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)-1alpha 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-1alpha. 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 PGC1alpha 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.
Rasbach
Kyle A
KA
Medical University of South Carolina, Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, 280 Calhoun St., P.O. Box 250140, Charleston, SC 29425, USA.
Schnellmann
Rick G
RG
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007529:Isoflavones / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D010101:Oxygen Consumption; D016601:RNA-Binding Proteins / Q000378:metabolism; D011817:Rabbits; D037761:Sirtuins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D007529:Isoflavones; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D037761:Sirtuins; D025261:Mitochondrial Proton-Translocating ATPases