Isoflavones promote mitochondrial biogenesis
Isoflavones promote mitochondrial biogenesis
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DOI：
10.1124/jpet.107.134882
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
--
作者：
Rasbach, Kyle A.;Schnellmann, Rick G.
线粒体损伤通常是由各种毒性损伤、缺氧或创伤引起的细胞损伤的原因和结果。肾近端小管细胞（RPTC）损伤后线粒体生物发生的增加加速了线粒体和细胞功能的恢复（Biochem Biophys Res Commun 355：734 - 739，2007）。然而，很少有药物是已知的，以增加线粒体生物合成。我们报告，大豆黄酮，染料木素，鹰嘴豆芽素A，芒柄花黄素，3-（2 '，4'-二氯苯基）-7-羟基-4H-色烯-4-酮（DCHC），7-羟基-4H-色烯-4-酮（7- C），4' 7-二甲氧基色烯（4 '，7- D）和5，7，4'-三甲氧基香豆素（5，7，4 '- T）增加的过氧化物酶体增殖物激活受体γ共激活因子（PGC）-1 α表达，并导致线粒体生物合成，如ATP合成酶β和ND 6表达增加，以及RPTC中呼吸和ATP增加1.5倍所示。用ICI 182780（氟维司群）抑制雌激素受体对大豆苷元诱导的线粒体生物合成没有影响。该衍生物对去乙酰化酶（SIRT）1（一种PGC- 1 α的脱乙酰酶和激活剂）的激活和表达表现出不同的影响。大豆黄酮和芒柄花素诱导RPTC中SIRT 1的表达和重组SIRT 1的活化，而DCHC和7- C仅诱导重组SIRT 1的活化。与此相反，染料木黄酮、鹰嘴豆芽素A、4 '，7- D和5，7，4'- T仅增加RPTC中SIRT 1的表达.我们已经鉴定了一系列取代的异黄酮，其通过PGC 1 α和增加的SIRT 1活性和/或表达产生线粒体生物合成，独立于雌激素受体。此外，不同的结构组分负责异黄酮的活性：7位的羟基需要SIRT 1活化，5位的羟基阻断SIRT 1活化，3位苯环或4 '-羟基或-甲氧基取代基的缺失阻断SIRT 1表达增加。
Mitochondrial damage is often both the cause and outcome of cell injury resulting from a variety of toxic insults, hypoxia, or trauma. Increasing mitochondrial biogenesis after renal proximal tubular cell ( RPTC) injury accelerated the recovery of mitochondrial and cellular functions ( Biochem Biophys Res Commun 355: 734 - 739, 2007). However, few pharmacological agents are known to increase mitochondrial biogenesis. We report that daidzein, genistein, biochanin A, formononetin, 3-(2', 4'- dichlorophenyl)- 7- hydroxy- 4H- chromen- 4- one ( DCHC), 7- hydroxy- 4H- chromen- 4- one ( 7- C), 4' 7- dimethoxyisoflavone ( 4', 7- D), and 5,7,4'- trimethoxyisoflavone ( 5,7,4 '- T) increased peroxisome proliferator- activated receptor gamma coactivator ( PGC)- 1 alpha expression and resulted in mitochondrial biogenesis as indicated by increased expression of ATP synthase beta and ND6, and 1.5- fold increases in respiration and ATP in RPTC. Inhibition of estrogen receptors with ICI182780 ( fulvestrant) had no effect on daidzein- induced mitochondrial biogenesis. The isoflavone derivatives showed differential effects on the activation and expression of sirtuin ( SIRT) 1, a deacetylase and activator of PGC- 1 alpha. Daidzein and formononetin induced the expression of SIRT1 in RPTC and the activation of recombinant SIRT1, whereas DCHC and 7- C only induced the activation of recombinant SIRT1. In contrast, genistein, biochanin A, 4 ', 7- D, and 5,7,4 '- T only increased SIRT1 expression in RPTC. We have identified a series of substituted isoflavones that produce mitochondrial biogenesis through PGC1 alpha and increased SIRT1 activity and/or expression, independently of the estrogen receptor. Furthermore, different structural components are responsible for the activities of isoflavones: the hydroxyl group at position 7 is required SIRT1 activation, a hydroxyl group at position 5 blocks SIRT1 activation, and the loss of the phenyl ring at position 3 or the 4 '- hydroxy or - methoxy substituent blocks increased SIRT1 expression.