The effect of paraquat on voltage-dependent anion channel and caspase-3, 8, 9 in the mitochondria of rat lung / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the effects of different concentrations of paraquat (PQ) poisoning on the expression of voltage-dependent anion channel (VDAC) and caspase family in the mitochondria of rat lung tissue, and to explore possible mechanisms of acute lung injury induced by acute PQ poisoning.</p><p><b>METHODS</b>Two hundred healthy adult Wister rats with equal numbers of male and female ones were randomly and equally divided into control group and poisoned group. The control group received one-time gastric lavage with 1 ml of normal saline, and the poisoned group with PQ (50 mg/kg) diluted in 1 ml of normal saline. Twenty rats were collected at 1, 24, 72, 120, and 168 h after lavage with normal saline or PQ and dissected after anesthesia. Mitochondria were separated from rat lung tissue, and the content of VDAC and caspase-3, -8, and -9 were determined.</p><p><b>RESULTS</b>The expression of VDAC and caspase-3, -8, and -9 in the poisoned rats were significantly higher than that in the control group (P < 0.001). At 1, 24, 72, 120, and 168 h after exposure, acute diffuse damages were found in alveolar capillary endothelial cells, alveolar epithelial cells, and pulmonary interstitial cells. Inflammatory cell infiltration in the pulmonary interstitium, alveolar structural disorder, and substantially increased fibroblasts were also found in rat lung tissue.</p><p><b>CONCLUSION</b>PQ poisoning can up-regulate the expression of VDAC and caspase-3, -8, and -9 in mitochondria of rat lung tissue to induce acute lung injury.</p>

Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death

Mitochondrial calcium uniporter (MCU) is a conserved Ca(2+) transporter at mitochondrial in eukaryotic cells. However, the role of MCU protein in oxidative stress-induced cell death remains unclear. Here, we showed that ectopically expressed MCU is mitochondrial localized in both HeLa and primary cerebellar granule neurons (CGNs). Knockdown of endogenous MCU decreases mitochondrial Ca(2+) uptake following histamine stimulation and attenuates cell death induced by oxidative stress in both HeLa cells and CGNs. We also found MCU interacts with VDAC1 and mediates VDAC1 overexpression-induced cell death in CGNs. This finding demonstrates that MCU-VDAC1 complex regulates mitochondrial Ca(2+) uptake and oxidative stress-induced apoptosis, which might represent therapeutic targets for oxidative stress related diseases.

Mitochondrial mechanisms of antisense oligodeoxynucleotide Stat3 induced apoptosis in laryngeal carcinoma cell / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To investigate the changes of mitochondrion by transferring antisense oligodeoxynucleotide Stat3 into laryngeal carcinoma Hep-2 cell, for elucidating the mechanism of laryngeal carcinoma Hep-2 cell apoptosis, for developing more effective treatment for laryngeal cancer.@*METHOD@#The designed Stat3 ASODN was transferred into laryngeal carcinoma Hep-2 cell by lipofection. Mitochondrion membrane potential, VDAC and Cyt-c were detected for determining the changes of mitochondrion.@*RESULT@#MMP was fell, Cyt-c and VDAC were increased with the heighten concentration of ASODN.@*CONCLUSION@#Mitochondria approach play an important role in the apoptosis mechanism of human Hep-2 cell by Stat3. This research elucidated the regulating mechanism of Hep-2 cell proliferation by Stat3, provided a new research focus for clinical therapy.

Mitochondrial modulation as a potential mechanism of Vetiveria zizanioides root extract against liver damage in mice

The relationship between the expression of mitochondrial voltage-dependent anion channels and the protective effects of methanolic extract of Vetiveria zizanioides Linn. Root against carbon tetrachloride-induced liver damage was investigated. Pretreatment of mice with Vetiveria zizanioides Linn. Root extract [300 and 500 mg/kg] significantly blocked the carbon tetrachloride-induced increase in both serum aspartate aminotransferase and serum alanine aminotransferase levels. The mitochondrial membrane potential was dropped from -188.0 +/- 2.5 mV to -156.8 +/- 3.0 mV [P < 0.01] after the mice had been treated with carbon tetrachloride. Pretreatment with methanolic extract of Vetiveria zizanioides Linn. Root [300 and 500 mg/kg] attenuated carbon tetrachloride -induced mitochondrial membrane potential dissipation [P< 0.05]. In addition, pretreatment of Vetiveria zizanioides Linn. Root extract at various concentrations exerted a dose-dependent effect against sensitivity to mitochondrial swelling induced by Calcium. Also, 500 mg/kg dose of extract significantly increased both transcription and translation of voltage-dependent anion channels, which was down-regulated by carbon tetrachloride treatment. The above data suggest that Vetiveria zizanioides Linn. Root extract mitigates the damage to liver mitochondria induced by carbon tetrachloride, possibly through the regulation of mitochondrial voltage-dependent anion channels, one of the most important proteins in the mitochondrial outer membrane

