Editors' ChoicePhysiology

Messaging by mitochondria

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Science Signaling  02 Mar 2021:
Vol. 14, Issue 672, eabh2832
DOI: 10.1126/scisignal.abh2832

Intercellular mitochondrial transfer promotes metabolic homeostasis and stimulates wound healing.

Functional mitochondria can be transferred between cells. Two papers identify a role for transfer of mitochondria between two different cell types using distinct mechanisms in separate physiological contexts. Brestoff et al. found that the transfer of mitochondria from adipocytes to resident macrophages in adipose tissue promoted metabolic homeostasis. Bone marrow transfer experiments and the use of mice expressing an adipocyte-specific mitochondrial reporter demonstrated that macrophages acquired and internalized mitochondria from white adipocytes. Compared to macrophages that did not take up mitochondria, those that acquired mitochondria from adipocytes had greater mitochondrial mass, decreased mitochondrial membrane potential, increased ROS production, and a distinct transcriptional profile. A CRISPR-Cas9 knockout screen revealed that ablation of genes encoding enzymes in the heparan sulfate biosynthetic pathway prevented BV2 cells from internalizing isolated mitochondria. Mitochondrial transfer to macrophages from adipocytes was reduced ex vivo and in vivo by diet-induced obesity. Furthermore, mitochondrial uptake and heparan sulfate biosynthesis were reduced in BV2 cells treated with the proinflammatory stimuli IFN-γ and LPS, suggesting that inflammation-associated obesity reduced mitochondrial transfer. The heparan sulfate biosynthetic enzyme Ext1 was required in macrophages for mitochondrial uptake and, compared to control mice, those that lacked Ext1 in macrophages had increased body mass, displayed greater epididymal white adipose mass and adiposity, and showed impaired glucose and insulin tolerance. Thus, mitochondrial transfer from adipocytes to macrophages helps to maintain metabolic homeostasis and this transfer is suppressed by obesity and inflammation.

Mesenchymal stem cells (MSCs) are being explored for tissue repair. Platelet-rich plasma improves the repair capabilities of MSCs, which Levoux et al. found was in part due to mitochondrial transfer from platelets to MSCs. As expected, wound closure in mice mediated by grafted human MSCs was enhanced if the MSCs were grafted with platelets and decreased if the platelets had been pretreated with respiratory chain inhibitors, indicating that functional mitochondria in platelets were required for the beneficial effects of platelets on wound healing. Mitochondrial transfer occurred through a dynamin-dependent, clathrin-mediated endocytic pathway. Mitochondrial transfer from platelets did not affect the differentiation, ability to regulate inflammation, proliferation, or survival of MSCs. Instead, the transferred mitochondria stimulated MSCs to increase the mRNA expression and secretion of the proangiogenic cytokines VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor) in vitro, in vivo, or both, and increased the number of endothelial cells in wounds. This effect was accompanied by an increase in citrate production through the TCA cycle that enhanced de novo fatty acid synthesis. Inhibition of fatty acid synthase prevented platelets from stimulating VEGF and HGF secretion from coincubated MSCs. Conversely, the application of citrate reversed the decreases in VEGF and HGF mRNA expression and secretion, fatty acid synthesis, and wound healing seen when MSCs were incubated with platelets treated with respiratory chain inhibitors. These results demonstrate that mitochondrial transfer from platelets to MSCs contributes to the wound-healing ability of MSCs. Together, these papers illustrate how the transfer of mitochondria constitutes a type of intercellular signaling that promotes homeostatic and repair processes.

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