Mitochondrial Dysfunction and Apoptosis in Brain Microvascular Endothelial Cells Following Blast Traumatic Brain Injury

Blood brain barrier (BBB) breakdown is a key driver of traumatic brain injury (TBI), contributing to prolonged neurological deficits and increased risk of death in TBI patients. Strikingly, the role of endothelium in the progression of BBB breakdown has not been sufficiently investigated, even though it constitutes the bulk of BBB structure. In the current study, we investigate TBI-induced changes in the brain endothelium at the subcellular level, particularly focusing on mitochondrial dysfunction, using a combination of confocal imaging, gene expression analysis, and molecular profiling by Raman spectrometry. Herein, we developed and applied an in-vitro blast-TBI (bTBI) model that employs an acoustic shock tube to deliver injury to cultured human brain microvascular endothelial cells (HBMVEC). We found that this injury results in aberrant expression of mitochondrial genes, as well as cytokines/ inflammasomes, and regulators of apoptosis. Furthermore, injured cells exhibit a significant increase in reactive oxygen species (ROS) and in Ca2+ levels. These changes are accompanied by overall reduction of intracellular proteins levels as well as profound transformations in mitochondrial proteome and lipidome. Finally, blast injury leads to a reduction in HBMVEC cell viability, with up to 50% of cells exhibiting signs of apoptosis following 24 h after injury. These findings led us to hypothesize that mitochondrial dysfunction in HBMVEC is a key component of BBB breakdown and TBI progression.

Automated summary

Blood brain barrier (BBB) breakdown is an important factor in traumatic brain injury (TBI), leading to prolonged neurological deficits and increased mortality risk in TBI patients. However, the role of endothelium in BBB breakdown has not been adequately studied. This study investigates TBI-induced changes in brain endothelium at the subcellular level, particularly focusing on mitochondrial dysfunction. The findings suggest that mitochondrial dysfunction in brain endothelial cells is a crucial component of BBB breakdown and TBI progression.