Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model
Volha Liaudanskaya, Nicholas J. Fiore, Yang Zhang, Yuka Milton, Marilyn Kelly, Marly Coe, Ariana Barreiro, Victoria K. Rose, Matthew R. Shapiro, Adam S. Mullis, Anna Shevzov-Zebrun, Mathew Blurton‐Jones, Michael J. Whalen, Aviva J. Symes, Irene Georgakoudi, Thomas J.F. Nieland, David L. Kaplan
Abstract
Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.