Isoflavones promote mitochondrial biogenesis

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.