The Effects of PK11195 and Protoporphyrin IX Can Modulate Chronic Alcohol Intoxication in Rat Liver Mitochondria under the Opening of the Mitochondrial Permeability Transition Pore.

Yulia Baburina,Olga Krestinina,Irina Odinokova

doi:10.3390/cells9081774

Yulia Baburina, Olga Krestinina + Show 1 more

Open Access

https://doi.org/10.3390/cells9081774

Copy DOI

Journal: Cells	Publication Date: Jul 24, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: Institute of Theoretical and Experimental Biophysics

Abstract

Decades of active research have shown that mitochondrial dysfunction, the associated oxidative stress, impaired anti-stress defense mechanisms, and the activation of the proapoptotic signaling pathways underlie pathological changes in organs and tissues. Pathologies caused by alcohol primarily affect the liver. Alcohol abuse is the cause of many liver diseases, such as steatosis, alcoholic steatohepatitis, fibrosis, cirrhosis, and, potentially, hepatocellular cancer. In this study, the effect of chronic alcohol exposure on rat liver mitochondria was investigated. We observed an ethanol-induced increase in sensitivity to calcium, changes in the level of protein kinase Akt and GSK-3β phosphorylation, an induction of the mitochondrial permeability transition pore (mPTP), and strong alterations in the expression of mPTP regulators. Moreover, we also showed an enhanced effect of PK11195 and PPIX, on the parameters of the mPTP opening in rat liver mitochondria (RLM) isolated from ethanol-treated rats compared to the RLM from control rats. We suggest that the results of this study could help elucidate the mechanisms of chronic ethanol action on the mitochondria and contribute to the development of new therapeutic strategies for treating the effects of ethanol-related diseases.

Highlights

Alcohol abuse is an important problem worldwide and is associated with various liver diseases; the mortality from these diseases is around 4% [1]
To develop strategies for the treatment of alcoholism, it will be necessary to determine the molecular and cellular mechanisms underlying alcohol use disorders. In connection with this goal, in the present work, we studied the effects of PK11195 and protoporphyrin IX on the functional state of mitochondria, the parameters of mitochondrial permeability transition pore (mPTP) opening, and the level of proteins modulating the permeability of mitochondrial membranes (TSPO, voltage-dependent anion channel (VDAC), and cyclic nucleotide-30 -phosphodiesterase (CNPase)) in the liver mitochondria from control rats (Control rat liver mitochondria (RLM)) and from rats chronically intoxicated with alcohol (Ethanol RLM)
Since we showed a change in the effects of PK11195 and PPIX in ethanol mitochondria compared with the control RLM, we suppose an existence of a special mechanism in chronic alcohol intoxication that activates the translocator protein (TSPO)-dependent pathways of ligand action

Summary

Introduction

Alcohol abuse is an important problem worldwide and is associated with various liver diseases; the mortality from these diseases is around 4% [1]. The mitochondria are primarily affected by chronic alcohol consumption [5]. Such consumption violates the integrity and structure of the mitochondria and disrupts their normal functioning [6,7,8]. Chronic exposure to ethanol leads to significant disruptions in the functionality of systems of fatty acid oxidation, the urea cycle, oxidative phosphorylation, and the production of reactive oxygen species (ROS) [10,11]. It was previously shown that the rate of ATP generation significantly decreases during oxidative phosphorylation in the mitochondria of rats susceptible to chronic alcohol intoxication [12,13]. According to the results of proteomic studies, these disorders are largely associated with changes in the expression of proteins of the

Methods

Results

Discussion

Conclusion