Modulatory Effect of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) on the 2-Oxoglutarate Mitochondrial Carrier.

IF 4.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecules Pub Date : 2024-10-31 DOI:10.3390/molecules29215154

Anna Spagnoletta, Daniela Valeria Miniero, Nicola Gambacorta, Francesca Oppedisano, Anna De Grassi, Orazio Nicolotti, Ciro Leonardo Pierri, Annalisa De Palma

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Abstract

The 2-oxoglutarate carrier (OGC), pivotal in cellular metabolism, facilitates the exchange of key metabolites between mitochondria and cytosol. This study explores the influence of NADPH on OGC transport activity using proteoliposomes. Experimental data revealed the ability of NADPH to modulate the OGC activity, with a significant increase of 60% at 0.010 mM. Kinetic analysis showed increased Vmax and a reduction in Km for 2-oxoglutarate, suggesting a direct regulatory role. Molecular docking pointed to a specific interaction between NADPH and cytosolic loops of OGC, involving key residues such as K206 and K122. This modulation was unique in mammalian OGC, as no similar effect was observed in a plant OGC structurally/functionally related mitochondrial carrier. These findings propose OGC as a responsive sensor for the mitochondrial redox state, coordinating with the malate/aspartate and isocitrate/oxoglutarate shuttles to maintain redox balance. The results underscore the potential role of OGC in redox homeostasis and its broader implications in cellular metabolism and oxidative stress responses.

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烟酰胺腺嘌呤二核苷酸磷酸（NADPH）对 2-氧代谷氨酸线粒体载体的调节作用。

2-氧代戊二酸载体（OGC）在细胞代谢中举足轻重，它促进了线粒体和细胞质之间关键代谢物的交换。本研究利用蛋白脂质体探讨了 NADPH 对 OGC 转运活性的影响。实验数据显示，NADPH 能够调节 OGC 的活性，在 0.010 mM 时，OGC 活性显著增加 60%。动力学分析表明，2-氧代戊二酸的 Vmax 增加了，Km 降低了，这表明 NADPH 起着直接调控作用。分子对接表明，NADPH 与 OGC 的细胞膜环之间存在特定的相互作用，涉及 K206 和 K122 等关键残基。这种调节作用在哺乳动物的 OGC 中是独一无二的，因为在结构/功能相关的植物线粒体载体 OGC 中没有观察到类似的效应。这些研究结果表明，OGC 是线粒体氧化还原状态的反应传感器，它与苹果酸/天门冬氨酸和异柠檬酸/氧谷氨酸穿梭器协调以维持氧化还原平衡。这些结果强调了 OGC 在氧化还原平衡中的潜在作用及其在细胞代谢和氧化应激反应中的广泛影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecules 化学-有机化学

CiteScore

7.40

自引率

8.70%

发文量

7524

审稿时长

1.4 months

期刊介绍： Molecules (ISSN 1420-3049, CODEN: MOLEFW) is an open access journal of synthetic organic chemistry and natural product chemistry. All articles are peer-reviewed and published continously upon acceptance. Molecules is published by MDPI, Basel, Switzerland. Our aim is to encourage chemists to publish as much as possible their experimental detail, particularly synthetic procedures and characterization information. There is no restriction on the length of the experimental section. In addition, availability of compound samples is published and considered as important information. Authors are encouraged to register or deposit their chemical samples through the non-profit international organization Molecular Diversity Preservation International (MDPI). Molecules has been launched in 1996 to preserve and exploit molecular diversity of both, chemical information and chemical substances.