Alcohol Impact on Traumatic Brain Injury: Focus on Mitochondrial Alterations

Abstract
Traumatic brain injury (TBI) affects millions of otherwise healthy individuals annually. A significant risk factor for
TBI is alcohol intoxication, with 30-50% of TBI cases in the US attributed to alcohol-intoxication at the time of
injury, potentially intensifying cognitive deficits and TBI-related disability, particularly in moderate to severe
cases. Moreover, following TBI, approximately 25% of TBI patients resume alcohol consumption, which can
also contribute to neuropathological outcomes. Several mechanisms can contribute to greater injury in alcohol
and TBI comorbid conditions. Prior work from our laboratory has shown enhanced neuroinflammation at site of
TBI in rodents exposed to alcohol, and delayed recovery of neurobehavioral function in TBI followed by alcohol
exposure. Enhanced neuroinflammation may be the result of mitochondrial components or metabolic
byproducts that act as damage-associated molecular patterns (DAMPs). Alcohol and TBI both alter cellular
metabolism, affects mitochondrial function and glutathione availability. The TBI and alcohol associated
disruption in brain metabolism, requires metabolic flexibility in energy substrate utilization to maintain adequate
ATP production. This metabolic shift may lead to glutathione depletion and reactive oxygen species
overproduction, triggering cell death and accentuated neuropathology that can significantly impact recovery
from TBI. Based on these data, we hypothesize that alcohol exacerbates TBI-induced alterations in
mitochondrial bioenergetics; particularly at the site of injury, leading to increased oxidative stress and cell
death. Ferroptosis, an iron-dependent programmed cell death mechanism, is highly sensitive to mitochondrial
bioenergetic alterations and is reported in TBI. The research-training plan proposes three specific aims to test
the hypothesis that a) alcohol impairs mitochondrial bioenergetics at the site of TBI injury, b) alcohol
accentuates oxidative stress affecting predominantly astrocytes at the site of TBI, c) and that ferroptosis is a
significant contributor to cell death at the TBI site. The applicant will leverage his background training in
mitochondrial mechanisms of tissue injury, translating them from cardiac tissue to the brain and from ischemic
injury to TBI, with emphasis of the role of alcohol in exacerbating these pathophysiological mechanisms.

Grant Number: 5F32AA031902-02
NIH Institute/Center: NIH
Principal Investigator: Xavier Chapa Dubocq