Effect of soluble nickel on cellular energy metabolism in A549 cells
Effect of soluble nickel on cellular energy metabolism in A549 cells
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DOI：
10.1177/153537020623100905
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发表时间：
2006-10-01
影响因子：
3.2
通讯作者：
Costa, Max
中科院分区：
文献类型：
--
作者：
Chen, Haobin;Costa, Max
铁是大多数生物体的必需营养素，并且积极参与氧气输送，电子传递，DNA合成和许多其他对细胞存活重要的生化反应。我们先前报道了镍（NI）离子暴露降低A549细胞中的细胞铁水平并将胞质乌头酸酶（c-乌头酸酶）转化为铁调节蛋白-1（Chen H，Davidson T，Singleton S，Garrick MD，Costa M. Toxicol Appl Pharmacol 206：275-287，2005）。在此，我们进一步研究了镍离子暴露对线粒体铁硫（Fe-S）酶活性和细胞能量代谢的影响。我们发现，急性镍离子处理高达1毫米表现出最小的毒性在A549细胞。Ni离子处理降低了与细胞能量代谢相关的几种Fe-S酶的活性，包括线粒体乌头酸酶（m-乌头酸酶）、琥珀酸脱氢酶（SDH）和NADH：泛醌氧化还原酶（复合物1）。低剂量Ni离子处理4周后，细胞糖酵解和NADH/NAD（+）（NADH/NAD（+））比值增加，但高剂量Ni离子处理抑制糖酵解。总的来说，我们的研究结果表明，镍离子降低细胞含铁（Fe）的酶的活性，抑制氧化磷酸化（OxPhos），并增加细胞的糖酵解活性。由于糖酵解增加是癌细胞能量代谢的根本改变之一（瓦尔堡效应），因此镍离子引起的Fe-S酶的抑制和随后的细胞能量代谢变化可能在镍致癌作用中起重要作用。
Iron is an essential nutrient to most organisms, and is actively involved in oxygen delivery, electron transport, DNA synthesis, and many other biochemical reactions important for cell survival. We previously reported that nickel (NI) ion exposure decreases cellular iron level and converts cytosolic aconitase (c-aconitase) to iron-regulatory protein-1 in A549 cells (Chen H, Davidson T, Singleton S, Garrick MD, Costa M. Toxicol Appl Pharmacol 206:275-287, 2005). Here, we further investigated the effect of Ni ion exposure on the activity of mitochondrial iron-sulfur (Fe-S) enzymes and cellular energy metabolism. We found that acute Ni ion treatment up to 1 mM exhibits minimal toxicity in A549 cells. Ni ion treatment decreases the activity of several Fe-S enzymes related to cellular energy metabolism, including mitochondrial aconitase (m-aconitase), succinate dehydrogenase (SDH), and NADH:ubiquinone oxidoreductase (complex 1). Low doses of Ni ion for 4 weeks resulted in an increased cellular glycolysis and NADH to NAD(+) (NADH/NAD(+)) ratio, although glycolysis was inhibited at higher levels. Collectively, our results show that Ni ions decrease the activity of cellular iron (Fe)-containing enzymes, inhibit oxidative phosphorylation (OxPhos), and increase cellular glycolytic activity. Since increased glycolysis is one of the fundamental alterations of energy metabolism in cancer cells (the Warburg effect), the inhibition of Fe-S enzymes and subsequent changes in cellular energy metabolism caused by Ni ions may play an important role in Ni carcinogenesis.