Dietary lipids inhibit mitochondria transfer to macrophages to divert adipocyte-derived mitochondria into the blood.

Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.

Mitochondria Transfer to CD4+ T Cells May Alleviate Rheumatoid Arthritis by Suppressing Pro-Inflammatory Cytokine Production.

CD4+ T cells contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). These cells infiltrate the joints of RA patients and produce cytokines, including Tumor necrosis factor (TNF)-α, that drive joint inflammation and bone destruction. Although biologic therapeutics targeting T cells and TNF-α have benefited patients suffering from RA, some patients are refractory to these therapies, develop antibodies that neutralize these biologics, or develop undesirable side effects. Recent studies indicate that CD4+ T cell cytokine production is regulated in part by specific metabolic modules, suggesting that immunometabolic pathways could represent a novel therapeutic strategy for T cell-mediated diseases such as RA. Wu et al. (2021) demonstrate that mitochondrial function is impaired in CD4+ T cells from RA patients, leading to reduced levels of various citric acid cycle metabolites (e.g., aspartate) that regulate TNF-α production. Treatment of RA-associated T cells with purified mitochondria was sufficient to restore these metabolic defects, limit production of numerous pro-inflammatory cytokines such as TNF-α and IL-17A, and reduce the development of RA-like disease in a humanized mouse model. These data suggest that T cells can be metabolically "re-engineered" ex vivo with exogenous mitochondria and that this mitochondria transfer approach confers anti-inflammatory properties that may reduce disease severity in RA and possibly other rheumatologic diseases. Increasing our understanding of how intercellular mitochondria transfer occurs may identify novel biological pathways that can be targeted therapeutically or harnessed to support cell engineering.

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.

Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.