Journal articles on the topic 'Mitochondrial apoptosis'
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1
Adhihetty, Peter J., Vladimir Ljubicic, and David A. Hood. "Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle." American Journal of Physiology-Endocrinology and Metabolism 292, no. 3 (March 2007): E748—E755. http://dx.doi.org/10.1152/ajpendo.00311.2006.
Abstract:
Chronic contractile activity of skeletal muscle induces an increase in mitochondria located in proximity to the sarcolemma [subsarcolemmal (SS)] and in mitochondria interspersed between the myofibrils [intermyofibrillar (IMF)]. These are energetically favorable metabolic adaptations, but because mitochondria are also involved in apoptosis, we investigated the effect of chronic contractile activity on mitochondrially mediated apoptotic signaling in muscle. We hypothesized that chronic contractile activity would provide protection against mitochondrially mediated apoptosis despite an elevation in the expression of proapoptotic proteins. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 h/day) rat muscle for 7 days. Chronic contractile activity did not alter the Bax/Bcl-2 ratio, an index of apoptotic susceptibility, and did not affect manganese superoxide dismutase levels. However, contractile activity increased antiapoptotic 70-kDa heat shock protein and apoptosis repressor with a caspase recruitment domain by 1.3- and 1.4-fold ( P < 0.05), respectively. Contractile activity elevated SS mitochondrial reactive oxygen species (ROS) production 1.4- and 1.9-fold ( P < 0.05) during states IV and III respiration, respectively, whereas IMF mitochondrial state IV ROS production was suppressed by 28% ( P < 0.05) and was unaffected during state III respiration. Following stimulation, exogenous ROS treatment produced less cytochrome c release (25–40%) from SS and IMF mitochondria, and also reduced apoptosis-inducing factor release (≈30%) from IMF mitochondria, despite higher inherent cytochrome c and apoptosis-inducing factor expression. Chronic contractile activity did not alter mitochondrial permeability transition pore (mtPTP) components in either subfraction. However, SS mitochondria exhibited a significant increase in the time to Vmax of mtPTP opening. Thus, chronic contractile activity induces predominantly antiapoptotic adaptations in both mitochondrial subfractions. Our data suggest the possibility that chronic contractile activity can exert a protective effect on mitochondrially mediated apoptosis in muscle.
2
Parsons, Melissa J., and Douglas R. Green. "Mitochondria in cell death." Essays in Biochemistry 47 (June 14, 2010): 99–114. http://dx.doi.org/10.1042/bse0470099.
Abstract:
Apoptosis can be thought of as a signalling cascade that results in the death of the cell. Properly executed apoptosis is critically important for both development and homoeostasis of most animals. Accordingly, defects in apoptosis can contribute to the development of autoimmune disorders, neurological diseases and cancer. Broadly speaking, there are two main pathways by which a cell can engage apoptosis: the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. At the centre of the intrinsic apoptotic signalling pathway lies the mitochondrion, which, in addition to its role as the bioenergetic centre of the cell, is also the cell’s reservoir of pro-death factors which reside in the mitochondrial IMS (intermembrane space). During intrinsic apoptosis, pores are formed in the OMM (outer mitochondrial membrane) of the mitochondria in a process termed MOMP (mitochondrial outer membrane permeabilization). This allows for the release of IMS proteins; once released during MOMP, some IMS proteins, notably cytochrome c and Smac/DIABLO (Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI), promote caspase activation and subsequent cleavage of structural and regulatory proteins in the cytoplasm and the nucleus, leading to the demise of the cell. MOMP is achieved through the co-ordinated actions of pro-apoptotic members and inhibited by anti-apoptotic members of the Bcl-2 family of proteins. Other aspects of mitochondrial physiology, such as mitochondrial bioenergetics and dynamics, are also involved in processes of cell death that proceed through the mitochondria. Proper regulation of these mitochondrial functions is vitally important for the life and death of the cell and for the organism as a whole.
3
Heikaus, Sebastian, Linda van den Berg, Tobias Kempf, Csaba Mahotka, Helmut Erich Gabbert, and Uwe Ramp. "HA14-1 is Able to Reconstitute the Impaired Mitochondrial Pathway of Apoptosis in Renal Cell Carcinoma Cell Lines." Analytical Cellular Pathology 30, no. 5 (January 1, 2008): 419–33. http://dx.doi.org/10.1155/2008/693095.
Abstract:
Renal cell carcinomas (RCCs) exhibit a marked resistance towards apoptosis. Although most apoptotic stimuli converge at the level of the mitochondria, little is known about the mitochondrial apoptosis pathway in renal cell carcinomas. The aim of the present study, therefore, was to investigate the functionality of the mitochondrial apoptosis pathway in renal cell carcinoma cell lines by exposure to TRAIL, etoposide, HA14-1 and betulinic acid activating the mitochondria by different mechanisms. Sensitivity to TRAIL-induced apoptosis correlated with cleavage of the initiator caspase-8, but the mitochondrial apoptosis pathway was not induced. Similarly, etoposide and betulinic acid could not induce mitochondrial damage. In contrast, HA14-1 was able to activate mitochondrial apoptosis, thereby demonstrating functionally inducible signalling pathways downstream of the mitochondria. The intactness of the pathways upstream of the mitochondria was shown by pretreatment of TRAIL-sensitive cell lines with HA14-1, which could reconstitute TRAIL-induced mitochondrial damage and resulted in a synergistic apoptosis induction.Our results demonstrate that the apoptotic pathways upstream and downstream of the mitochondria are intact and inducible in renal cell carcinoma cell lines. However, resistance towards mitochondrial apoptosis is located on the level of the mitochondria themselves.
4
Zamzami, N., S. A. Susin, P. Marchetti, T. Hirsch, I. Gómez-Monterrey, M. Castedo, and G. Kroemer. "Mitochondrial control of nuclear apoptosis." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1533–44. http://dx.doi.org/10.1084/jem.183.4.1533.
Abstract:
Anucleate cells can be induced to undergo programmed cell death (PCD), indicating the existence of a cytoplasmic PCD pathway that functions independently from the nucleus. Cytoplasmic structures including mitochondria have been shown to participate in the control of apoptotic nuclear disintegration. Before cells exhibit common signs of nuclear apoptosis (chromatin condensation and endonuclease-mediated DNA fragmentation), they undergo a reduction of the mitochondrial transmembrane potential (delta psi m) that may be due to the opening of mitochondrial permeability transition (PT) pores. Here, we present direct evidence indicating that mitochondrial PT constitutes a critical early event of the apoptotic process. In a cell-free system combining purified mitochondria and nuclei, mitochondria undergoing PT suffice to induce chromatin condensation and DNA fragmentation. Induction of PT by pharmacological agents augments the apoptosis-inducing potential of mitochondria. In contrast, prevention of PT by pharmacological agents impedes nuclear apoptosis, both in vitro and in vivo. Mitochondria from hepatocytes or lymphoid cells undergoing apoptosis, but not those from normal cells, induce disintegration of isolated Hela nuclei. A specific ligand of the mitochondrial adenine nucleotide translocator (ANT), bongkreik acid, inhibits PT and reduces apoptosis induction by mitochondria in a cell-free system. Moreover, it inhibits the induction of apoptosis in intact cells. Several pieces of evidence suggest that the proto-oncogene product Bcl-2 inhibits apoptosis by preventing mitochondrial PT. First, to inhibit nuclear apoptosis, Bcl-2 must be localized in mitochondrial but not nuclear membranes. Second, transfection-enforced hyperexpression of Bcl-2 directly abolishes the induction of mitochondrial PT in response to a protonophore, a pro-oxidant, as well as to the ANT ligand atractyloside, correlating with its apoptosis-inhibitory effect. In conclusion, mitochondrial PT appears to be a critical step of the apoptotic cascade.
5
Majewski, Nathan, Veronique Nogueira, R. Brooks Robey, and Nissim Hay. "Akt Inhibits Apoptosis Downstream of BID Cleavage via a Glucose-Dependent Mechanism Involving Mitochondrial Hexokinases." Molecular and Cellular Biology 24, no. 2 (January 15, 2004): 730–40. http://dx.doi.org/10.1128/mcb.24.2.730-740.2004.
