Traumatic brain injury and alcohol: A narrative review of the role of mitochondrial dysfunction and ferroptosis in neurocognitive outcomes

Document Type

Article

Publication Date

3-8-2026

Publication Title

Alcohol, Clinical & Experimental Research

Abstract

Traumatic brain injury (TBI) is a major global health concern, affecting over 30 million individuals annually and leading to significant disability and mortality. In the United States, the health burden of TBI is compounded by the high incidence of alcohol involvement, with up to 50% of cases occurring in intoxicated individuals and approximately 26% of patients consuming alcohol post-injury. This review synthesizes current research exploring the complex interplay between TBI and alcohol misuse, with a particular focus on their combined effects on mitochondrial function, energy metabolism, and cellular redox homeostasis. We discuss how TBI-induced mitochondrial dysfunction, manifested as impaired adenosine triphosphate (ATP) production, excessive reactive oxygen species (ROS) generation, and subsequent depletion of glutathione, intersects with alcohol-mediated metabolic reprogramming, resulting in disrupted glucose metabolism and a shift toward glutaminolysis. This metabolic perturbation predisposes neural tissue to lipid peroxidation and ferroptosis, an iron-dependent form of cell death that is characterized by the peroxidation of polyunsaturated fatty acid-containing phospholipids. Here we highlight how alterations in glutamate homeostasis in combination with exacerbated neuroinflammatory signaling contribute to post-TBI cognitive impairments and hinder the recovery process. Integrating findings from biomarker studies and preclinical models, we highlight the critical need for targeted therapies that address these interconnected molecular pathways. A comprehensive understanding of these pathways promises to uncover druggable targets leading to novel neuroprotective strategies, offering hope for improved clinical outcomes in patients suffering from TBI, particularly those with concurrent alcohol exposure.

First Page

e70267

PubMed ID

41795844

Volume

50

Issue

3

Rights

© 2026 Research Society on Alcohol

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