Department of Membrane Biochemistry, Institute of Animal Biochemistry and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Bratislava, Slovakia.
Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.
Biochim Biophys Acta Bioenerg. 2024 Nov 1;1865(4):149501. doi: 10.1016/j.bbabio.2024.149501. Epub 2024 Jul 29.
A mood-stabilizing anticonvulsant valproic acid (VPA) is a drug with a pleiotropic effect on cells. Here, we describe the impact of VPA on the metabolic function of human HAP1 cells. We show that VPA altered the biosynthetic pathway of cardiolipin (CL) and affected the activities of mitochondrial enzymes such as pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and NADH dehydrogenase. We demonstrate that a therapeutic dose of VPA (0.6 mM) has a harmful effect on cell growth and increases the production of reactive oxygen species and superoxides. On the contrary, less concentrated VPA (0.06 mM) increased the activities of CL-dependent enzymes leading to an increased level of oxidative phosphorylation and ATP production. The effect of VPA was also tested on the Barth syndrome model, which is characterized by a reduced amount of CL and an increased level of monolyso-CL. In this model, VPA treatment slightly attenuated the mitochondrial defects by altering the activities of CL-dependent enzymes. However, the presence of CL was essential for the increase in ATP production by VPA. Our findings highlight the potential therapeutic role of VPA in normalizing mitochondrial function in BTHS and shed light on the intricate interplay between lipid metabolism and mitochondrial physiology in health and disease. SUMMARY: This study investigates the dose-dependent effect of valproate, a mood-stabilizing drug, on mitochondrial function. The therapeutic concentration reduced overall cellular metabolic activity, while a subtherapeutic concentration notably improved the function of cardiolipin-dependent proteins within mitochondria. These findings shed light on novel aspects of valproate's effect and suggest potential practical applications for its use. By elucidating the differential effects of valproate doses on mitochondrial activity, this research underscores the drug's multifaceted role in cellular metabolism and highlights avenues for further exploration in therapeutic interventions.
一种稳定情绪的抗惊厥药丙戊酸（VPA）对细胞具有多效作用。在这里，我们描述了 VPA 对人 HAP1 细胞代谢功能的影响。我们表明，VPA 改变了心磷脂（CL）的生物合成途径，并影响了丙酮酸脱氢酶、α-酮戊二酸脱氢酶和 NADH 脱氢酶等线粒体酶的活性。我们证明，治疗剂量的 VPA（0.6 mM）对细胞生长有有害影响，并增加活性氧和超氧化物的产生。相反，浓度较低的 VPA（0.06 mM）增加了 CL 依赖性酶的活性，导致氧化磷酸化和 ATP 产生水平增加。还在 Barth 综合征模型中测试了 VPA 的作用，该模型的特征是 CL 含量减少和单酰基-CL 水平增加。在该模型中，VPA 治疗通过改变 CL 依赖性酶的活性轻微减弱了线粒体缺陷。然而，CL 的存在对于 VPA 增加 ATP 产生是必不可少的。我们的研究结果强调了 VPA 在正常化 Barth 综合征中线粒体功能方面的潜在治疗作用，并阐明了在健康和疾病中脂质代谢和线粒体生理学之间复杂的相互作用。
本研究调查了丙戊酸（一种稳定情绪的药物）对线粒体功能的剂量依赖性影响。治疗浓度降低了整体细胞代谢活性，而亚治疗浓度显著改善了线粒体中心磷脂依赖性蛋白的功能。这些发现揭示了丙戊酸作用的新方面，并为其在治疗中的潜在应用提供了依据。通过阐明丙戊酸剂量对线粒体活性的不同影响，本研究强调了该药物在细胞代谢中的多效作用，并突出了在治疗干预中进一步探索的途径。
