Mitovesicles are a novel population of extracellular vesicles of mitochondrial origin altered in Down syndrome

  • Sci Adv. 2021 Feb 12;7(7):eabe5085. doi: 10.1126/sciadv.abe5085.
Pasquale D'Acunzo  1  2 ,  Rocío Pérez-González  1  2 ,  Yohan Kim  1  2 ,  Tal Hargash  1 ,  Chelsea Miller  1 ,  Melissa J Alldred  1  2 ,  Hediye Erdjument-Bromage  3  4 ,  Sai C Penikalapati  1 ,  Monika Pawlik  1 ,  Mitsuo Saito  2  5 ,  Mariko Saito  2  6 ,  Stephen D Ginsberg  1  2  7  8 ,  Thomas A Neubert  3  4 ,  Chris N Goulbourne  1 ,  Efrat Levy  9  2  7  10
Affiliations
  • 1. Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
  • 2. Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
  • 3. Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
  • 4. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
  • 5. Division of Analytical Psychopharmacology, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
  • 6. Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
  • 7. NYU Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA.
  • 8. Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA.
  • 9. Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. [email protected].
  • 10. Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
PMID: 33579698 DOI: 10.1126/sciadv.abe5085
Abstract

Mitochondrial dysfunction is an established hallmark of aging and neurodegenerative disorders such as Down syndrome (DS) and Alzheimer's Disease (AD). Using a high-resolution density gradient separation of extracellular vesicles (EVs) isolated from murine and human DS and diploid control Brains, we identify and characterize a previously unknown population of double-membraned EVs containing multiple mitochondrial proteins distinct from previously described EV subtypes, including microvesicles and Exosomes. We term these newly identified mitochondria-derived EVs "mitovesicles." We demonstrate that brain-derived mitovesicles contain a specific subset of mitochondrial constituents and that their levels and cargo are altered during pathophysiological processes where mitochondrial dysfunction occurs, including in DS. The development of a method for the selective isolation of mitovesicles paves the way for the characterization in vivo of biological processes connecting EV biology and mitochondria dynamics and for innovative therapeutic and diagnostic strategies.