pyruvate carrier.
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DOI：
10.1016/j.molcel.2014.09.024
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发表时间：
2014-11-06
期刊：
影响因子：
16
通讯作者：
Metallo CM
中科院分区：
文献类型：
--
作者：
Vacanti NM;Divakaruni AS;Green CR;Parker SJ;Henry RR;Ciaraldi TP;Murphy AN;Metallo CM
丙酮酸位于连接碳水化合物、氨基酸和脂肪酸代谢的中心生化节点，并且丙酮酸流入线粒体的调节代表影响许多疾病的中间代谢的关键步骤。为了表征线粒体丙酮酸转运受损背景下线粒体底物利用率的变化，我们在转录或药理学抑制线粒体丙酮酸载体（MPC）后对细胞进行了13 C代谢通量分析（MFA）。尽管葡萄糖和丙酮酸氧化都受到了深刻的抑制，但细胞生长、氧消耗和三羧酸（TCA）代谢出人意料地得以维持。氧化TCA通量是通过增强对通过苹果酸酶和丙酮酸脱氢酶（PDH）以及脂肪酸和支链氨基酸氧化的β-氨基解的依赖来实现的。因此，与复合物I或PDH的抑制相反，丙酮酸转运的抑制诱导与使用脂质和氨基酸作为分解代谢和合成代谢燃料相关的代谢灵活性的形式。
Pyruvate lies at a central biochemical node connecting carbohydrate, amino acid, and fatty acid metabolism, and the regulation of pyruvate flux into mitochondria represents a critical step in intermediary metabolism impacting numerous diseases. To characterize changes in mitochondrial substrate utilization in the context of compromised mitochondrial pyruvate transport, we applied 13C metabolic flux analysis (MFA) to cells after transcriptional or pharmacological inhibition of the mitochondrial pyruvate carrier (MPC). Despite profound suppression of both glucose and pyruvate oxidation, cell growth, oxygen consumption, and tricarboxylic acid (TCA) metabolism were surprisingly maintained. Oxidative TCA flux was achieved through enhanced reliance on glutaminolysis through malic enzyme and pyruvate dehydrogenase (PDH) as well as fatty acid and branched chain amino acid oxidation. Thus, in contrast to inhibition of complex I or PDH, suppression of pyruvate transport induces a form of metabolic flexibility associated with use of lipids and amino acids as catabolic and anabolic fuels.