Molecular Regulators of Mitochondrial Dynamics in the Progression of Secondary Injury Following Trauma

Traumatic brain injury (TBI) affects 1.7 million Americans each year and is the leading cause of disability worldwide. TBI is defined as having two distinct pathophysiological phases: the primary injury, or initial impact, leads to a secondary injury cascade that lasts minutes to years later defined by an energy deficit and ionic imbalance in cells that contribute to neuronal death. Mitochondria play a large role in maintaining cellular homeostasis and meeting energetic requirements of neurons, making their dysfunction integral to the pathophysiology of secondary injury. Central to the health of the mitochondria, and therefore to the cell, is the tight regulation of coordinated cycles of fission and fusion, known as dynamics. Imbalance between these states leads to an altered electrochemical gradient and membrane potential, which reduces energetic efficiency, and resembles the hallmarks of the TBI secondary cascade. My hypothesis is that the disruption of key molecular regulators of mitochondrial dynamics plays a causal role in the progression of secondary injury following trauma. To test this, I will 1: establish the extent and timing of mitochondrial morphologic disruption after in vitro primary neuron axon stretch injury (ASI) using super-resolution live-cell microscopy with Ca2+, ROS, and ΔΨm fluorescent probes paired with the machine learning mitochondrial morphology classifier developed in the Sanderson lab. I will then gain insight into the activation and influence of fission and fusion regulatory proteins after ASI using novel gain- and loss- of function primary neurons from the lab’s transgenic conditional knockouts of Drp1 and Oma1, which mediate fission and inhibit fusion, respectively. Furthermore, I will 2: interrogate the role of mitochondrial dynamic regulatory proteins in the progression of secondary injury using the controlled cortical impact (CCI) mouse model paired with the Drp1 and Oma1 conditional knockout transgenic mice. Behavioral deficits and lesion size will be measured to confirm injury, and cutting-edge biochemical and imaging techniques, including whole slice immunofluorescence and mitochondrial segmentation of key brain regions, will be used to measure changes in pathology. Collectively, this research will provide crucial insight into the molecular underpinnings of mitochondrial dysfunction after brain trauma, potentially providing a route of therapeutic development to reduce cell death during the progression of the secondary injury. Project Number: 1F31NS147419-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Reagan Speas | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $43,714 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-L (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11313138