Chronic Alcohol Exposure Induces Aberrant Mitochondrial Morphology and Inhibits Respiratory Capacity in the Medial Prefrontal Cortex of Mice

Abstract

Alcohol use disorder (AUD) is characterized as a chronic, relapsing disease with a pattern of excessive drinking despite negative consequences to an individual's life. Severe chronic alcohol use impairs the function of the medial prefrontal cortex (mPFC), which contributes to alcohol-induced cognitive and executive dysfunction. The mPFC contains more mitochondria compared to other cortical areas, which suggests mitochondrial damage may occur in AUD and trigger subsequent behavior change. Here, we identified morphological and functional changes in mitochondria in the mPFC in C57BL6/J mice after 8 h of withdrawal from chronic intermittent alcohol (CIA) exposure. Three-dimensional serial block-face scanning electron microscopy (SBFSEM) reconstruction revealed that CIA exposure elongated mPFC mitochondria and formed mitochondria-on-a-string (MOAS). Furthermore, alcohol significantly affected mitochondrial bioenergetics, including oxidative phosphorylation and electron transport, with inhibited aerobic respiration in mPFC mitochondria after CIA exposure. We also found decreased expression of fusion (mitofusin 2, Mfn2) and increased fission (mitochondrial fission 1 protein, Fis1) proteins in the mPFC of alcohol-treated mice. In sum, our study suggests that CIA exposure impairs mitochondrial dynamics and function in the mPFC.

Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer’s Disease

“…In addition, mitochondrial fission protein Drp1 levels are significantly elevated after alcohol treatment in a concentration-dependent manner (Bonet-Ponce et al, 2015 ). Our own studies have demonstrated both morphological and functional changes in mitochondria in the prefrontal cortex in response to alcohol exposure (Shang et al, 2020 ). Distinct types of fission have been observed that determine the fate of mitochondria.…”

Chronic Intermittent Ethanol Exposure Alters Behavioral Flexibility in Aged Rats Compared to Adult Rats and Modifies Protein and Protein Pathways Related to Alzheimer’s Disease

“…Among the pathways that were dysregulated only in young adult rats based on between-treatment-group proteomics differences (Table S5) were those related to mitochondrial respiratory function, which concurred with previous reports that involved chronic ethanol exposure. , Ethanol was found to induce mitochondrial reactive oxygen species production, and we found pathways related to the cellular response to reactive oxygen species (hydrogen peroxide in particular) were downregulated. Pathways related to phosphatidylinositol phosphate (in particular phosphatidylinositol-4,5 biphosphate; PIP 2 ), GDP, and GTP binding as well as GTPase activity were estimated to be downregulated, suggesting the signaling transduction pathways and other regulatory pathwayssuch as ion channel regulation and exocytosis , using these major signaling molecules might also be downregulated.…”

Cellular Bioenergetics: Experimental Evidence for Alcohol-induced Adaptations

“…This was associated with significant reduction in mitochondrial bioenergetics, including ETC, decreased gene expression of Mfn2, and increased fission. 37 In the brain there were no changes in the substrate shuttles and ethanol oxidation, but there was decreased NAD + /NADH ratio and impaired OXPHOS. 220 Isolated brain mitochondria from chronic alcohol fed-mice had decreased CI and V activity and decreased carnitine palmitoyl transferase 1 (cPT1) and cPT2 levels that are required of acylation of fatty acids from outer to inner mitochondrial membrane for ATP production.…”