D-Lactate altered mitochondrial energy production in rat brain and heart but not liver.
D-Lactate altered mitochondrial energy production in rat brain and heart but not liver.
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DOI：
10.1186/1743-7075-9-6
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发表时间：
2012-02-01
影响因子：
4.5
通讯作者：
Zello GA
中科院分区：
文献类型：
--
作者：
Ling B;Peng F;Alcorn J;Lohmann K;Bandy B;Zello GA
在人类和动物中，血D-乳酸(DLA)浓度显著升高与神经心脏毒性有关。神经系统症状类似于遗传性或获得性丙酮酸代谢异常。我们推测DLA干扰脑和心脏线粒体对L-乳酸和丙酮酸的利用。分别用DLA、LLA和丙酮酸分别测定大鼠脑、心和肝线粒体的呼吸频率。在脑线粒体中，以DLA为底物的状态3呼吸分别比LLA和丙酮酸低53%和75%(p<；0.05)。同样，在心肌线粒体中，以DLA为底物的状态3呼吸分别比LLA或丙酮酸低39%和86%(p<；0.05)。然而，肝脏线粒体中DLA、LLA和丙酮酸的状态3呼吸速率相似。DLA与LLA或丙酮酸联合孵育可显着损害状态3脑和心脏线粒体的呼吸频率(p<；0.05)，但对肝脏线粒体无明显影响。大脑和心脏线粒体的DLA脱氢酶活性分别比肝脏低61%和51%，而LLA脱氢酶活性在这三个组织中都相似。乳酸脱氢酶抑制剂阻断了三种组织中以LLA为底物的状态3呼吸。一种单羧酸盐转运蛋白抑制剂阻止了所有三种底物的呼吸。DLA是脑和心脏线粒体的不良呼吸底物，并抑制这些组织中LLA和丙酮酸的使用。有必要进行进一步的研究，以评估这些发现是否在一定程度上支持高DLA水平可能导致的神经和心脏毒性。
Substantially elevated blood D-lactate (DLA) concentrations are associated with neurocardiac toxicity in humans and animals. The neurological symptoms are similar to inherited or acquired abnormalities of pyruvate metabolism. We hypothesized that DLA interferes with mitochondrial utilization of L-lactate and pyruvate in brain and heart. Respiration rates in rat brain, heart and liver mitochondria were measured using DLA, LLA and pyruvate independently and in combination. In brain mitochondria, state 3 respiration was 53% and 75% lower with DLA as substrate when compared with LLA and pyruvate, respectively (p < 0.05). Similarly in heart mitochondria, state 3 respiration was 39% and 86% lower with DLA as substrate when compared with LLA or pyruvate, respectively (p < 0.05). However, state 3 respiration rates were similar between DLA, LLA and pyruvate in liver mitochondria. Combined incubation of DLA with LLA or pyruvate markedly impaired state 3 respiration rates in brain and heart mitochondria (p < 0.05) but not in liver mitochondria. DLA dehydrogenase activities were 61% and 51% lower in brain and heart mitochondria compared to liver, respectively, whereas LLA dehydrogenase activities were similar across all three tissues. An LDH inhibitor blocked state 3 respiration with LLA as substrate in all three tissues. A monocarboxylate transporter inhibitor blocked respiration with all three substrates. DLA was a poor respiratory substrate in brain and heart mitochondria and inhibited LLA and pyruvate usage in these tissues. Further studies are warranted to evaluate whether these findings support, in part, the possible neurological and cardiac toxicity caused by high DLA levels.