Abstract:
ABSTRACT The serine/threonine kinase Akt/protein kinase B inhibits apoptosis induced by a variety of stimuli, including overexpression or activation of proapoptotic Bcl-2 family members. The precise mechanisms by which Akt prevents apoptosis are not completely understood, but Akt may function to maintain mitochondrial integrity, thereby preventing cytochrome c release following an apoptotic insult. This effect may be mediated, in part, via promotion of physical and functional interactions between mitochondria and hexokinases. Here we show that growth factor deprivation induced proteolytic cleavage of the proapoptotic Bcl-2 family member BID to yield its active truncated form, tBID. Activated Akt inhibited mitochondrial cytochrome c release and apoptosis following BID cleavage. Akt also antagonized tBID-mediated BAX activation and mitochondrial BAK oligomerization, two downstream events thought to be critical for tBID-induced apoptosis. Glucose deprivation, which impaired the ability of Akt to maintain mitochondrion-hexokinase association, prevented Akt from inhibiting BID-mediated apoptosis. Interestingly, tBID independently elicited dissociation of hexokinases from mitochondria, an effect that was antagonized by activated Akt. Ectopic expression of the amino-terminal half of hexokinase II, which is catalytically active and contains the mitochondrion-binding domain, consistently antagonized tBID-induced apoptosis. These results suggest that Akt inhibits BID-mediated apoptosis downstream of BID cleavage via promotion of mitochondrial hexokinase association and antagonism of tBID-mediated BAX and BAK activation at the mitochondria.
6
Seo, Young Ah, Veronica Lopez, and Shannon L. Kelleher. "A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function." American Journal of Physiology-Cell Physiology 300, no. 6 (June 2011): C1479—C1489. http://dx.doi.org/10.1152/ajpcell.00420.2010.
Abstract:
Female reproductive tissues such as mammary glands, ovaries, uterus, and placenta are phenotypically dynamic, requiring tight integration of bioenergetic and apoptotic mechanisms. Mitochondrial zinc (Zn) pools have emerged as a central player in regulating bioenergetics and apoptosis. Zn must first be imported into mitochondria to modulate mitochondrion-specific functions; however, mitochondrial Zn import mechanisms have not been identified. Here we documented that the Zn transporter ZnT2 is associated with the inner mitochondrial membrane and acts as an auxiliary Zn importer into mitochondria in mammary cells. We found that attenuation of ZnT2 expression significantly reduced mitochondrial Zn uptake and total mitochondrial Zn pools. Moreover, expression of a ZnT2-hemagglutinin (HA) fusion protein was localized to mitochondria and significantly increased Zn uptake and mitochondrial Zn pools, directly implicating ZnT2 in Zn import into mitochondria. Confocal microscopy of truncated and point mutants of ZnT2-green fluorescent protein (GFP) fusion proteins revealed a histidine-rich motif (51HH XH54) in the NH2 terminus that is important for mitochondrial targeting of ZnT2. More importantly, the expansion of mitochondrial Zn pools by ZnT2 overexpression significantly reduced ATP biogenesis and mitochondrial oxidation concurrent with increased apoptosis, suggesting a functional role for ZnT2-mediated Zn import into mitochondria. These results identify the first Zn transporter directly associated with mitochondria and suggest that unique secretory tissues such as the mammary gland require novel mechanisms to modulate mitochondrion-specific functions.
7
Tang, Ho Lam, Anh-Huy Phan Le, and Hong Lok Lung. "The increase in mitochondrial association with actin precedes Bax translocation in apoptosis." Biochemical Journal 396, no. 1 (April 26, 2006): 1–5. http://dx.doi.org/10.1042/bj20060241.
Abstract:
Accumulating evidence indicates the potential role of actin cytoskeleton in facilitating the mitochondrial recruitment of various pro-apoptotic proteins from the cytosol to initiate apoptosis. In the present paper, we report the observation of the increase in mitochondrial association of actin in early apoptosis. Using cell fractionation and Western blot analysis, we found that mitochondrial accumulation of β-actin occurred before the mitochondrial insertion of Bax and release of cytochrome c in apoptosis. The mitochondrial accumulation of β-actin was observed with various apoptotic stimuli in various cell lines, suggesting that this is a general apoptotic phenomenon in mammalian systems. Using fluorescence microscopy, we have shown that an apoptotic induction triggered the reorganization of the F-actin (filamentous actin) network with an increase in the association with mitochondria, which was observed before mitochondrial fission and nuclear condensation. Perhaps actin could contribute to the initiation of apoptosis by enabling cytosolic pro-apoptotic proteins to be carried to mitochondria by the cytoskeleton-driven trafficking system.
8
Mayer, Bernd, and Rainer Oberbauer. "Mitochondrial Regulation of Apoptosis." Physiology 18, no. 3 (June 2003): 89–94. http://dx.doi.org/10.1152/nips.01433.2002.
Abstract:
Mitochondria play a central part in cellular survival and apoptotic death. These processes are highly regulated by pro- and antiapoptotic Bcl-2 superfamily members. A key feature within apoptosis cascades is disruption of mitochondrial transmembrane potential and apoptogenic protein release, caused by opening of the permeability transition pore (PT). New data, however, indicate that mitochondrial apoptosis may occur without PT involvement.
9
Sugioka, Rie, Shigeomi Shimizu, and Yoshihide Tsujimoto. "Fzo1, a Protein Involved in Mitochondrial Fusion, Inhibits Apoptosis." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 52726–34. http://dx.doi.org/10.1074/jbc.m408910200.
Abstract:
Mitochondrial morphology and physiology are regulated by the processes of fusion and fission. Some forms of apoptosis are reported to be associated with mitochondrial fragmentation. We showed that overexpression of Fzo1A/B (rat) proteins involved in mitochondrial fusion, or silencing of Dnm1 (rat)/Drp1 (human) (a mitochondrial fission protein), increased elongated mitochondria in healthy cells. After apoptotic stimulation, these interventions inhibited mitochondrial fragmentation and cell death, suggesting that a process involved in mitochondrial fusion/fission might play a role in the regulation of apoptosis. Consistently, silencing of Fzo1A/B or Mfn1/2 (a human homolog of Fzo1A/B) led to an increase of shorter mitochondria and enhanced apoptotic death. Overexpression of Fzo1 inhibited cytochromecrelease and activation of Bax/Bak, as assessed from conformational changes and oligomerization. Silencing of Mfn or Drp1 caused an increase or decrease of mitochondrial sensitivity to apoptotic stimulation, respectively. These results indicate that some of the proteins involved in mitochondrial fusion/fission modulate apoptotic cell death at the mitochondrial level.
10
Su, Ching-Chieh, Jia-Ying Yang, Hsin-Ban Leu, Yumay Chen, and Ping H. Wang. "Mitochondrial Akt-regulated mitochondrial apoptosis signaling in cardiac muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 3 (February 2012): H716—H723. http://dx.doi.org/10.1152/ajpheart.00455.2011.
Abstract:
We recently reported translocation and activation of Akt in cardiac mitochondria. This study was to determine whether activation of Akt in mitochondria could inhibit apoptosis of cardiac muscle cells. Insulin stimulation induced translocation of phosphorylated Akt to the mitochondria in primary cardiomyocytes. A mitochondria-targeted constitutively active Akt was overexpressed via adenoviral vector and inhibited efflux of cytochrome c and apoptosis-inducing factor from mitochondria to cytosol and partially prevented loss of mitochondria cross-membrane electrochemical gradient. Activation of caspase 3 was suppressed in the cardiomyocytes transduced with mitochondria-targeted active Akt, whereas a mitochondria-targeted dominant negative Akt enhanced activation of caspase 3. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay showed that mitochondrial activation of Akt significantly reduced the number of apoptotic cells. When the endogenous Akt was abolished by LY294002, the antiapoptotic actions of mitochondrial Akt remained effective. These experiments suggested that mitochondrial Akt suppressed apoptosis signaling independent of cytosolic Akt in cardiac muscle cells.
11
Karbowski, Mariusz, Damien Arnoult, Hsiuchen Chen, David C. Chan, Carolyn L. Smith, and Richard J. Youle. "Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis." Journal of Cell Biology 164, no. 4 (February 9, 2004): 493–99. http://dx.doi.org/10.1083/jcb.200309082.
Abstract:
A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix–targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis.
12
Feng, Jinzhou, Tao Tao, Weiping Yan, Cindy Si Chen, and Xinyue Qin. "Curcumin Inhibits Mitochondrial Injury and Apoptosis from the Early Stage in EAE Mice." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/728751.
Abstract:
The exact pathophysiological change concerning mitochondrial injury and oligodendrocyte apoptosis in MS and EAE model is still unknown. Whether curcumin is able to inhibit mitochondrial injury and suppress the apoptosis in the early stages of MS/EAE is still unclear. We first explored mitochondrial injury and apoptosis at different time points p.i. in C57 BL/6 EAE mice. We then explored the effects of curcumin on mitochondria and apoptosis. Results showed that mitochondrial injury can be observed 3 days p.i. Apoptosis in the spinal cord occurred 3 days p.i. and the apoptotic cells were shown to be oligodendrocytes and neuronal cells. Curcumin significantly reduced the number of apoptotic cells and inhibited the upregulation of cyt-c, caspase-9, and caspase-3 at 7 days p.i. in the EAE mice. These observations demonstrate that mitochondrial injury and oligodendrocyte/neuronal apoptosis occur in the early stages of EAE. Curcumin can inhibit apoptosis in EAE mice which maybe act through protection of mitochondrial injury and inhibition of the intrinsic apoptotic pathway.