Voltage-dependent anion channel and hematological malignancies / 中国实验血液学杂志

Voltage-dependent anion channel(VDAC)is mainly located on the outer mitochondrial membrane. High-resolution atomic force microscopy topography shows an eye-shaped VDAC with 3.8 nm x 2.7 nm pore dimensions. New work suggests pore formation by the assembly of homo-oligomers and supramolecule of VDAC or hetero oligomers composed of VDAC and pro-apoptotic proteins, such as Bax. The oligomeric VDAC pore allows for release of cytochrome C. Thus, VDAC plays a central role in the cell life and apoptosis. It has been shown that the hexokinase (HK)-VDAC1 interaction is critical for preventing induction of apoptosis in tumor cells. VDACs are expressed more highly in cancer cells than normal cells, thus can be used as the target in chemotherapy for cancer. VDAC is also involved in pathogenesis of hematological malignancies such as myeloma and chronic lymphocytic leukemia. Following identification of sequence and structure of VDAC, studies have focused on VDAC as important pharmacological target for new anticancer therapy. To induce apoptosis, agents directly interact with VDAC or detach HK from VDAC to disrupt the anti-apoptosis activity of VDAC-HK interaction, such as methyl jasmonate (MJ) and VDAC1-based peptides. In this review, the function, modulation, structure and location of the VDAC, progress of its researches in hematological malignancies and potential as targets of anti-cancer drugs are summarized.

A mechanistic view of mitochondrial death decision pores

Mitochondria increase their outer and inner membrane permeability to solutes, protons and metabolites in response to a variety of extrinsic and intrinsic signaling events. The maintenance of cellular and intraorganelle ionic homeostasis, particularly for Ca2+, can determine cell survival or death. Mitochondrial death decision is centered on two processes: inner membrane permeabilization, such as that promoted by the mitochondrial permeability transition pore, formed across inner membranes when Ca2+ reaches a critical threshold, and mitochondrial outer membrane permeabilization, in which the pro-apoptotic proteins BID, BAX, and BAK play active roles. Membrane permeabilization leads to the release of apoptogenic proteins: cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi, and endonuclease G. Cytochrome c initiates the proteolytic activation of caspases, which in turn cleave hundreds of proteins to produce the morphological and biochemical changes of apoptosis. Voltage-dependent anion channel, cyclophilin D, adenine nucleotide translocase, and the pro-apoptotic proteins BID, BAX, and BAK may be part of the molecular composition of membrane pores leading to mitochondrial permeabilization, but this remains a central question to be resolved. Other transporting pores and channels, including the ceramide channel, the mitochondrial apoptosis-induced channel, as well as a non-specific outer membrane rupture may also be potential release pathways for these apoptogenic factors. In this review, we discuss the mechanistic models by which reactive oxygen species and caspases, via structural and conformational changes of membrane lipids and proteins, promote conditions for inner/outer membrane permeabilization, which may be followed by either opening of pores or a rupture of the outer mitochondrial membrane.

Voltage-dependent anion channels (VDAC) on human sperm membrane / 中华男科学杂志

<p><b>OBJECTIVE</b>To further study gene expression and characterization of voltage-dependent anion channels (VDACs) on human spermatozoa.</p><p><b>METHODS</b>VDACs were cloned by PCR from the testis cDNA library. Recombinant human sperm VDACs were produced in E. coli system by molecular cloning technology. Sperm membrane protein was extracted by 1% Triton X-100 and separated by chloroform/methanol.</p><p><b>RESULTS</b>The gene expression of VDACs was found in the human testis cDNA library and VDAC protein was detected located on the sperm membrane by alpha-helix.</p><p><b>CONCLUSION</b>VDAC proteins, abundant on the human sperm membrane and responsible for anion transportation, play an important role in sperm signaling transduction and fertility.</p>

Molecular mechanisms of mitochondrial apoptogenic factor release through pores and megachannels

Mitochondrial membrane permeabilization is a biochemically well-defined phenomenon that occurs in response to numerous physiological and pathological processes that regulate cell survival. In many situations, mitochondrial membrane permeabilization is triggered by an excess of reactive oxygen species (ROS), Ca2+ overload, and the interference of BH3-only proteins of the BCL-2 family, as well as by activated caspases that can act on components of the inner or outer membrane to cause the opening, assembly and/or activation of membrane mitochondrial permeability transition pores. These pores permit the release of apoptogenic factors such as cytochrome c, apoptosis-inducing factor, Smac/Diablo, HtrA2/Omi and endonuclease G from the intermembrane space to the cytosol where they mediate many of the biochemical and morphological features of apoptosis and necrosis. In this review, we discuss the pharmacological, genetic and biochemical evidence that proteins, protein complexes and membrane structures can form pores through which apoptogenic factors can be released from mitochondria.