The Effect of Astaxanthin on Mitochondrial Dynamics in Rat Heart Mitochondria under ISO-Induced Injury.

Mitochondria are dynamic organelles that produce ATP in the cell and are sensitive to oxidative damage that impairs mitochondrial function in pathological conditions. Mitochondria are involved not only in a healthy heart but also in the development of heart disease. Therefore, attempts should be made to enhance the body's defense response against oxidative stress with the help of various antioxidants in order to decrease mitochondrial damage and reduce mitochondrial dysfunction. Mitochondrial fission and fusion play an important role in the quality control and maintenance of mitochondria. The ketocarotenoid astaxanthin (AX) is an antioxidant able to maintain mitochondrial integrity and prevent oxidative stress. In the present study, we investigated the effect of the protective effect of AX on the functioning of rat heart mitochondria (RHM). Changes in the content of proteins responsible for mitochondrial dynamics, prohibitin 2 (PHB2) as a protein that performs the function of quality control of mitochondrial proteins and participates in the stabilization of mitophagy, and changes in the content of cardiolipin (CL) in rat heart mitochondria after isoproterenol (ISO)-induced damage were examined. AX improved the respiratory control index (RCI), enhanced mitochondrial fusion, and inhibited mitochondrial fission in RHM after ISO injury. Rat heart mitochondria (RHM) were more susceptible to Ca2+-induced mitochondrial permeability pore (mPTP) opening after ISO injection, while AX abolished the effect of ISO. AX is able to perform a protective function in mitochondria, improving their efficiency. Therefore, AX can be considered an important ingredient in the diet for the prevention of cardiovascular disease. Therefore, AX can be examined as an important component of the diet for the prevention of heart disease.

Melatonin Can Enhance the Effect of Drugs Used in the Treatment of Leukemia.

Melatonin (N-acetyl-5-methoxytryptamine, MEL), secreted by the pineal gland, plays an important role in regulation of various functions in the human body. There is evidence that MEL exhibits antitumor effect in various types of cancer. We studied the combined effect of MEL and drugs from different pharmacological groups, such as cytarabine (CYT) and navitoclax (ABT-737), on the state of the pool of acute myeloid leukemia (AML) tumor cell using the MV4-11 cell line as model. The combined action of MEL with CYT or ABT-737 contributed to the decrease in proliferative activity of leukemic cells, decrease in the membrane potential of mitochondria, and increase in the production of reactive oxygen species (ROS) and cytosolic Ca2+. We have shown that introduction of MEL together with CYT or ABT-737 increases expression of the C/EBP homologous protein (CHOP) and the autophagy marker LC3A/B and decreases expression of the protein disulfide isomerase (PDI) and binding immunoglobulin protein (BIP), and, therefore, could modulate endoplasmic reticulum (ER) stress and initiate autophagy. The findings support an early suggestion that MEL is able to provide benefits for cancer treatment and be considered as an adjunct to the drugs used in cancer therapy.

Astaxanthin Is Able to Prevent Alcohol-Induced Dysfunction of Liver Mitochondria.

The search for new targets for the pathological action of ethanol remains an urgent task of biomedicine. Since degenerative changes in the liver are associated with the development of oxidative stress, antioxidants are promising agents for the treatment of alcohol-related diseases. In this work, we studied the ability of the carotenoid antioxidant, astaxanthin (AX), to prevent ethanol-induced changes in the liver of rats. It was shown that AX is able to protect the structure of mitochondria from degenerative changes caused by ethanol to improve mitochondrial functions. AX positively influences the activity and expression of proteins of the mitochondrial respiratory chain complexes and ATPase. In addition, a protective effect of AX on the rate and activity of mitochondrial respiration was demonstrated in the work. Thus, studies have shown that AX is involved in protective mechanisms in response to ethanol-induced mitochondrial dysfunction.

The Improvement of Functional State of Brain Mitochondria with Astaxanthin in Rats after Heart Failure.

