Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity

• Published in: Cell metabolism Vol. 33; no. 2; pp. 270 - 282.e8
• Main Authors: Brestoff, Jonathan R., Wilen, Craig B., Moley, John R., Li, Yongjia, Zou, Wei, Malvin, Nicole P., Rowen, Marina N., Saunders, Brian T., Ma, Hongming, Mack, Madison R., Hykes, Barry L., Balce, Dale R., Orvedahl, Anthony, Williams, Jesse W., Rohatgi, Nidhi, Wang, Xiaoyan, McAllaster, Michael R., Handley, Scott A., Kim, Brian S., Doench, John G., Zinselmeyer, Bernd H., Diamond, Michael S., Virgin, Herbert W., Gelman, Andrew E., Teitelbaum, Steven L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.02.2021
• Subjects: Adipose Tissue, White - metabolism; Animals; beige adipose tissue; brown adipose tissue; Homeostasis; horizontal mitochondria transfer; immunometabolism; intercellular mitochondria transfer; macrophage; Macrophages - metabolism; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; mitochondria; Mitochondria - metabolism; obesity; Obesity - metabolism; white adipose tissue; intercellular mitochondria transfer; beige adipose tissue; white adipose tissue; brown adipose tissue; immunometabolism; mitochondria; macrophage; metabolism; obesity; horizontal mitochondria transfer
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.11.008

Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity. [Display omitted] •Adipocytes transfer their mitochondria to macrophages in vivo•Mitochondria transfer from adipocytes to macrophages is decreased in obesity•Mitochondria uptake by macrophages is mediated by heparan sulfates•Mice that lack heparan sulfates on macrophages exhibit metabolic dysfunction Brestoff et al. show that adipose-tissue-resident macrophages acquire mitochondria from neighboring adipocytes in a heparan-sulfate-dependent process that is impaired in obesity. Genetic disruption of mitochondria uptake by macrophages reduces energy expenditure and exacerbates diet-induced obesity in mice, indicating that intercellular mitochondria transfer to macrophages mediates systemic metabolic homeostasis.