@article{7a19fb9efb014848bc990d98c2cddcd2,
title = "Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes",
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",
author = "Clair Crewe and Funcke, {Jan Bernd} and Shujuan Li and Nolwenn Joffin and Gliniak, {Christy M.} and Ghaben, {Alexandra L.} and An, {Yu A.} and Sadek, {Hesham A.} and Ruth Gordillo and Yucel Akgul and Shiuhwei Chen and Dmitri Samovski and Pamela Fischer-Posovszky and Kusminski, {Christine M.} and Samuel Klein and Scherer, {Philipp E.}",
note = "Funding Information: We thank Charlotte E. Lee and Histology Core at UT Southwestern for assistance in embedding and processing of histological samples. Additionally, we kindly thank the Metabolic Phenotyping Core for mitoB/P measurements, the Proteomics Core for protein identification, the Transgenic Core for their help in the generation of mice, and the Live Cell Imaging Core Facility and Electron Microscopy Core Facility. We thank Shimadzu Scientific Instruments for the collaborative efforts in mass spectrometry technology resources. We also thank Dr. Gerald Shadel for supplying us with the TRE-SOD2 shRNA mouse. We thank Dr. Martin Wabitsch (Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center) for permission to use SGBS cells. The graphical abstract was made using BioRender.com. This study was supported by US National Institutes of Health (NIH) grants R01-DK55758 , R01-DK127274 , R01-DK099110 , RC2 DK118620 , and P01-AG051459 (P.E.S.). C.C. is supported by grant K99DK122019 . J.-B.F. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant 414232833 . Y.A.A. is supported by NIH grant K01-DK125447 . P.F.-P. is supported by a DFG Heisenberg professorship (Fi1700/7-1). Funding Information: We thank Charlotte E. Lee and Histology Core at UT Southwestern for assistance in embedding and processing of histological samples. Additionally, we kindly thank the Metabolic Phenotyping Core for mitoB/P measurements, the Proteomics Core for protein identification, the Transgenic Core for their help in the generation of mice, and the Live Cell Imaging Core Facility and Electron Microscopy Core Facility. We thank Shimadzu Scientific Instruments for the collaborative efforts in mass spectrometry technology resources. We also thank Dr. Gerald Shadel for supplying us with the TRE-SOD2 shRNA mouse. We thank Dr. Martin Wabitsch (Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center) for permission to use SGBS cells. The graphical abstract was made using BioRender.com. This study was supported by US National Institutes of Health (NIH) grants R01-DK55758, R01-DK127274, R01-DK099110, RC2 DK118620, and P01-AG051459 (P.E.S.). C.C. is supported by grant K99DK122019. J.-B.F. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant 414232833. Y.A.A. is supported by NIH grant K01-DK125447. P.F.-P. is supported by a DFG Heisenberg professorship (Fi1700/7-1). C.C. designed and conducted all experiments with the exception of those listed below. J.-B.F. generated the adipo-mitoFlag mouse and assisted in mouse and human cell culture experiments. S.L. and S.C. performed the cardiac IR surgery. S.L. performed echocardiography. N.J. Y.A.A. C.M.G. and C.M.K. assisted in mouse experiments. C.M.G. did mtDNA assays. A.L.G. developed the protein carbonylation assay. H.A.S. provided instrumentation and consultation. R.G. processed and analyzed tissues from the mitoB/P studies. Y.A. provided human adipose tissue for primary adipocyte isolation. S.K. and D.S. provided human plasma and plasma sEVs from MHL, MHO, and MUO groups. P.F.-P. provided SGBS cells. P.E.S. and C.C. analyzed and interpreted the data and wrote the manuscript. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = sep,
day = "7",
doi = "10.1016/j.cmet.2021.08.002",
language = "English (US)",
volume = "33",
pages = "1853--1868.e11",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "9",
}