Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.
Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.
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DOI：
10.1083/jcb.201612067
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发表时间：
2017-04-03
期刊：
影响因子：
--
通讯作者：
Murphy AN
中科院分区：
文献类型：
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作者：
Divakaruni AS;Wallace M;Buren C;Martyniuk K;Andreyev AY;Li E;Fields JA;Cordes T;Reynolds IJ;Bloodgood BL;Raymond LA;Metallo CM;Murphy AN
在皮质神经元和海马片培养中，阻止线粒体丙酮酸摄取重新连接新陈代谢，以增加对谷氨酸的依赖，以促进TCA循环。这减少了容易释放的神经元谷氨酸池，并最大限度地减少了兴奋性毒性损伤的正反馈级联反应。谷氨酸是大脑中主要的兴奋性神经递质，但在代谢应激条件下，谷氨酸可以积累到兴奋毒性水平。虽然兴奋性氨基酸受体的药理调节已经被很好地研究，但针对线粒体谷氨酸代谢来控制神经递质水平的研究还很少。在这里，我们证明了对线粒体丙酮酸载体(MPC)的化学抑制可以保护初级皮质神经元免于兴奋性死亡。线粒体丙酮酸摄取的减少不会影响细胞的能量代谢，这表明神经元代谢的灵活性。相反，MPC抑制改变了线粒体底物的代谢，从而优先增加对谷氨酸的依赖，以补充能量和逆转。动员神经元谷氨酸池进行氧化减少了去极化时释放的谷氨酸的数量，进而限制了兴奋性毒性神经元损伤的正反馈级联反应。这一发现将线粒体丙酮酸代谢与谷氨酸能神经传递联系起来，并将MPC确立为治疗以兴奋毒性为特征的神经退行性疾病的治疗靶点。
In cortical neurons and hippocampal slice cultures, blocking mitochondrial pyruvate uptake rewires metabolism to increase reliance on glutamate to fuel the TCA cycle. This diminishes the readily releasable pool of neuronal glutamate and minimizes the positive-feedback cascade of excitotoxic injury. Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity.