Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes

  • Cell Metab. 2021 Sep 7;33(9):1853-1868.e11. doi: 10.1016/j.cmet.2021.08.002.
Clair Crewe  1 ,  Jan-Bernd Funcke  1 ,  Shujuan Li  2 ,  Nolwenn Joffin  1 ,  Christy M Gliniak  1 ,  Alexandra L Ghaben  1 ,  Yu A An  1 ,  Hesham A Sadek  3 ,  Ruth Gordillo  1 ,  Yucel Akgul  4 ,  Shiuhwei Chen  1 ,  Dmitri Samovski  5 ,  Pamela Fischer-Posovszky  6 ,  Christine M Kusminski  1 ,  Samuel Klein  5 ,  Philipp E Scherer  7
Affiliations
  • 1. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatric Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4. Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5. Center for Human Nutrition and the Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 6. Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89075 Ulm, Germany.
  • 7. Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected].
PMID: 34418352 DOI: 10.1016/j.cmet.2021.08.002
Abstract

Adipocytes undergo intense energetic stress in Obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by Obesity.

Keywords
adipocyte; cardiovascular disease; diabetes; exosomes; extracellular vesicles; mitochondria; mitochondrial dysfunction; mitohormesis; obesity; stress response.