13
Susin, Santos A., Hans K. Lorenzo, Naoufal Zamzami, Isabel Marzo, Catherine Brenner, Nathanael Larochette, Marie-Christine Prévost, Pedro M. Alzari, and Guido Kroemer. "Mitochondrial Release of Caspase-2 and -9 during the Apoptotic Process." Journal of Experimental Medicine 189, no. 2 (January 18, 1999): 381–94. http://dx.doi.org/10.1084/jem.189.2.381.
Abstract:
The barrier function of mitochondrial membranes is perturbed early during the apoptotic process. Here we show that the mitochondria contain a caspase-like enzymatic activity cleaving the caspase substrate Z-VAD.afc, in addition to three biological activities previously suggested to participate in the apoptotic process: (a) cytochrome c; (b) an apoptosis-inducing factor (AIF) which causes isolated nuclei to undergo apoptosis in vitro; and (c) a DNAse activity. All of these factors, which are biochemically distinct, are released upon opening of the permeability transition (PT) pore in a coordinate, Bcl-2–inhibitable fashion. Caspase inhibitors fully neutralize the Z-VAD.afc–cleaving activity, have a limited effect on the AIF activity, and have no effect at all on the DNase activities. Purification of proteins reacting with the biotinylated caspase substrate Z-VAD, immunodetection, and immunodepletion experiments reveal the presence of procaspase-2 and -9 in mitochondria. Upon induction of PT pore opening, these procaspases are released from purified mitochondria and become activated. Similarly, upon induction of apoptosis, both procaspases redistribute from the mitochondrion to the cytosol and are processed to generate enzymatically active caspases. This redistribution is inhibited by Bcl-2. Recombinant caspase-2 and -9 suffice to provoke full-blown apoptosis upon microinjection into cells. Altogether, these data suggest that caspase-2 and -9 zymogens are essentially localized in mitochondria and that the disruption of the outer mitochondrial membrane occurring early during apoptosis may be critical for their subcellular redistribution and activation.
14
Khera, Samira Y., and Nan-Shan Chang. "Role of p53 Tumor Suppressor in Mitochondrial Apoptosis." Guthrie Journal 70, no. 3 (July 2001): 98–103. http://dx.doi.org/10.3138/guthrie.70.3.098.
Abstract:
The p53 tumor suppressor plays an important role in controlling gene expression, cell growth and apoptosis. Mutation of p53 has been found in more than 50% of cancers, suggesting its role in cancer development. P53 induces the expression of a variety of apoptosis inducing proteins, some of which are located in mitochondria. In addition to its nuclear localization, p53 is also found in the mitochondria and translocates from the nucleus to this organelle during apoptosis. P53 appears to play a homeostatic role of mitochondrial biogenesis, function and apoptosis. P53 physically associates with a mitochondrial protein WOX1 (WW domain oxidoreductase). Without WOX1, the p53 apoptotic function is impaired. This review discusses the functional significance of p53 and WOX1 in mitochondrial apoptosis.
15
Kroemer, Guido. "Mitochondrial control of apoptosis: an overview." Biochemical Society Symposia 66 (September 1, 1999): 1–15. http://dx.doi.org/10.1042/bss0660001.
Abstract:
The mitochondrial permeability transition (PT) pore, also called the mitochondrial megachannel, is a multiprotein complex formed at the contact site between the mitochondrial inner and outer membranes, exactly the same location at which Bax, Bcl-2 and Bcl-XL are particularly abundant. The PT pore participates in the regulation of matrix Ca2+, pH, transmembrane potential and volume, and functions as a Ca2+-, voltage-, pH- and redox-gated channel with several levels of conductance and little, if any, ion selectivity. We have obtained three independent lines of evidence implicating the mitochondrial PT pore in apoptosis. First, in intact cells, apoptosis is accompanied by an early dissipation of the mitochondrial transmembrane potential, ΔΨm. In several models of apoptosis, specific agents inhibiting the mitochondrial PT pore abolish this dissipation of the ΔΨm and simultaneously prevent activation of downstream caspases and endonucleases, indicating that PT pore opening can be a critical event of the apoptotic process. Secondly, mitochondria are rate-limiting for caspase and nuclease activation in several cell-free systems of apoptosis. Isolated mitochondria release apoptogenic factors capable of activating pro-caspases or endonucleases upon opening of the mitochondrial megachannel in vitro. Thirdly, opening of the purified PT pore complex reconstituted into liposomes is inhibited by recombinant Bcl-2 or Bcl-XL, two apoptosis-inhibitory proteins that also prevent PT pore opening in cells and isolated mitochondria. Altogether, our results suggest that PT pore opening is sufficient and (mostly) necessary for triggering apoptosis. The implications of these findings are examined in the light of pharmacological interventions in apoptosis.
16
Weber, Arnim, Stefan A. Paschen, Klaus Heger, Florian Wilfling, Tobias Frankenberg, Heike Bauerschmitt, Barbara M. Seiffert, Susanne Kirschnek, Hermann Wagner, and Georg Häcker. "BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins." Journal of Cell Biology 177, no. 4 (May 21, 2007): 625–36. http://dx.doi.org/10.1083/jcb.200610148.
Abstract:
Release of apoptogenic proteins such as cytochrome c from mitochondria is regulated by pro- and anti-apoptotic Bcl-2 family proteins, with pro-apoptotic BH3-only proteins activating Bax and Bak. Current models assume that apoptosis induction occurs via the binding and inactivation of anti-apoptotic Bcl-2 proteins by BH3-only proteins or by direct binding to Bax. Here, we analyze apoptosis induction by the BH3-only protein BimS. Regulated expression of BimS in epithelial cells was followed by its rapid mitochondrial translocation and mitochondrial membrane insertion in the absence of detectable binding to anti-apoptotic Bcl-2 proteins. This caused mitochondrial recruitment and activation of Bax and apoptosis. Mutational analysis of BimS showed that mitochondrial targeting, but not binding to Bcl-2 or Mcl-1, was required for apoptosis induction. In yeast, BimS enhanced the killing activity of Bax in the absence of anti-apoptotic Bcl-2 proteins. Thus, cell death induction by a BH3-only protein can occur through a process that is independent of anti-apoptotic Bcl-2 proteins but requires mitochondrial targeting.
17
Susin, S. A., N. Zamzami, M. Castedo, T. Hirsch, P. Marchetti, A. Macho, E. Daugas, M. Geuskens, and G. Kroemer. "Bcl-2 inhibits the mitochondrial release of an apoptogenic protease." Journal of Experimental Medicine 184, no. 4 (October 1, 1996): 1331–41. http://dx.doi.org/10.1084/jem.184.4.1331.
Abstract:
Bcl-2 belongs to a family of apoptosis-regulatory proteins which incorporate into the outer mitochondrial as well as nuclear membranes. The mechanism by which the proto-oncogene product Bcl-2 inhibits apoptosis is thus far elusive. We and others have shown previously that the first biochemical alteration detectable in cells undergoing apoptosis, well before nuclear changes become manifest, is a collapse of the mitochondrial inner membrane potential (delta psi m), suggesting the involvement of mitochondrial products in the apoptotic cascade. Here we show that mitochondria contain a pre-formed approximately 50-kD protein which is released upon delta psi m disruption and which, in a cell-free in vitro system, causes isolated nuclei to undergo apoptotic changes such as chromatin condensation and internucleosomal DNA fragmentation. This apoptosis-inducing factor (AIF) is blocked by N-benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (Z-VAD.fmk), an antagonist of interleukin-1 beta-converting enzyme (ICE)-like proteases that is also an efficient inhibitor of apoptosis in cells. We have tested the effect of Bcl-2 on the formation, release, and action of AIF. When preventing mitochondrial permeability transition (which accounts for the pre-apoptotic delta psi m disruption in cells), Bcl-2 hyperexpressed in the outer mitochondrial membrane also impedes the release of AIF from isolated mitochondria in vitro. In contrast, Bcl-2 does not affect the formation of AIF, which is contained in comparable quantities in control mitochondria and in mitochondria from Bcl-2-hyperexpressing cells. Furthermore, the presence of Bcl-2 in the nuclear membrane does not interfere with the action of AIF on the nucleus, nor does Bcl-2 hyperexpression protect cells against AIF. It thus appears that Bcl-2 prevents apoptosis by favoring the retention of an apoptogenic protease in mitochondria.
