17β-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle

Maria J. Torres, Kim A. Kew, Terence E. Ryan, Edward Ross Pennington, Chien Te Lin, Katherine A. Buddo, Amy M. Fix, Cheryl A. Smith, Laura A. Gilliam, Sira Karvinen, Dawn A. Lowe, Espen E. Spangenburg, Tonya N. Zeczycki, Saame Raza Shaikh, P. Darrell Neufer

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Abstract

Menopause results in a progressive decline in 17β-estradiol (E2) levels, increased adiposity, decreased insulin sensitivity, and a higher risk for type 2 diabetes. Estrogen therapies can help reverse these effects, but the mechanism(s) by which E2 modulates susceptibility to metabolic disease is not well understood. In young C57BL/6N mice, short-term ovariectomy decreased—whereas E2 therapy restored—mitochondrial respiratory function, cellular redox state (GSH/GSSG), and insulin sensitivity in skeletal muscle. E2 was detected by liquid chromatography-mass spectrometry in mitochondrial membranes and varied according to whole-body E2 status independently of ERα. Loss of E2 increased mitochondrial membrane microviscosity and H2O2 emitting potential, whereas E2 administration in vivo and in vitro restored membrane E2 content, microviscosity, complex I and I + III activities, H2O2 emitting potential, and submaximal OXPHOS responsiveness. These findings demonstrate that E2 directly modulates membrane biophysical properties and bioenergetic function in mitochondria, offering a direct mechanism by which E2 status broadly influences energy homeostasis. Loss of estrogen from menopause increases the risk of developing metabolic diseases. Torres et al. show that 17β-estradiol (E2) localizes to mitochondrial membranes consistent with whole-body E2 status. The presence of E2 decreases microviscosity, which improves bioenergetic function, thus offering a biophysical mechanism by which E2 influences energy homeostasis.

Original languageEnglish (US)
Pages (from-to)167-179.e7
JournalCell Metabolism
Volume27
Issue number1
DOIs
StatePublished - Jan 9 2018

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Keywords

  • estrogen
  • hormone replacement therapy
  • hydrogen peroxide
  • insulin resistance
  • membrane viscosity
  • menopause
  • mitochondria
  • ovariectomy

Cite this

Torres, M. J., Kew, K. A., Ryan, T. E., Pennington, E. R., Lin, C. T., Buddo, K. A., Fix, A. M., Smith, C. A., Gilliam, L. A., Karvinen, S., Lowe, D. A., Spangenburg, E. E., Zeczycki, T. N., Shaikh, S. R., & Neufer, P. D. (2018). 17β-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle. Cell Metabolism, 27(1), 167-179.e7. https://doi.org/10.1016/j.cmet.2017.10.003