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血钠升高是心脏中线粒体代谢的一种动态和可逆的调节剂。

Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart.

机构信息

School of Cardiovascular and Metabolic Medicine and Sciences, King's College, London, UK.

School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.

出版信息

Nat Commun. 2024 May 20;15(1):4277. doi: 10.1038/s41467-024-48474-z.

DOI:10.1038/s41467-024-48474-z
PMID:38769288
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11106256/
Abstract

Elevated intracellular sodium Na adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Na decreases Gibb's free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH, which are all reversed on lowering Na to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Na elevation. Elevated Na plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.

摘要

细胞内钠离子浓度升高（Na+）会对线粒体代谢产生不利影响，这是心力衰竭的一个常见特征。在 Langendorff 灌注的大鼠心脏中，使用 Na+/K+-ATP 酶抑制剂哇巴因和肌球蛋白解偶联剂对氨基苯甲脒来维持恒定的能量需求，评估了急性 Na+诱导的代谢变化的可逆性。升高的 Na+降低了 ATP 水解的吉布斯自由能，增加了 TCA 循环中间产物琥珀酸和富马酸，降低了复合物 I、II 和 III 的电子传递链（ETC）活性，并导致 CoQ 向 CoQH 的氧化还原转移，所有这些变化在将 Na+降低到基线水平时都得到逆转。尽管组织氧合正常，但仍观察到假性缺氧和 HIF-1α 的稳定。用 CGP-37517 抑制线粒体 Na+/Ca2+交换或用线粒体 ROS 清除剂 MitoQ 处理可防止 Na+升高期间发生代谢改变。升高的 Na+在代谢和功能变化中起可逆作用，是纠正心力衰竭代谢功能障碍的一个新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/04f1c9e33768/41467_2024_48474_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/525059871244/41467_2024_48474_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/177ffe7b0baf/41467_2024_48474_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/3127399ea8f7/41467_2024_48474_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/e0126c0f2bbd/41467_2024_48474_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/2cd804645a38/41467_2024_48474_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/7a76dca41aad/41467_2024_48474_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/f7e820b3ea67/41467_2024_48474_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/04f1c9e33768/41467_2024_48474_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/525059871244/41467_2024_48474_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/177ffe7b0baf/41467_2024_48474_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/3127399ea8f7/41467_2024_48474_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/e0126c0f2bbd/41467_2024_48474_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/2cd804645a38/41467_2024_48474_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/7a76dca41aad/41467_2024_48474_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/f7e820b3ea67/41467_2024_48474_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d11/11106256/04f1c9e33768/41467_2024_48474_Fig8_HTML.jpg

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