The relationship between neurological damage and cardiovascular disease is often observed. This type of damage is both a cause and an effect of cardiovascular disease. Mitochondria are the key organelles of the cell and are primarily subject to oxidative stress. Mitochondrial dysfunctions are involved in the etiology of various diseases. A decrease in the efficiency of the heart muscle can lead to impaired blood flow and decreased oxygen supply to the brain. Astaxanthin (AST), a marine-derived xanthophyll carotenoid, has multiple functions and its effects have been shown in both experimental and clinical studies. We investigated the effects of AST on the functional state of brain mitochondria in rats after heart failure. Isoproterenol (ISO) was used to cause heart failure. In the present study, we found that ISO impaired the functional state of rat brain mitochondria (RBM), while the administration of AST resulted in an improvement in mitochondrial efficiency. The respiratory control index (RCI) in RBM decreased with the use of ISO, while AST administration led to an increase in this parameter. Ca2+ retention capacity (CRC) decreased in RBM isolated from rat brain after ISO injection, and AST enhanced CRC in RBM after heart failure. The study of changes in the content of regulatory proteins such as adenine nucleotide translocase 1 and 2 (ANT1/2), voltage dependent anion channel (VDAC), and cyclophilin D (CyP-D) of mitochondrial permeability transition pore (mPTP) showed that ISO reduced their level, while AST restored the content of these proteins almost to the control value. In general, AST improves the functional state of mitochondria and can be considered as a prophylactic drug in various therapeutic approaches.

The Identification of Prohibitin in the Rat Heart Mitochondria in Heart Failure.

Mitochondria are considered the main organelles in the cell. They play an important role in both normal and abnormal heart function. There is a supramolecular organization between the complexes of the respiratory chain (supercomplexes (SCs)), which are involved in mitochondrial respiration. Prohibitins (PHBs) participate in the regulation of oxidative phosphorylation (OXPHOS) activity and interact with some subunits of the OXPHOS complexes. In this study, we identified a protein whose level was decreased in the mitochondria of the heart in rats with heart failure. This protein was PHB. Isoproterenol (ISO) has been used as a compound to induce heart failure in rats. We observed that astaxanthin (AX) increased the content of PHB in rat heart mitochondria isolated from ISO-injected rats. Since it is known that PHB forms complexes with some mitochondrial proteins and proteins that are part of the complexes of the respiratory chain, the change in the levels of these proteins was investigated under our experimental conditions. We hypothesized that PHB may be a target for the protective action of AX.

Mitochondrion as a Target of Astaxanthin Therapy in Heart Failure.

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.

Melatonin Can Modulate the Effect of Navitoclax (ABT-737) in HL-60 Cells.

Melatonin (N-acetyl-5-methoxytryptamine MEL) is an indolamine that has antioxidant, anti-inflammatory and anti-tumor properties. Moreover, MEL is capable of exhibiting both anti-apoptotic and pro-apoptotic effects. In the normal cells, MEL possesses antioxidant property and has an anti-apoptotic effect, while in the cancer cells it has pro-apoptotic action. We investigated the combined effect of MEL and navitoclax (ABT-737), which promotes cell death, on the activation of proliferation in acute promyelocytic leukemia on a cell model HL-60. The combined effect of these compounds leads to a reduction of the index of mitotic activity. The alterations in the level of anti- and pro-apoptotic proteins such as BclxL, Bclw, Mcl-1, and BAX, membrane potential, Ca2+ retention capacity, and ROS production under the combined action of MEL and ABT-737 were performed. We obtained that MEL in combination with ABT-737 decreased Ca2+ capacity, dropped membrane potential, increased ROS production, suppressed the expression of anti-apoptotic proteins such as BclxL, Bclw, and Mcl-1, and enhanced the expression of pro-apoptotic BAX. Since, MEL modulates autophagy and endoplasmic reticulum (ER) stress in cancer cells, the combined effect of MEL and ABT-737 on the expression of ER stress and autophagy markers was checked. The combined effect of MEL and ABT-737 (0.2 µM) increased the expression of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), leading to a decrease in the level of binding immunoglobulin protein (BIP) followed by an increase in the level of C/EBP homologous protein (CHOP). In this condition, the expression of ERO1 decreased, which could lead to a decrease in the level of protein disulfide isomerase (PDI). The obtained data suggested that melatonin has potential usefulness in the treatment of cancer, where it is able to modulate ER stress, autophagy and apoptosis.

