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

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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

Bibliographical note

Funding Information:
We would like to acknowledge SCIEX application specialist Robert Proos (Framingham, MA), for his help on further validation of MS/MS data and analysis. This work was supported by U.S. Public Health Services grants R01 HL123647 , R01 AT008375 (S.R.S.), ADA BS-1-15-170 (E.E.S.), R01 AG031743 (D.A.L), and R01 DK096907 and R01 DK110656 (P.D.N.).

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

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

Fingerprint

Dive into the research topics of '17β-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle'. Together they form a unique fingerprint.

Cite this