线粒体NADPH为线粒体脂肪酸合成和脂酰化提供燃料，为氧化代谢提供动力，这一成果由德克萨斯大学Gerta Hoxhaj课题组经过不懈努力而取得。这一研究成果于2025年4月21日发表在国际顶尖学术期刊《自然—细胞生物学》上。

在这里，研究人员证明了NAD⁺激酶2 (NADK2)，负责线粒体NADPH产生的主要酶，对于维持蛋白质脂酰化至关重要，这是一种保守的脂质修饰，是多种线粒体酶复合物（包括丙酮酸脱氢酶复合物）的最佳活性所必需的。线粒体脂肪酸合成（mtFAS）途径利用NADPH生成蛋白质结合的酰基，包括硫辛酸。通过开发一种基于质谱的方法来评估哺乳动物mtFAS，小组发现NADK2对mtFAS活性至关重要。NADK2缺乏损害mtFAS相关过程，导致细胞呼吸和线粒体翻译减少。他们的发现支持了一个模型，即线粒体NADPH为mtFAS途径提供燃料，从而维持蛋白质脂酰化和线粒体氧化代谢。

据悉，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）是大分子生物合成和抗氧化应激所必需的重要电子供体。虽然NADPH在细胞质和线粒体内被区隔，但线粒体NADPH的具体功能在很大程度上仍未被探索。

附：英文原文

Title: Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism

Author: Kim, Dohun, Kesavan, Rushendhiran, Ryu, Kevin, Dey, Trishna, Marckx, Austin, Menezes, Cameron, Praharaj, Prakash P., Morley, Stewart, Ko, Bookyong, Soflaee, Mona H., Tom, Harrison J., Brown, Harrison, Vu, Hieu S., Tso, Shih-Chia, Brautigam, Chad A., Lemoff, Andrew, Mettlen, Marcel, Mishra, Prashant, Cai, Feng, Allen, Doug K., Hoxhaj, Gerta

Issue&Volume: 2025-04-21

Abstract: Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.

DOI: 10.1038/s41556-025-01655-4

Source: https://www.nature.com/articles/s41556-025-01655-4