Comprehensive Profile of Acute Mitochondrial Dysfunction in a Preclinical Model of Severe Penetrating TBI.

Jignesh D Pandya,Deborah A Shear,Ying Deng-Bryant,William J Flerlage,Xiaofang Yang,Lai Yee Leung,Janice S Gilsdorf

doi:10.3389/fneur.2019.00605

Abstract

Mitochondria constitute a central role in brain energy metabolism, and play a pivotal role in the development of secondary pathophysiology and subsequent neuronal cell death following traumatic brain injury (TBI). Under normal circumstances, the brain consumes glucose as the preferred energy source for adenosine triphosphate (ATP) production over ketones. To understand the comprehensive picture of substrate-specific mitochondrial bioenergetics responses following TBI, adult male rats were subjected to either 10% unilateral penetrating ballistic-like brain injury (PBBI) or sham craniectomy (n = 5 animals per group). At 24 h post-injury, mitochondria were isolated from pooled brain regions (frontal cortex and striatum) of the ipsilateral hemisphere. Mitochondrial bioenergetics parameters were measured ex vivo in the presence of four sets of metabolic substrates: pyruvate+malate (PM), glutamate+malate (GM), succinate (Succ), and β-hydroxybutyrate+malate (BHBM). Additionally, mitochondrial matrix dehydrogenase activities [i.e., pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase complex (α-KGDHC), and glutamate dehydrogenase (GDH)] and mitochondrial membrane-bound dehydrogenase activities [i.e., electron transport chain (ETC) Complex I, II, and IV] were compared between PBBI and sham groups. Furthermore, mitochondrial coenzyme contents, including NAD(t) and FAD(t), were quantitatively measured in both groups. Collectively, PBBI led to an overall significant decline in the ATP synthesis rates (43–50%; *p < 0.05 vs. sham) when measured using each of the four sets of substrates. The PDHC and GDH activities were significantly reduced in the PBBI group (42–53%; *p < 0.05 vs. sham), whereas no significant differences were noted in α-KGDHC activity between groups. Both Complex I and Complex IV activities were significantly reduced following PBBI (47–81%; *p < 0.05 vs. sham), whereas, Complex II activity was comparable between groups. The NAD(t) and FAD(t) contents were significantly decreased in the PBBI group (27–35%; *p < 0.05 vs. sham). The decreased ATP synthesis rates may be due to the significant reductions in brain mitochondrial dehydrogenase activities and coenzyme contents observed acutely following PBBI. These results provide a basis for the use of “alternative biofuels” for achieving higher ATP production following severe penetrating brain trauma.

Highlights

There is a growing interest in further understanding of the brain metabolic responses following traumatic brain injury (TBI) to facilitate acute critical care management of TBI patients; and develop novel targeted therapeutic interventions for TBI
The current study was designed to examine the acute brain mitochondrial bioenergetics dysfunction following penetrating ballistic-like brain injury (PBBI) based on our previous observations of the cerebral metabolomics alterations in this brain injury model
Results of the current study demonstrate mitochondrial bioenergetics failure evident at 24 h post-PBBI, which was likely due to a global declines in substrate utilization for energy production, including altered mitochondrial dehydrogenase activities and coenzyme contents

Summary

Introduction

There is a growing interest in further understanding of the brain metabolic responses following traumatic brain injury (TBI) to facilitate acute critical care management of TBI patients; and develop novel targeted therapeutic interventions for TBI. Several clinical reviews have recommended early intervention of supplying energy intermediate substrates for improvements in mortality and neurological outcomes following TBI [13,14,15]

Methods

Results

Conclusion