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

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.

Carbenoxolon Is Capable to Regulate the Mitochondrial Permeability Transition Pore Opening in Chronic Alcohol Intoxication

“…Moreover, our studies and the work of other groups have shown the direct involvement of mPTP in the mechanisms acting in the mitochondria in chronic alcoholism [ 8 , 10 , 11 ]. It is known that the effect of alcohol in the mitochondria of the liver triggers the opening of mPTP [ 7 , 11 ].…”

“…Moreover, our studies and the work of other groups have shown the direct involvement of mPTP in the mechanisms acting in the mitochondria in chronic alcoholism [ 8 , 10 , 11 ]. It is known that the effect of alcohol in the mitochondria of the liver triggers the opening of mPTP [ 7 , 11 ]. We also obtained data about the existence of a new mechanism in rat liver mitochondria (RLM) in response to degenerative changes caused by ethanol that includes changes in the functioning of mPTP, the level of key regulators of mPTP and is possibly regulated by protein kinases [ 11 ].…”

“…In particular, there is evidence that alcohol intoxication results in disturbances in the functioning of the mPTP [ 8 , 10 ]. Chronic alcohol consumption increases the sensitivity of mitochondria to the induction of mPTP and, as a result, enhances the permeability of the inner mitochondrial membrane, as well as its depolarization, swelling and causes a damage to the outer membrane [ 7 , 11 ]. However, the mechanism of action of ethanol on mitochondria remains unclear.…”

“…We have previously shown that two other pharmacological agents, Protoporphyrin IX and PK 11195, have the same enhancing effect in Ethanol RLM [ 11 ]. Protoporphyrin IX and PK 11195 are ligands of the TSPO but they are also capable of acting by other, TSPO-independent mechanisms [ 29 ].…”

“…It is known that the effect of alcohol in the mitochondria of the liver triggers the opening of mPTP [ 7 , 11 ]. We also obtained data about the existence of a new mechanism in rat liver mitochondria (RLM) in response to degenerative changes caused by ethanol that includes changes in the functioning of mPTP, the level of key regulators of mPTP and is possibly regulated by protein kinases [ 11 ]. In this work, we continued to study the operation of this system, as well as to search for objects of influence mPTP and potential regulators of its functioning.…”