18
Shah, Sumit J., and Paul W. Sylvester. "Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells." Biochemistry and Cell Biology 83, no. 1 (February 1, 2005): 86–95. http://dx.doi.org/10.1139/o04-127.
Abstract:
Tocotrienols and tocopherols represent the 2 subgroups within the vitamin E family of compounds, but tocotrienols display significantly greater apoptotic activity against a variety of cancer cell types. However, the exact mechanism mediating tocotrienol-induced apoptosis is not understood. Studies were conducted to determine the effects of tocotrienols on mitochondrial-stress-mediated apoptotic signaling in neoplastic +SA mammary epithelial cells grown in vitro. Exposure for 24 h to 0–20 µmol/L γ-tocotrienol resulted in a dose–responsive increase in +SA cells undergoing apoptosis, as determined by flow cytometric analysis of Annexin V staining. However, tocotrienol-induced apoptosis was not associated with a disruption or loss of mitochondrial membrane potential, or the release of mitochondrial cytochrome c into the cytoplasm, as determined by JC-1 flow cytometric staining and ELISA assay, respectively. Interestingly, apoptotic +SA cells showed a paradoxical decrease in mitochondrial levels of pro-apoptotic proteins Bid, Bax, and Bad, and a corresponding increase in mitochondrial levels of anti-apoptotic proteins, Bcl-2 and Bcl-xL, suggesting that mitochondrial membrane stability and integrity might actually be enhanced for a limited period of time following acute tocotrienol exposure. In summary, these findings clearly demonstrate that tocotrienol-induced apoptosis occurs independently of mitochondrial stress apoptotic signaling in neoplastic +SA mammary epithelial cells.Key words: breast cancer, tocotrienols, apoptosis, mitochondria, Bcl-2.
19
No, Mi-Hyun, Youngju Choi, Jinkyung Cho, Jun-Won Heo, Eun-Jeong Cho, Dong-Ho Park, Ju-Hee Kang, et al. "Aging Promotes Mitochondria-Mediated Apoptosis in Rat Hearts." Life 10, no. 9 (September 5, 2020): 178. http://dx.doi.org/10.3390/life10090178.
Abstract:
Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a necessary phenomenon for maintaining homeostasis and normal function of the heart. However, the mechanism of mitochondria-mediated apoptosis in aged hearts remains poorly understood. Here, we used male Fischer 344 rats of various ages, representing very young (1 month), young (4 months), middle-aged (12 months), and old (20 months) rats, to determine whether mitochondria-mediated apoptotic signals and apoptosis in the left ventricle of the heart are altered notably with aging. As the rats aged, the extramyocyte space and myocyte cross-sectional area in their left ventricle muscle increased, while the number of myocytes decreased. Additionally, mitochondrion-mediated apoptotic signals and apoptosis increased remarkably during aging. Therefore, our results demonstrate that aging promotes remarkable morphological changes and increases the degree of mitochondrion-mediated apoptosis in the left ventricle of rat hearts.
20
Cho, Sung-Gyu, Quansheng Du, Shuang Huang, and Zheng Dong. "Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis." American Journal of Physiology-Renal Physiology 299, no. 1 (July 2010): F199—F206. http://dx.doi.org/10.1152/ajprenal.00716.2009.
Abstract:
Recent studies revealed a striking morphological change of mitochondria during apoptosis. Mitochondria become fragmented and notably, the fragmentation contributes to mitochondrial outer membrane permeabilization and consequent release of apoptotic factors. In renal tubular cells, mitochondrial fragmentation involves the activation of Drp1, a key mitochondrial fission protein. However, it is unclear how Drp1 is regulated during tubular cell apoptosis. In this study, we examined Drp1 regulation during tubular cell apoptosis following ATP depletion. Rat kidney proximal tubular cells (RPTC) were subjected to azide treatment or severe hypoxia in glucose-free medium to induce ATP depletion. During ATP depletion, Drp1 was shown to be dephosphorylated at serine-637. Drp1 dephosphorylation could be suppressed by cyclosporine A and FK506, two calcineurin inhibitors. Importantly, cyclosporine A and FK506 could also prevent mitochondrial fragmentation, Bax accumulation, cytochrome c release, and apoptosis following ATP depletion in RPTC. The results suggest that calcineurin-mediated serine-637 dephosphorylation is involved in Drp1 activation during ATP depletion in renal tubular cells. Upon activation, Drp1 contributes to mitochondrial fragmentation and outer membrane permeabilization, resulting in the release of apoptogenic factors and apoptosis.
21
Li, Fu-Lun, Rong Xu, Qing-chun Zeng, Xin Li, Jie Chen, Yi-Fei Wang, Bin Fan, Lin Geng, and Bin Li. "Tanshinone IIA Inhibits Growth of Keratinocytes through Cell Cycle Arrest and Apoptosis: Underlying Treatment Mechanism of Psoriasis." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/927658.
Abstract:
The aim of the present investigation was to elucidate the cellular mechanisms whereby Tanshinone IIA (Tan IIA) leads to cell cycle arrest and apoptosisin vitroin keratinocytes, the target cells in psoriasis. Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. Furthermore, Tan IIA-induced apoptosis and mitochondrial membrane potential changes were also further demonstrated by DNA fragmentation, single-cell gel electrophoresis assay (SCGE), and flow cytometry methods. Apoptosis was partially blocked by the caspase-3 inhibitor Ac-DEVD-CHO. Mitochondrial regulation of apoptosis further downstream was investigated, showing changes in the mitochondrial membrane potential, cytochrome c release into the cytoplasm, and enhanced activation of cleaved caspase-3 and Poly ADP-ribose polymerase (PARP). There was also no translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus in apoptotic keratinocytes, indicating Tan IIA-induced apoptosis occurs mainly through the caspase pathway. Our findings provide the molecular mechanisms by which Tan IIA can be used to treat psoriasis and support the traditional use ofSalvia miltiorrhiza Bungee (Labiatae)for psoriasis and related skin diseases.
22
Gao, Wenhua, Yongmei Pu, Kathy Q. Luo, and Donald C. Chang. "Temporal relationship between cytochrome c release and mitochondrial swelling during UV-induced apoptosis in living HeLa cells." Journal of Cell Science 114, no. 15 (August 1, 2001): 2855–62. http://dx.doi.org/10.1242/jcs.114.15.2855.
Abstract:
During apoptosis, cytochrome c is released from mitochondria to the cytosol to activate a caspase cascade, which commits the cell to the death process. It has been proposed that the release of cytochrome c is caused by a swelling of the mitochondrial matrix triggered by the apoptotic stimuli. To test this theory, we measured directly the dynamic re-distribution of green fluorescence protein (GFP)-tagged cytochrome c and morphological change of mitochondria within living HeLa cells during u.v.-induced apoptosis. We observed that mitochondria did not swell when cytochrome c was released from mitochondria to cytosol during apoptosis. Instead, mitochondria swelled to spherical shapes within 10 minutes of cytochrome c release. This finding strongly suggests that cytochrome c release in apoptosis was not caused by mitochondrial swelling. This conclusion was further supported in two separated experiments using an immunostaining method and carbonyl cyanide m-chlorophenyl-hydrazone (CCCP) treatment. In addition, we found evidence that cytochrome c was also released before mitochondrial swelling in apoptosis induced by other cell death-inducing treatments, including tumor necrosis factor (TNF) and actinomycin D.
23
Ariës, Ingrid M., Kimberly Bodaar, Salmaan A. Karim, Triona Ni Chonghaile, Laura Hinze, Melissa A. Burns, Maren Pfirrmann, et al. "PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia." Journal of Experimental Medicine 215, no. 12 (November 7, 2018): 3094–114. http://dx.doi.org/10.1084/jem.20180570.
Abstract:
The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.
24
Qian, Ting, and John J. Lemasters. "Accelerated Mitochondrial Reactive Oxygen Species Formation Induces OnsẸt of the Mitochondrial Permeability Transition and Mitochondrial Swelling in Cultured Hepatocytes After TNFα Exposure." Microscopy and Microanalysis 7, S2 (August 2001): 604–5. http://dx.doi.org/10.1017/s1431927600029093.
Abstract:
INTRODUCTION: The mitochondrial permeability transition (MPT) is implicated in mediating TNFα-induced apoptosis in cultured hepatocytes. Opening of permeability transition (PT) pores in the mitochondrial inner membrane causes the MPT. After the MPT, mitochondria swell, the outer membrane bursts, and pro-apoptotic cytochrome c is released into the cytosol. in isolated mitochondria, ROS formation promotes onset of the MPT. However, how mitochondrial ROS formation regulates the MPT in intact cells in TNFα-induced apoptosis is unknown. AIM: The present study was designed to determine the role of mitochondrial ROS formation in TNFα-induced MPT and apoptosis in cultured rat hepatocytes.METHODS: Hepatocytes expressing an IkB superrepressor were pretreated with 2 μM t-BuOOH 4 hours before TNFα exposure with and without CsA (2 μM, an inhibitor of the PT pore) and the antioxidants, desferal (0.5 mM) or diphenylphenylendiamine (DPPD, 10 μM). Cell viability was monitored by propidium iodide fluorometry.
