https://orcid.org/0000-0002-5494-589X
Key Points
Traumatically injured brains release metabolically aberrant extracellular mitochondria that are endocytosed by endothelial cells.
These extracellular mitochondria induce intracellular oxidative stress and apoptosis of endothelial cells.
Traumatic brain injury (TBI) causes endothelial injuries both at the site of injury and in remote regions of the brain. TBI-induced endotheliopathy also disseminates to extracranial organs, such as the lungs. This TBI-induced systemic endotheliopathy has been extensively reported in clinical studies, but its underlying mechanism remains poorly understood. Here we report results from a study designed to investigate the role of extracellular mitochondria (exMt) in TBI-induced endotheliopathy. We showed that exMt are released from injured brains into the circulation, reaching a maximal level of 1.8x104/µl at 3 hours after mice were subjected to severe TBI. These exMt express peroxidized cardiolipin on their surface and generate significant amounts of reactive oxygen species, but they produce less ATP compared to intracellular mitochondria of normal cells. When infused into non-injured mice, exMt induce systemic endotheliopathy defined by increased endothelial permeability, tissue edema, and perivascular bleeding. We further demonstrated that endothelial cells endocytose exMt through the lipid-scavenging receptor CD36 and dynamin-driven clathrin-mediated pathway. The endocytosed exMt interacted with the endoplasmic reticulum (ER) of ECs through newly formed mitochondria-associated membrane, leading to intracellular ER stress and resultant apoptosis. This study delineates a new pathway of exMt-induced endotheliopathy during acute TBI. It also demonstrates a causal role of exMt in endothelial injuries associated with (poly)trauma, severe infection, and autoimmune diseases.
