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Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure

机译:线粒体转氢酶的逆转导致心力衰竭的氧化应激

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Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.
机译:线粒体活性氧(ROS)在大多数与衰老相关的疾病中起着核心作用。 ROS在呼吸链上产生,需要NADH进行电子传输,并被需要NADPH的酶消除。烟酰胺核苷酸转氢酶(Nnt)基于其从NADH再生NADPH的能力而被认为是关键的抗氧化酶。在这里,我们表明病理性代谢需求逆转了Nnt的方向,消耗了NADPH以支持NADH和ATP的生产,但是却以NADPH相关的抗氧化能力为代价。在心脏方面,在压力过载期间,反向模式Nnt是ROS的主要来源。由于Nnt基因的突变,近交小鼠品系C57BL / 6J被保护免受氧化应激,心力衰竭和死亡的困扰,这使其在心血管研究中的应用出现了问题。用四肽SS-31靶向Nnt介导的ROS可以挽救压力超负荷引起的心力衰竭的死亡率,因此对患有这种综合征的患者具有治疗潜力。

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