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Putri, Mustika Anggiane, Patwa Amani, Donna Adriani, and Rita Khairani. "Importance of Exercise in Mitigating Age-Related Cardiac Apoptosis." Sriwijaya Journal of Medicine 6, no. 3 (December 20, 2023): 94–101. http://dx.doi.org/10.32539/sjm.v6i3.208.
Abstract:
Aging causes a progressive decline in heart function. Loss of cardiomyocytes through programmed cell death or apoptosis is a critical factor contributing to this age-related damage. As we age, the heart undergoes structural changes, such as loss of cardiomyocytes, cardiomyocyte hypertrophy, and increased connective tissue with changes in heart geometry. It is widely known that mitochondria are vital sites of apoptosis. Mitochondrial-mediated apoptotic pathways are important regulators of apoptosis with aging. Mitochondrial dysfunction and oxidative stress also contribute to the cardiac remodeling and apoptosis associated with the aging process. On the other hand, exercise can improve heart function and reduce the risk of heart disease. Recent studies suggest that aging increases apoptotic signaling in the left ventricle. However, chronic exercise reduces this mitochondrial-mediated apoptotic signaling pathway in the aging heart. This review will describe the impacts of aging and exercise on cardiac apoptosis, highlighting the importance of exercise in reducing age-related cardiac apoptosis.
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Lam, Minh, Nancy L. Oleinick, and Anna-Liisa Nieminen. "Photodynamic Therapy-induced Apoptosis in Epidermoid Carcinoma Cells." Journal of Biological Chemistry 276, no. 50 (September 28, 2001): 47379–86. http://dx.doi.org/10.1074/jbc.m107678200.
Abstract:
Photodynamic therapy (PDT), a novel and promising cancer treatment that employs a combination of a photosensitizing chemical and visible light, induces apoptosis in human epidermoid carcinoma A431 cells. However, the precise mechanism of PDT-induced apoptosis is not well characterized. To dissect the pathways of PDT-induced apoptosis, we investigated the involvement of mitochondrial damage by examining a second generation photosensitizer, the silicon phthalocyanine 4 (Pc 4). By using laser-scanning confocal microscopy, we found that Pc 4 localized to cytosolic membranes primarily, but not exclusively, in mitochondria. Formation of mitochondrial reactive oxygen species (ROS) was detected within minutes when cells were exposed to Pc 4 and 670–675 nm light. This was followed by mitochondrial inner membrane permeabilization, depolarization and swelling, cytochromecrelease, and apoptotic death. Desferrioxamine prevented mitochondrial ROS production and the events thereafter. Cyclosporin A plus trifluoperazine, blockers of the mitochondrial permeability transition, inhibited mitochondrial inner membrane permeabilization and depolarization without affecting mitochondrial ROS generation. These data indicate that the mitochondrial ROS are critical in initiating mitochondrial inner membrane permeabilization, which leads to mitochondrial swelling, cytochromecrelease to the cytosol, and apoptotic death during PDT with Pc 4.
27
Hirpara, Jayshree L., Mohamed A. Seyed, Kok W. Loh, Hui Dong, R. Manjunatha Kini, and Shazib Pervaiz. "Induction of mitochondrial permeability transition and cytochrome C release in the absence of caspase activation is insufficient for effective apoptosis in human leukemia cells." Blood 95, no. 5 (March 1, 2000): 1773–80. http://dx.doi.org/10.1182/blood.v95.5.1773.005k17_1773_1780.
Abstract:
Induction of mitochondrial permeability transition (MPT) and cytosolic translocation of cytochrome C are considered essential components of the apoptotic pathway. Hence, there is the realization that mitochondrial-specific drugs could have potential for use as chemotherapeutic agents to trigger apoptosis in tumor cells. Recently, we showed that photoproducts of merocyanine 540 (pMC540) induced tumor cell apoptosis. In this study, we focused on identifying mitochondrial-specific compounds from pMC540 and studied their apoptotic potential. One purified fraction, C5, induced a drop in mitochondrial transmembrane potential and cytosolic translocation of cytochrome C in HL60 human leukemia cells. Moreover, the addition of C5 to purified rat liver mitochondria induced MPT as indicated by mitochondrial matrix swelling, which was completely inhibited by cyclosporin A, an inhibitor of the inner-membrane pore. Supernatant of C5-treated mitochondria showed a dose-dependent increase in cytochrome C, which was also inhibited in the presence of cyclosporin A, strongly indicating a direct effect on the inner-membrane pore. Despite the strong mitochondrial reactivity, C5 elicited minimal cytotoxicity (less than 25%) against HL60 leukemia and M14 melanoma cells because of inefficient caspase activation. However, prior exposure to C5 significantly enhanced the apoptotic response to etoposide or the CD95 receptor. Thus, we demonstrate that MPT induction and cytochrome C release by the novel compound C5, in the absence of effective caspase activation, is insufficient for triggering efficient apoptosis in tumor cells. However, when used in combination with known apoptosis inducers, such compounds could enhance the sensitivity of tumor cells to apoptosis.
28
Lu, Ailing, Michael Frink, Mashkoor A. Choudhry, William J. Hubbard, Loring W. Rue, Kirby I. Bland, and Irshad H. Chaudry. "Mitochondria play an important role in 17β-estradiol attenuation of H2O2-induced rat endothelial cell apoptosis." American Journal of Physiology-Endocrinology and Metabolism 292, no. 2 (February 2007): E585—E593. http://dx.doi.org/10.1152/ajpendo.00413.2006.
Abstract:
Studies have shown salutary effects of 17β-estradiol following trauma-hemorrhage on different cell types. 17β-Estradiol also induces improved circulation via relaxation of the aorta and has an anti-apoptotic effect on endothelial cells. Because mitochondria play a pivotal role in apoptosis, we hypothesized that 17β-estradiol will maintain mitochondrial function and will have protective effects against H2O2-induced apoptosis in endothelial cells. Endothelial cells were isolated from rats' aorta and cultured in the presence or absence of H2O2, a potent inducer of apoptosis. In additional studies, endothelial cells were pretreated with 17β-estradiol. Flow cytometry analysis revealed H2O2-induced apoptosis in 80.9% of endothelial cells; however, prior treatment of endothelial cells with 17β-estradiol resulted in an ∼40% reduction in apoptosis. This protective effect of 17β-estradiol was abrogated when endothelial cells were cultured in the presence ICI-182780, indicating the involvement of estrogen receptor (ER). Fluorescence microscopy revealed a 17β-estradiol-mediated attenuation of H2O2-induced mitochondrial condensation. Western blot analysis demonstrated that H2O2-induced cytochrome c release from mitochondrion to cytosol and the activation of caspase-9 and -3 were decreased by 17β-estradiol. These findings suggest that 17β-estradiol attenuated H2O2-induced apoptosis via ER-dependent activation of caspase-9 and -3 in rat endothelial cells through mitochondria.
29
Shen, Liang, and Xianquan Zhan. "Mitochondrial Dysfunction Pathway Alterations Offer Potential Biomarkers and Therapeutic Targets for Ovarian Cancer." Oxidative Medicine and Cellular Longevity 2022 (April 20, 2022): 1–22. http://dx.doi.org/10.1155/2022/5634724.
Abstract:
The mitochondrion is a very versatile organelle that participates in some important cancer-associated biological processes, including energy metabolism, oxidative stress, mitochondrial DNA (mtDNA) mutation, cell apoptosis, mitochondria-nuclear communication, dynamics, autophagy, calcium overload, immunity, and drug resistance in ovarian cancer. Multiomics studies have found that mitochondrial dysfunction, oxidative stress, and apoptosis signaling pathways act in human ovarian cancer, which demonstrates that mitochondria play critical roles in ovarian cancer. Many molecular targeted drugs have been developed against mitochondrial dysfunction pathways in ovarian cancer, including olive leaf extract, nilotinib, salinomycin, Sambucus nigra agglutinin, tigecycline, and eupatilin. This review article focuses on the underlying biological roles of mitochondrial dysfunction in ovarian cancer progression based on omics data, potential molecular relationship between mitochondrial dysfunction and oxidative stress, and future perspectives of promising biomarkers and therapeutic targets based on the mitochondrial dysfunction pathway for ovarian cancer.
