Proteomic Analysis and Biochemical Correlates of Mitochondrial Dysfunction after Low-Intensity Primary Blast Exposure

Abstract

Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures >100 kPa, whereas understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with a peak overpressure at 46.6 kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. In this study, we used tandem mass tagged (TMT) quantitative proteomics and bioinformatics analysis to seek insights into the molecular mechanisms underlying ultrastructural pathology. Changes in global- and phospho-proteomes were determined at 3 and 24 h and at 7 and 30 days post injury (DPI), in order to investigate the biochemical and molecular correlates of mitochondrial dysfunction. Results showed striking dynamic changes in a total of 2216 proteins and 459 phosphorylated proteins at vary time points after blast. Disruption of key canonical pathways included evidence of mitochondrial dysfunction, oxidative stress, axonal/cytoskeletal/synaptic dysregulation, and neurodegeneration. Bioinformatic analysis identified blast-induced trends in networks related to cellular growth/development/movement/assembly and cell-to-cell signaling interactions. With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration-relevant enzyme activities. Insights on the early pathogenesis of primary LIB-induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers, and targets for intervention.

Department(s)

Mining Engineering

Comments

This publication was made possible by funding from the DoD Congressionally Directed Medical Research Programs (CDMRP) for the Peer Reviewed Alzheimer's Research Program Convergence Science Research Award (PRARP-CSRA; AZ140109) and the research funds of the University of Missouri (Z.G.). This study was also supported by the awards I21BX002215, I01BX003527, and I21BX003807 from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development and the Cure Alzheimer's Fund (W.X.).

Keywords and Phrases

Mitochondrial Dysfunction; Open-Field LIB; Oxidative Stress; Quantitative Proteomics

International Standard Serial Number (ISSN)

0897-7151; 1557-9042

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2019 Mary Ann Liebert Inc., All rights reserved.

Publication Date

01 May 2019

PubMed ID

30484371

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