Transgenic Control of Mitochondrial Fission Induces Mitochondrial Uncoupling and Relieves Diabetic Oxidative Stress

  1. Yisang Yoon1,2,6
  1. 1Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
  2. 2Mitochondrial Research and Innovation Group, University of Rochester School of Medicine and Dentistry, Rochester, New York
  3. 3Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York
  4. 4Center for Oral Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York
  5. 5James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York
  6. 6Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
  1. Corresponding author: Yisang Yoon, yyoon{at}georgiahealth.edu.
  1. C.A.G. and H.L. contributed equally to this work.

Abstract

Mitochondria are the essential eukaryotic organelles that produce most cellular energy. The energy production and supply by mitochondria appear closely associated with the continuous shape change of mitochondria mediated by fission and fusion, as evidenced not only by the hereditary diseases caused by mutations in fission/fusion genes but also by aberrant mitochondrial morphologies associated with numerous pathologic insults. However, how morphological change of mitochondria is linked to their energy-producing activity is poorly understood. In this study, we found that perturbation of mitochondrial fission induces a unique mitochondrial uncoupling phenomenon through a large-scale fluctuation of a mitochondrial inner membrane potential. Furthermore, by genetically controlling mitochondrial fission and thereby inducing mild proton leak in mice, we were able to relieve these mice from oxidative stress in a hyperglycemic model. These findings provide mechanistic insight into how mitochondrial fission participates in regulating mitochondrial activity. In addition, these results suggest a potential application of mitochondrial fission to control mitochondrial reactive oxygen species production and oxidative stress in many human diseases.

Footnotes

  • H.L. and Y.Y. are currently affiliated with the Department of Physiology, Georgia Health Sciences University, Augusta, Georgia.

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1640/-/DC1.

  • See accompanying commentary, p. 1915.

  • B.S.J. is currently affiliated with the Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.

  • T.Y. is currently affiliated with Alfaisal University College of Medicine, Riyadh, Kingdom of Saudi Arabia.

  • Received November 27, 2011.
  • Accepted March 10, 2012.

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  1. Diabetes vol. 61 no. 8 2093-2104
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