30
McCormick, A. Louise, Vanessa L. Smith, Dar Chow, and Edward S. Mocarski. "Disruption of Mitochondrial Networks by the Human Cytomegalovirus UL37 Gene Product Viral Mitochondrion-Localized Inhibitor of Apoptosis." Journal of Virology 77, no. 1 (January 1, 2003): 631–41. http://dx.doi.org/10.1128/jvi.77.1.631-641.2003.
Abstract:
ABSTRACT By 24 h after infection with human cytomegalovirus, the reticular mitochondrial network characteristic of uninfected fibroblasts was disrupted as mitochondria became punctate and dispersed. These alterations were associated with expression of the immediate-early (α) antiapoptotic UL37x1 gene product viral mitochondrion-localized inhibitor of apoptosis (vMIA). Similar alterations in mitochondrial morphology were induced directly by vMIA in transfected cells. A 68-amino-acid antiapoptotic derivative of vMIA containing the mitochondrial localization and antiapoptotic domains also induced disruption, whereas a mutant lacking the antiapoptotic domain failed to cause disruption. These data suggest that the fission and/or fusion process that normally controls mitochondrial networks is altered by vMIA. Mitochondrial fission has been implicated in the induction of apoptosis and vMIA-mediated inhibition of apoptosis may occur subsequent to this event.
31
Zaib, Sumera, Aqsa Hayyat, Naba Ali, Asma Gul, Muhammad Naveed, and Imtiaz Khan. "Role of Mitochondrial Membrane Potential and Lactate Dehydrogenase A in Apoptosis." Anti-Cancer Agents in Medicinal Chemistry 22, no. 11 (July 2022): 2048. http://dx.doi.org/10.2174/1871520621666211126090906.
Abstract:
: Apoptosis is a programmed cell death that occurs due to the production of several catabolic enzymes. During this process, several morphological and biochemical changes occur in mitochondria, the main organelle in the cell that participates in apoptosis and controls apoptotic pathways. During apoptosis, cytochrome c is released from mitochondria, and different proteins activate caspase cascades that carry out the cell towards the death process. Apoptosis mainly occurs due to p53 protein that allows the abnormal cells to proliferate. Bcl-2 and Bcl-xl are two anti-apoptotic members of the protein family that prevents apoptosis. The membrane potential of mitochondria decreases by the opening of the permeability transition pore (PTP). These PTP are formed by the binding of Bax with adenine nucleotide translocator (ANT) and cause depolarization in the membrane. The depolarization releases apoptogenic factors (cytochrome c) that result in the loss of oxidative phosphorylation. Knockdown in lactate dehydrogenase (LDH) is the cause of the decrease in mitochondrial membrane potential elevating the levels of reactive oxygen species (ROS) and Bax. Consequently, causing an increase in the release of cytochrome c that ultimately leads to apoptosis. In this review, we have summarized the combined effect of mitochondrial membrane potential and LDH enzyme that triggers apoptosis in cells and their role in the mechanism of apoptosis.
32
Granville, David J., and Roberta A. Gottlieb. "Mitochondria: Regulators of Cell Death and Survival." Scientific World JOURNAL 2 (2002): 1569–78. http://dx.doi.org/10.1100/tsw.2002.809.
Abstract:
The past 5 years has seen an intense surge in research devoted toward understanding the critical role of mitochondria in the regulation of cell death. Apoptosis can be initiated by a wide array of stimuli, inducing multiple signaling pathways that, for the most part, converge at the mitochondrion. Although classically considered the powerhouses of the cell, it is now understood that mitochondria are also “gatekeepers” that ultimately determine the fate of the cell. The mitochondrial decision as to whether a cell lives or dies is complex, involving protein-protein interactions, ionic changes, reactive oxygen species, and other mechanisms that require further elucidation. Once the death process is initiated, mitochondria undergo conformational changes, resulting in the release of cytochrome c (cyt c), caspases, endonucleases, and other factors leading to the onset and execution of apoptosis. The present review attempts to outline the complex milieu of events regulating the mitochondrial commitment to and processes involved in the implementation of the executioner phase of apoptotic cell death.
33
Schoeniger, Axel, Philipp Wolf, and Frank Edlich. "How Do Hexokinases Inhibit Receptor-Mediated Apoptosis?" Biology 11, no. 3 (March 8, 2022): 412. http://dx.doi.org/10.3390/biology11030412.
Abstract:
The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.
34
Mancini, Mariangela, Benjamin O. Anderson, Elizabeth Caldwell, Monireh Sedghinasab, Philip B. Paty, and David M. Hockenbery. "Mitochondrial Proliferation and Paradoxical Membrane Depolarization during Terminal Differentiation and Apoptosis in a Human Colon Carcinoma Cell Line." Journal of Cell Biology 138, no. 2 (July 28, 1997): 449–69. http://dx.doi.org/10.1083/jcb.138.2.449.
Abstract:
Herbimycin A, a tyrosine kinase inhibitor, induces cellular differentiation and delayed apoptosis in Colo-205 cells, a poorly differentiated human colon carcinoma cell line. Cell cycle analysis in conjunction with end labeling of DNA fragments revealed that G2 arrest preceded apoptotic cell death. Ultrastructural examination of herbimycin-treated cells demonstrated morphologic features of epithelial differentiation, including formation of a microvillar apical membrane and lateral desmosome adhesions. A marked accumulation of mitochondria was also observed. Fluorometric analysis using the mitochondrial probes nonyl-acridine orange and JC-1 confirmed a progressive increase in mitochondrial mass. However these cells also demonstrated a progressive decline in unit mitochondrial transmembrane potential (ΔΨm) as determined by the ΔΨm-sensitive fluorescent probes rhodamine 123 and JC-1 analyzed for red fluorescence. In concert with these mitochondrial changes, Colo-205 cells treated with herbimycin A produced increased levels of reactive oxygen species as evidenced by oxidation of both dichlorodihydrofluorescein diacetate and dihydroethidium. Cell-free assays for apoptosis using rat-liver nuclei and extracts of Colo-205 cells at 24 h showed that apoptotic activity of Colo-205 lysates requires the early action of mitochondria. Morphological and functional mitochondrial changes were observed at early time points, preceding cleavage of poly (ADP-ribose) polymerase. These results suggest that apoptosis in differentiated Colo-205 cells involves unrestrained mitochondrial proliferation and progressive membrane dysfunction, a novel mechanism in apoptosis.
35
Kokkinopoulou, Ioanna, and Paraskevi Moutsatsou. "Mitochondrial Glucocorticoid Receptors and Their Actions." International Journal of Molecular Sciences 22, no. 11 (June 3, 2021): 6054. http://dx.doi.org/10.3390/ijms22116054.
Abstract:
Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.
36
Chen, Min, Alan D. Guerrero, Li Huang, Zainuer Shabier, Michael Pan, Tse-Hua Tan, and Jin Wang. "Caspase-9-induced Mitochondrial Disruption through Cleavage of Anti-apoptotic BCL-2 Family Members." Journal of Biological Chemistry 282, no. 46 (September 24, 2007): 33888–95. http://dx.doi.org/10.1074/jbc.m702969200.
Abstract:
Mitochondrial disruption during apoptosis results in the release of cytochrome c that forms apoptosomes with Apaf-1 and caspase-9. Activation of caspase-9 by dimerization in apoptosomes then triggers a caspase signaling cascade. In addition, other apoptosis signaling molecules released from the mitochondrion, such as apoptosis-inducing factor and endonuclease G, may induce caspase-9-independent apoptosis. To determine the signaling events induced by caspase-9, we used chemically induced dimerization for specific activation of caspase-9. We observed that caspase-9 dimerization resulted in the loss of mitochondrial membrane potential and the cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1. Moreover, cleavage-resistant Bcl-2, Bcl-xL, or Mcl-1 potently inhibited caspase-9-dependent loss of mitochondrial membrane potential and the release of cytochrome c. Our data suggest that a caspase-9 signaling cascade induces feedback disruption of the mitochondrion through cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1.
37
Shoshan-Barmatz, Varda, Anna Shteinfer-Kuzmine, and Ankit Verma. "VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases." Biomolecules 10, no. 11 (October 26, 2020): 1485. http://dx.doi.org/10.3390/biom10111485.
Abstract:
The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer.
38
Minamikawa, T., A. Sriratana, D. A. Williams, D. N. Bowser, J. S. Hill, and P. Nagley. "Chloromethyl-X-rosamine (MitoTracker Red) photosensitises mitochondria and induces apoptosis in intact human cells." Journal of Cell Science 112, no. 14 (July 15, 1999): 2419–30. http://dx.doi.org/10.1242/jcs.112.14.2419.
