Metabolically aberrant extracellular mitochondria induce oxidative endotheliopathy in traumatic brain injury.

Abstract

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 reported extensively 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 show that exMt are released from injured brains into the circulation, reaching a maximal level of 1.8 × 104/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 adenosine triphosphate compared with intracellular mitochondria of normal cells. When infused into noninjured mice, exMt induce systemic endotheliopathy defined by increased endothelial permeability, tissue edema, and perivascular bleeding. We further demonstrate that endothelial cells (ECs) 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 membranes, leading to 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.