发育中大鼠心脏线粒体丙酸血症累积的代谢产物引起的生物能学和钙稳态的紊乱。,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

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发育中大鼠心脏线粒体丙酸血症累积的代谢产物引起的生物能学和钙稳态的紊乱。
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.bbadis.2020.165682
Ana Cristina Roginski ₁ , Alessandro Wajner ₁ , Cristiane Cecatto ₁ , Simone Magagnin Wajner ₂ , Roger Frigério Castilho ₃ , Moacir Wajner ₄ , Alexandre Umpierrez Amaral ₅

Affiliation

丙酸血症是由丙酰辅酶A羧化酶活性不足引起的。它的生化特征是丙酸（PA）和3-羟基丙酸（3OHPA）酸的积累，临床上的特征是严重的脑病和心肌病。在受影响的患者中还发现了马来酸（MA）和2-甲基柠檬酸（2MCA）的高尿排泄物。考虑到丙酸血症中心脏病的潜在机制实际上未知，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脏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），丙酮酸加苹果酸或α-酮戊二酸支持的线粒体中的第4种状态（非磷酸化）和非耦合（CCCP刺激）呼吸与ATP产生减少有关，而PA和3OHPA引起的抑制作用较弱，而2MCA则完全没有改变。辅酶A补充剂减弱了MA诱导的呼吸功能减弱。另外，MA显着抑制α-酮戊二酸脱氢酶活性。在心脏粗匀浆和透化的心肌细胞中获得了相似的数据。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，并导致装载Ca2 +的线粒体肿胀。值得注意的是，环孢菌素A和ADP完全防止或减弱了ΔΨm塌陷和线粒体肿胀，表明线粒体通透性转变参与。因此，有人提出，由MA以及较小程度地由PA和3OHPA引起的线粒体能量和钙稳态的紊乱可能与通常影响丙酸血症患者的心肌病有关。

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Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats.

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.

更新日期：2020-01-10

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