Abstract:
We report that chloromethyl-X-rosamine (MitoTracker Red), a mitochondrion-selective fluorescent probe, has a strong photosensitising action. Photoirradiation of intact cells loaded with chloromethyl-X-rosamine induces depolarisation of the inner mitochondrial membrane and swelling of mitochondria, subsequently resulting in apoptosis. We have studied human osteosarcoma 143B TK-(rho+) cells and the derived (rho)0 206 cell line devoid of mitochondrial DNA. Colony formation tests revealed that chloromethyl-X-rosamine itself has no toxicity to either cell line in the concentration range 100–250 nM (unless photoirradiated). Chloromethyl-X-rosamine has potent phototoxicity such that almost quantitative cell killing was achieved at light doses of >2 J/cm2. These photodamaged cells initially showed swollen degenerative mitochondria and, later, uptake of propidium iodide in their apoptotic nuclei was observed. When cells were loaded with chloromethyl-X-rosamine (100 nM) and imaged by laser scanning confocal microscopy, photoirradiation by the laser beam under routine scanning conditions was sufficient to induce mitochondrial damage in both cell lines. This was evidenced by a rapid decrease of fluorescence intensity of co-loaded rhodamine 123 (indicative of mitochondrial depolarisation). Globular swelling of mitochondria took place within 15 minutes, imaged by the residual fluorescence of chloromethyl-X-rosamine itself, which also markedly decreased in intensity after imaging. Mitochondrial membrane depolarisation of cells loaded with chloromethyl-X-rosamine after photoirradiation using a measured dose of visible light was independently confirmed in 143B TK- and (rho)0 206 cells, by the significant decrease in uptake into cells of [3H]methyltriphenylphosphonium ions. Photoactivation of chloromethyl-X-rosamine in 143B TK-(rho+) cells, whose mitochondria had previously been loaded with calcein, caused rapid release of the mitochondrially entrapped calcein into the cytosol and nucleus. This major change in permeability of the mitochondrial inner membrane could not be prevented by cyclosporin A. Immunohistochemical study of cytochrome c revealed its diffuse redistribution into the cytoplasm in chloromethyl-X-rosamine-loaded cells after irradiation, as opposed to its specific mitochondrial localisation in non-irradiated cells. As a photosensitiser specifically targeted to mitochondria, and also a reporter of membrane potential and morphology, chloromethyl-X-rosamine may provide versatile new applications in studies of mitochondrial roles in cell death.
39
Zhang, Shi-Wen, Hao Wang, You-Yu Qiu, Ren-Chao Huang, Zi-Chen Dong, Lu Zhang, Liu-Fang Zhao, Hong-Yang Xu, and Wei-Di Sun. "Photothermolysis Mediated by Gold Nanorods Conjugated with Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody Induces Apoptosis via the Mitochondrial Apoptosis Pathway in Laryngeal Squamous Cell Cancer." Journal of Biomedical Nanotechnology 18, no. 3 (March 1, 2022): 754–62. http://dx.doi.org/10.1166/jbn.2022.3272.
Abstract:
Gold nanorods (AuNRs) have unique optical properties and biological affinity and can be used to treat tumors when conjugated with other protein molecules. Our previous studies have shown that EGFR monoclonal antibody (EGFRmAb)-modified AuNRs exert strong antitumor activity in vitro by inducing apoptosis. In this study, we tested the effects of EGFRmAb-modified AuNRs on laryngeal squamous cell cancer (LSCC) in vitro and in vivo. The in vitro results showed that EGFRmAb-modified AuNRs inhibited NP-69, BEAS-2B and Hep-2 cell growth and induced mitochondria-dependent apoptosis. The mitochondrial membrane potential was reduced, leading to the release of cytochrome C (Cyt C) and consequent activation of the intrinsic mitochondrial apoptosis pathway. Moreover, we observed that the occurrence of mitochondrial apoptosis is related to the destruction of the lysosome-mitochondria axis. To verify the effects in vivo, we also established a laryngeal tumor model in nude mice by subcutaneous transplantation. In model mice treated with EGFRmAb-modified AuNRs and irradiated with an NIR laser, tumor cell apoptosis and tumor growth were inhibited. These results suggest that EGFRmAb-modified AuNRs induced apoptosis through the intrinsic mitochondrial apoptotic pathway and are a potential candidate for cancer therapy.
40
Brooks, Craig, Sung-Gyu Cho, Cong-Yi Wang, Tianxin Yang, and Zheng Dong. "Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis." American Journal of Physiology-Cell Physiology 300, no. 3 (March 2011): C447—C455. http://dx.doi.org/10.1152/ajpcell.00402.2010.
Abstract:
Recent studies have shown mitochondrial fragmentation during cell stress and have suggested a role for the morphological change in mitochondrial injury and ensuing apoptosis. However, the underlying mechanism remains elusive. Here we demonstrate that mitochondrial fragmentation facilitates Bax insertion and activation in mitochondria, resulting in the release of apoptogenic factors. In HeLa cells, overexpression of mitofusins attenuated mitochondrial fragmentation during cisplatin- and azide-induced cell injury, which was accompanied by less apoptosis and less cytochrome c release from mitochondria. Similar effects were shown by inhibiting the mitochondrial fission protein Drp1 with a dominant negative mutant (dn-Drp1). Mitofusins and dn-Drp1 did not seem to significantly affect Bax translocation/accumulation to mitochondria; however, they blocked Bax insertion and activation in mitochondrial membrane. Consistently, in rat kidney proximal tubular cells, small interfering RNA knockdown of Drp1 prevented mitochondrial fragmentation during azide-induced ATP depletion, which was accompanied by less Bax activation, insertion, and oligomerization in mitochondria. These cells released less cytochrome c and AIF from mitochondria and showed significantly lower apoptosis. Finally, mitofusin-null mouse embryonic fibroblasts (MEF) had fragmented mitochondria. These MEFs were more sensitive to cisplatin-induced Bax activation, release of cytochrome c, and apoptosis. Together, this study provides further support for a role of mitochondrial fragmentation in mitochondrial injury and apoptosis. Mechanistically, mitochondrial fragmentation may sensitize the cells to Bax insertion and activation in mitochondria, facilitating the release of apoptogenic factors and consequent apoptosis.
41
Krysko, Dmitri V., Frank Roels, Luc Leybaert, and Katharina D'Herde. "Mitochondrial Transmembrane Potential Changes Support the Concept of Mitochondrial Heterogeneity During Apoptosis." Journal of Histochemistry & Cytochemistry 49, no. 10 (October 2001): 1277–84. http://dx.doi.org/10.1177/002215540104901010.
Abstract:
Dissipation of mitochondrial membrane potential (Δψm) and release of cytochrome c from mitochondria appear to be key events during apoptosis. The precise relationship (cause or consequence) between both is currently unclear. We previously showed in a model of serum-free cultured granulosa explants that cytochrome c is retained in a subset of respiring mitochondria until late in the apoptotic process. In this study we further investigated the issue of heterogeneity by using the Δψm-sensitive probe CM-H2TMRos in combination with a DNA fluorochrome. Changes of Δψm were assessed qualitatively by epifluorescence microscopy and were quantified using digital imaging microscopy. This approach yielded the following results: (a) CM-H2TMRos staining is a reliable and specific procedure to detect Δψm changes in granulosa cells explants; (b) dissipation of transmembrane potential is an early event during apoptosis preceding nuclear changes but is confined to a subpopulation of mitochondria within an individual cell; (c) in frankly apoptotic cells a few polarized mitochondria can be detected. These findings support the hypothesis that ATP needed for completion of the apoptotic cascade can be generated during apoptosis in a subset of respiring mitochondria and is not necessarily derived from anaerobic glycolysis.
42
Belkacemi, Louiza, Mina Desai, D. Michael Nelson, and Michael G. Ross. "Altered mitochondrial apoptotic pathway in placentas from undernourished rat gestations." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301, no. 6 (December 2011): R1599—R1615. http://dx.doi.org/10.1152/ajpregu.00100.2011.
Abstract:
Maternal undernutrition (MUN) during pregnancy results in intrauterine growth-restricted (IUGR) fetuses and small placentas. Although reduced fetal nutrient supply has been presumed to be etiologic in IUGR, MUN-induced placental dysfunction may occur prior to detectable fetal growth restriction. Placental growth impairment may result from apoptosis signaled by mitochondria in response to reduced energy substrate. Therefore, we sought to determine the presence of mitochondrial-induced apoptosis under MUN and ad libitum diet (AdLib) pregnancies. Pregnant rats were fed an AdLib or a 50% MUN diet from embryonic day 10 (E10) to E20. At E20, fetuses and placentas from proximal- and mid-horns (extremes of nutrient/oxygen supply) were collected. Right-horn placentas were used to quantify apoptosis. Corresponding left-horn placentas were separated into basal (hormone production) and labyrinth (feto-maternal exchange) zones, and protein expression of the mitochondrial pathway was determined. Our results show that the MUN placentas had significantly increased apoptosis, with lower expression of cytosolic and mitochondrial anti-apoptotic Bcl2 and Bcl-XL, and significantly higher expression of pro-apoptotic Bax and Bak especially in the labyrinth zone. This was paralleled by higher coimmunostaining with the mitochondrial marker manganese superoxide dismutase (MnSOD), indicating transition of pro-apoptotic factors to the mitochondrial membrane. Also, cytosolic cytochrome c and activated caspases-9 and -3 were significantly higher in all MUN. Conversely, peroxisome proliferator-activator receptor-γ (PPARγ), a member of the nuclear receptor family with anti-apoptotic properties, was significantly downregulated in both zones and horns. Our results suggest that MUN during rat pregnancy enhances mitochondria-dependent apoptosis in the placenta, probably due to the downregulation of PPARγ expression.
