Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure

• Jakob D Wikstrom ^[1] ; Kiana Mahdaviani ^[2] ; Marc Liesa ^[2] ; Samuel B Sereda ^[2] ; Yaguang Si ^[2] ; Guy Las ^[4] ; Gilad Twig ^[1] ; Natasa Petrovic ^[5] ; Cristina Zingaretti ^[6] ; Adam Graham ^[3] ; Saverio Cinti ^[6] ; Barbara E Corkey ^[2] ; Barbara Cannon ^[5] ; Jan Nedergaard ^[5] ; Orian S Shirihai ^[4]
  1. [1] Boston University

     Boston University

     City of Boston, Estados Unidos

     
  2. [2] Boston University School of Medicine

     Boston University School of Medicine

     City of Boston, Estados Unidos

     
  3. [3] Harvard University

     Harvard University

     City of Cambridge, Estados Unidos

     
  4. [4] 1 Department of Medicine, Boston University School of Medicine Boston, MA, USA; 3 Department of Clinical Biochemistry, Faculty of Medicine, Ben Gurion University of the Negev Beer-Sheva, Israel
  5. [5] 2 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University Stockholm, Sweden
  6. [6] 5 Department of Experimental and Clinical Medicine, University of Ancona Ancona, Italy

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 33, Nº. 5, 2014, págs. 418-436
• Idioma: inglés
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• Resumen

  • Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.