代谢物可以引起处于在发育状态的大鼠心脏线粒体丙酸血症中积累引起的生物能量学和钙稳态紊乱

Disturbance of bioenergetics and calcium homeostasis provoked by metabolites

accumulating in propionic acidemia in heart mitochondria of developing rats

Keywords：Propionic acidemia，Propionic acid，Maleic acid，Cardiomyopathy，Mitochondrial functions

关键词：丙酸血症，丙酸，马来酸，心肌病，线粒体功能

作者：Roginski AC, Wajner A, Cecatto Cristiane, Wajner SM, Castilho RF, Wajner M, Amaral Alexandre U 
出版期刊：《BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE》 2020/5/1

Abstract：

Propionic acidemia is caused by lack of propionyl-CoA carboxylase activity. It is biochemically characterized by accumulation of propionic (PA) and 3-hydroxypropionic (3OHPA) acids and clinically by severe encephalopathy and cardiomyopathy. High urinary excretion of maleic acid (MA) and 2-methylcitric acid (2MCA) is also found in the affected patients. Considering that the underlying mechanisms of cardiac disease in propionic acidemia are practically unknown, we investigated the effects of PA, 3OHPA, MA and 2MCA (0.05–5 mM) on important mitochondrial functions in isolated rat heart mitochondria, as well as in crude heart homogenates and  cultured cardiomyocytes. MA markedly inhibited state 3 (ADP-stimulated), state 4 (non-phosphorylating) and uncoupled (CCCP-stimulated) respiration in mitochondria supported by pyruvate plus malate or α-ketoglutarate associated with reduced ATP production, whereas PA and 3OHPA provoked less intense inhibitory effects and 2MCA no alterations at all. MA-induced impaired respiration was attenuated by coenzyme A supplementation. In addition,MA significantly inhibited α-ketoglutarate dehydrogenase activity. Similar data were obtained in heart crude homogenates and permeabilized cardiomyocytes. MA, and PA to a lesser degree, also decreased mitochondrial membrane potential (ΔΨm), NAD(P)H content and Ca2+ retention capacity, and caused swelling in Ca2+-loaded mitochondria. Noteworthy, ΔΨm collapse and mitochondrial swelling were fully prevented or attenuated by cyclosporin A and ADP, indicating the involvement of mitochondrial permeability transition. It is therefore proposed that disturbance of mitochondrial energy and calcium homeostasis caused by MA, as well as by PA and 3OHPA to a lesser extent, may be involved in the cardiomyopathy commonly affecting propionic acidemic
patients.

文章摘要：

丙酸血症是由缺乏丙酰辅酶A羧化酶活性引起的。它的生化特征是丙酸 (PA) 和 3-羟基丙酸 (3OHPA) 酸的积累，临床上表现为严重的脑病和心肌病。在受影响的患者中也发现高尿排泄马来酸 (MA) 和 2-甲基柠檬酸 (2MCA)。考虑到丙酸血症中心脏病的潜在机制实际上是未知的，我们研究了 PA、3OHPA、MA 和 2MCA（0.05-5 mM）对离体大鼠心脏线粒体以及粗心匀浆中重要线粒体功能的影响和培养的心肌细胞。 MA 显着抑制状态 3（ADP 刺激）、状态 4（非磷酸化）和解偶联（CCCP 刺激的）线粒体呼吸由丙酮酸加苹果酸或 α-酮戊二酸支持，与 ATP 产生减少相关，而 PA 和 3OHPA 引起的抑制作用较弱，而 2MCA 完全没有改变。 MA 诱导的呼吸障碍通过补充辅酶 A 减弱。此外，MA显着抑制α-酮戊二酸脱氢酶活性。在心脏粗匀浆和透化心肌细胞中获得了类似的数据。 MA 和 PA 在较小程度上也降低了线粒体膜电位 (ΔΨm)、NAD(P)H 含量和 Ca2+保留能力，并导致负载 Ca2+的肿胀线粒体。值得注意的是，环孢菌素 A 和 ADP 完全阻止或减弱了 ΔΨm 塌陷和线粒体肿胀，表明线粒体通透性转变的参与。因此有人提出，由 MA 以及由 PA 和 3OHPA 在较小程度上引起的线粒体能量和钙稳态紊乱可能与通常影响丙酸血症的心肌病有关。

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