Globular CTRP3 promotes mitochondrial biogenesis in cardiomyocytes through AMPK/PGC-1 alpha pathway
Globular CTRP3 promotes mitochondrial biogenesis in cardiomyocytes through AMPK/PGC-1 alpha pathway
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球状 CTRP3 通过 AMPK/PGC-1α 途径促进心肌细胞线粒体生物发生
DOI：
10.1016/j.bbagen.2016.10.022
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发表时间：
2017
影响因子：
3
通讯作者：
Wu Li-Ling
中科院分区：
文献类型：
--
作者：
Zhang Cheng-Lin;Feng Han;Li Li;Wang Jin-Yu;Wu Dan;Hao Yan-Ting;Wang Zheng;Zhang Yan;Wu Li-Ling
背景线粒体的生物合成对于维持线粒体功能和细胞内环境的稳定至关重要。C1 q/肿瘤坏死因子相关蛋白3（CTRP 3）是一种脂肪因子，在代谢和心血管疾病中具有多种功能。然而，CTRP 3是否影响心肌细胞线粒体生物合成仍然未知。MethodsNeonatal大鼠心室肌细胞培养和治疗与球状CTRP 3（gCTRP 3）。实时荧光定量PCR和Western blot分析线粒体生物合成相关基因的表达。通过透射电子显微镜评估线粒体形态。结果gCTRP 3可增加过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）、核呼吸因子1（NRF-1）、核呼吸因子2（NRF-2）、线粒体转录因子A（TFAM）、细胞色素B、氧化磷酸化复合物III和V的表达，增加线粒体嵴成分和OCR。此外，gCTRP 3还能增加线粒体DNA拷贝数和ATP含量，而PGC-1α的敲低可抑制gCTRP 3的诱导作用。gCTRP 3增加AMP活化蛋白激酶（AMPK）的磷酸化，而AMPK抑制剂腺嘌呤9-β-d-阿拉伯呋喃糖苷（AraA）减弱gCTRP 3介导的NRF-1、TFAM以及复合物III和V的诱导。gCTRP 3增加sirtuin 1的表达和活性，而EX-527抑制sirtuin 1减弱gCTRP 3诱导的反应。同时，AraA减弱了gCTRP 3介导的sirtuin 1激活。结论CTRP 3通过AMPK/PGC-1α途径促进心肌细胞线粒体生物合成，具有重要意义CTRP 3是线粒体生物合成的内源性调节剂，可能通过改善线粒体功能障碍来保护心肌细胞。
BackgroundMitochondrial biogenesis is crucial for the maintenance of mitochondrial function and cellular homeostasis. C1q/tumor necrosis factor-related protein-3 (CTRP3) is an adipokine that owns multiple functions on metabolic and cardiovascular diseases. However, whether CTRP3 affects mitochondrial biogenesis in cardiomyocytes remains unknown.MethodsNeonatal rat ventricular myocytes were cultured and treated with globular CTRP3 (gCTRP3). The expression of mitochondrial biogenesis related genes was measured by real-time PCR and western blot analysis. Mitochondrial morphology was assessed by a transmission electron microscope. ATP content, oxygen consumption rate (OCR), and sirtuin1 activity were measured with commercial kits.ResultsgCTRP3 increased the expression of peroxisome proliferators activated receptor-γ co-activator-1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), NRF-2, mitochondrial transcription factor A (TFAM), cytochrome B, and oxidative phosphorylation complexes III and V, and increased mitochondrial cristae components and OCR. Additionally, gCTRP3 enhanced mitochondrial DNA copy number and ATP content, while the induction was inhibited by knockdown of PGC-1αviasmall interfering RNA. gCTRP3 increased phosphorylation of AMP-activated protein kinase (AMPK), whereas adenine 9-β-d-arabinofuranoside (AraA), an AMPK inhibitor, attenuated gCTRP3-mediated induction of NRF-1, TFAM, and complexes III and V. gCTRP3 increased both the expression and activity of sirtuin1, whereas inhibition of sirtuin1 by EX-527 attenuated gCTRP3-induced responses. Meanwhile, gCTRP3-mediated activation of sirtuin1 was attenuated by AraA. Moreover, gCTRP3 restored the reduction of sirtuin1, PGC-1α, NRF-1, complex III and ATP content induced by hypoxia-reoxygenation injury.ConclusionCTRP3 promotes mitochondrial biogenesis in cardiomyocytesviaAMPK/PGC-1α pathway.General significanceCTRP3 is an endogenous modulator for mitochondrial biogenesis, and may protect cardiomyocytes by ameliorating mitochondrial dysfunction.