Isoproterenol-Induced Permeability Transition Pore-Related Dysfunction of Heart Mitochondria Is Attenuated by Astaxanthin.

Mitochondria are key organelles of the cell because their main function is the capture of energy-rich substrates from the cytoplasm and oxidative cleavage with the generation of carbon dioxide and water, processes that are coupled with the synthesis of ATP. Mitochondria are subject to oxidative stress through the formation of the mitochondrial permeability transition pore (mPTP). Various antioxidants are used to reduce damage caused by oxidative stress and to improve the protection of the antioxidant system. Astaxanthin (AST) is considered to be a dietary antioxidant, which is able to reduce oxidative stress and enhance the antioxidant defense system. In the present investigation, the effect of AST on the functional state of rat heart mitochondria impaired by isoproterenol (ISO) under mPTP functioning was examined. It was found that AST raised mitochondrial respiration, the Ca2+ retention capacity (CRC), and the rate of TPP+ influx in rat heart mitochondria (RHM) isolated from ISO-injected rats. However, the level of reactive oxygen species (ROS) production increased. In addition, the concentrations of cardiolipin (CL), Mn-SOD2, and the proteins regulating mPTP rose after the injection of ISO in RHM pretreated with AST. Based on the data obtained, we suggest that AST has a protective effect in rat heart mitochondria.

Astaxanthin Prevents Mitochondrial Impairment Induced by Isoproterenol in Isolated Rat Heart Mitochondria.

Mitochondria are considered to be a power station of the cell. It is known that they play a major role in both normal and pathological heart function. Alterations in mitochondrial bioenergetics are one of the main causes of the origin and progression of heart failure since they have an inhibitory effect on the activity of respiratory complexes in the inner mitochondrial membrane. Astaxanthin (AST) is a xanthophyll carotenoid of mainly marine origin. It has both lipophilic and hydrophilic properties and may prevent mitochondrial dysfunction by permeating the cell membrane and co-localizing within mitochondria. The carotenoid suppresses oxidative stress-induced mitochondrial dysfunction and the development of diseases. In the present study, it was found that the preliminary oral administration of AST upregulated the activity of respiratory chain complexes and ATP synthase and the level of their main subunits, thereby improving the respiration of rat heart mitochondria (RHM) in the heart injured by isoproterenol (ISO). AST decreased the level of cyclophilin D (CyP-D) and increased the level of adenine nucleotide translocase (ANT) in this condition. It was concluded that AST could be considered as a potential mitochondrial-targeted agent in the therapy of pathological conditions associated with oxidative damage and mitochondrial dysfunction. AST, as a dietary supplement, has a potential in the prevention of cardiovascular diseases.

Astaxanthin Inhibits Mitochondrial Permeability Transition Pore Opening in Rat Heart Mitochondria.

The mitochondrion is the main organelle of oxidative stress in cells. Increased permeability of the inner mitochondrial membrane is a key phenomenon in cell death. Changes in membrane permeability result from the opening of the mitochondrial permeability transition pore (mPTP), a large-conductance channel that forms after the overload of mitochondria with Ca2+ or in response to oxidative stress. The ketocarotenoid astaxanthin (AST) is a potent antioxidant that is capable of maintaining the integrity of mitochondria by preventing oxidative stress. In the present work, the effect of AST on the functioning of mPTP was studied. It was found that AST was able to inhibit the opening of mPTP, slowing down the swelling of mitochondria by both direct addition to mitochondria and administration. AST treatment changed the level of mPTP regulatory proteins in isolated rat heart mitochondria. Consequently, AST can protect mitochondria from changes in the induced permeability of the inner membrane. AST inhibited serine/threonine protein kinase B (Akt)/cAMP-responsive element-binding protein (CREB) signaling pathways in mitochondria, which led to the prevention of mPTP opening. Since AST improves the resistance of rat heart mitochondria to Ca2+-dependent stress, it can be assumed that after further studies, this antioxidant will be considered an effective tool for improving the functioning of the heart muscle in general under normal and medical conditions.