Mitochondrial Changes in Rat Brain Endothelial Cells Associated with Hepatic Encephalopathy: Relation to the Blood-Brain Barrier Dysfunction.

Abstract

The mechanisms underlying cerebral vascular dysfunction and edema during hepatic encephalopathy (HE) are unclear. Blood-brain barrier (BBB) impairment, resulting from increased vascular permeability, has been reported in acute and chronic HE. Mitochondrial dysfunction is a well-documented result of HE mainly affecting astrocytes, but much less so in the BBB-forming endothelial cells. Here we review literature reports and own experimental data obtained in HE models emphasizing alterations in mitochondrial dynamics and function as a possible contributor to the status of brain endothelial cell mitochondria in HE. Own studies on the expression of the mitochondrial fusion-fission controlling genes rendered HE animal model-dependent effects: increase of mitochondrial fusion controlling genes opa1, mfn1 in cerebral vessels in ammonium acetate-induced hyperammonemia, but a decrease of the two former genes and increase of fis1 in vessels in thioacetamide-induced HE. In endothelial cell line (RBE4) after 24 h ammonia and/or TNFα treatment, conditions mimicking crucial aspects of HE in vivo, we observed altered expression of mitochondrial fission/fusion genes: a decrease of opa1, mfn1, and, increase of the fission related fis1 gene. The effect in vitro was paralleled by the generation of reactive oxygen species, decreased total antioxidant capacity, decreased mitochondrial membrane potential, as well as increased permeability of RBE4 cell monolayer to fluorescein isothiocyanate dextran. Electron microscopy documented enlarged mitochondria in the brain endothelial cells of rats in both in vivo models. Collectively, the here observed alterations of cerebral endothelial mitochondria are indicative of their fission, and decreased potential of endothelial mitochondria are likely to contribute to BBB dysfunction in HE.

• Authors: Krzysztof Milewski, Karolina Orzeł-Gajowik, Magdalena Zielińska
• Journal: Neurochemical research (Neurochem Res) Vol. 49 Issue 6 Pg. 1489-1504 (Jun 2024) ISSN: 1573-6903 [Electronic] United States
• PMID: 35917006 (Publication Type: Journal Article, Review)
• Copyright: © 2022. The Author(s).

Topics

• Animals
• Hepatic Encephalopathy (metabolism, pathology)
• Blood-Brain Barrier (metabolism, pathology)
• Endothelial Cells (metabolism, pathology)
• Rats
• Mitochondria (metabolism)
• Brain (metabolism, pathology)
• Mitochondrial Dynamics (physiology)