43
Deng, Lin, Tetsuya Adachi, Kikumi Kitayama, Yasuaki Bungyoku, Sohei Kitazawa, Satoshi Ishido, Ikuo Shoji, and Hak Hotta. "Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway." Journal of Virology 82, no. 21 (September 3, 2008): 10375–85. http://dx.doi.org/10.1128/jvi.00395-08.
Abstract:
ABSTRACT We previously reported that cells harboring the hepatitis C virus (HCV) RNA replicon as well as those expressing HCV NS3/4A exhibited increased sensitivity to suboptimal doses of apoptotic stimuli to undergo mitochondrion-mediated apoptosis (Y. Nomura-Takigawa, et al., J. Gen. Virol. 87:1935-1945, 2006). Little is known, however, about whether or not HCV infection induces apoptosis of the virus-infected cells. In this study, by using the chimeric J6/JFH1 strain of HCV genotype 2a, we demonstrated that HCV infection induced cell death in Huh7.5 cells. The cell death was associated with activation of caspase 3, nuclear translocation of activated caspase 3, and cleavage of DNA repair enzyme poly(ADP-ribose) polymerase, which is known to be an important substrate for activated caspase 3. These results suggest that HCV-induced cell death is, in fact, apoptosis. Moreover, HCV infection activated Bax, a proapoptotic member of the Bcl-2 family, as revealed by its conformational change and its increased accumulation on mitochondrial membranes. Concomitantly, HCV infection induced disruption of mitochondrial transmembrane potential, followed by mitochondrial swelling and release of cytochrome c from mitochondria. HCV infection also caused oxidative stress via increased production of mitochondrial superoxide. On the other hand, HCV infection did not mediate increased expression of glucose-regulated protein 78 (GRP78) or GRP94, which are known as endoplasmic reticulum (ER) stress-induced proteins; this result suggests that ER stress is not primarily involved in HCV-induced apoptosis in our experimental system. Taken together, our present results suggest that HCV infection induces apoptosis of the host cell through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway(s).
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Oursler, Merry Jo, Elizabeth W. Bradley, Sarah L. Elfering, and Cecilia Giulivi. "Native, not nitrated, cytochrome c and mitochondria-derived hydrogen peroxide drive osteoclast apoptosis." American Journal of Physiology-Cell Physiology 288, no. 1 (January 2005): C156—C168. http://dx.doi.org/10.1152/ajpcell.00092.2004.
Abstract:
Two unresolved aspects of the role of mitochondria-derived cytochrome c in apoptosis are whether there is a separate pool of cytochrome c within mitochondria that participates in the activation of apoptosis and whether a chemically modified cytochrome c drives apoptosis. These questions were investigated using osteoclasts, because they are rich in mitochondria and because osteoclast apoptosis is critical in bone metabolism regulation. H2O2 production was increased during culture, preceding cytochrome c release; both processes occurred anterior to apoptosis. With the addition of a mitochondrial uncoupler, H2O2 production and apoptosis were blocked, indicating the prominent role of mitochondria-derived H2O2. Trapping H2O2-derived hydroxyl radical decreased apoptosis. Cytosolic cytochrome c was originated from a single mitochondrial compartment, supporting a common pool involved in respiration and apoptosis, and it was chemically identical to the native form, with no indication of oxidative or nitrative modifications. Protein levels of Bcl-2 and Bc-xL were decreased before apoptosis, whereas expression of wild-type Bcl-2 repressed apoptosis, confirming that cytochrome c release is critical in initiating apoptosis. Cytosolic cytochrome c participated in activating caspase-3 and -9, both required for apoptosis. Collectively, our data indicate that the mitochondria-dependent apoptotic pathway is one of the major routes operating in osteoclasts.
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Makinwa, Yetunde, Yibo Luo, Phillip R. Musich, and Yue Zou. "Canonical and Noncanonical Functions of the BH3 Domain Protein Bid in Apoptosis, Oncogenesis, Cancer Therapeutics, and Aging." Cancers 16, no. 12 (June 12, 2024): 2199. http://dx.doi.org/10.3390/cancers16122199.
Abstract:
Effective cancer therapy with limited adverse effects is a major challenge in the medical field. This is especially complicated by the development of acquired chemoresistance. Understanding the mechanisms that underlie these processes remains a major effort in cancer research. In this review, we focus on the dual role that Bid protein plays in apoptotic cell death via the mitochondrial pathway, in oncogenesis and in cancer therapeutics. The BH3 domain in Bid and the anti-apoptotic mitochondrial proteins (Bcl-2, Bcl-XL, mitochondrial ATR) it associates with at the outer mitochondrial membrane provides us with a viable target in cancer therapy. We will discuss the roles of Bid, mitochondrial ATR, and other anti-apoptotic proteins in intrinsic apoptosis, exploring how their interaction sustains cellular viability despite the initiation of upstream death signals. The unexpected upregulation of this Bid protein in cancer cells can also be instrumental in explaining the mechanisms behind acquired chemoresistance. The stable protein associations at the mitochondria between tBid and anti-apoptotic mitochondrial ATR play a crucial role in maintaining the viability of cancer cells, suggesting a novel mechanism to induce cancer cell apoptosis by freeing tBid from the ATR associations at mitochondria.
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Kim, Sin Ri, Ji Won Park, You-Jin Choi, Seong Keun Sonn, Goo Taeg Oh, Byung-Hoon Lee, and Tong-Shin Chang. "Mitochondrial H2O2 Is a Central Mediator of Diclofenac-Induced Hepatocellular Injury." Antioxidants 13, no. 1 (December 21, 2023): 17. http://dx.doi.org/10.3390/antiox13010017.
Abstract:
Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (ROS). The primary ROS responsible for inducing diclofenac-related hepatocellular toxicity and the principal antioxidant that mitigates these ROS remain unknown. Peroxiredoxin III (PrxIII) is the most abundant and potent H2O2-eliminating enzyme in the mitochondria of mammalian cells. Here, we investigated the role of mitochondrial H2O2 and the protective function of PrxIII in diclofenac-induced mitochondrial dysfunction and apoptosis in hepatocytes. Mitochondrial H2O2 levels were differentiated from other types of ROS using a fluorescent H2O2 indicator. Upon diclofenac treatment, PrxIII-knockdown HepG2 human hepatoma cells showed higher levels of mitochondrial H2O2 than PrxIII-expressing controls. PrxIII-depleted cells exhibited higher mitochondrial dysfunction as measured by a lower oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, and caspase activation, and were more sensitive to apoptosis. Ectopic expression of mitochondrially targeted catalase in PrxIII-knockdown HepG2 cells or in primary hepatocytes derived from PrxIII-knockout mice suppressed the diclofenac-induced accumulation of mitochondrial H2O2 and decreased apoptosis. Thus, we demonstrated that mitochondrial H2O2 is a key mediator of diclofenac-induced hepatocellular damage driven by mitochondrial dysfunction and apoptosis. We showed that PrxIII loss results in the critical accumulation of mitochondrial H2O2 and increases the harmful effects of diclofenac. PrxIII or other antioxidants targeting mitochondrial H2O2 could be explored as potential therapeutic agents to protect against the hepatotoxicity associated with NSAID use.
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Wasilenko, Shawn T., Adrienne F. A. Meyers, Kathleen Vander Helm, and Michele Barry. "Vaccinia Virus Infection Disarms the Mitochondrion-Mediated Pathway of the Apoptotic Cascade by Modulating the Permeability Transition Pore." Journal of Virology 75, no. 23 (December 1, 2001): 11437–48. http://dx.doi.org/10.1128/jvi.75.23.11437-11448.2001.
Abstract:
ABSTRACT Many viruses have evolved strategies that target crucial components within the apoptotic cascade. One of the best studied is the caspase 8 inhibitor, crmA/Spi-2, encoded by members of the poxvirus family. Since many proapoptotic stimuli induce apoptosis through a mitochondrion-dependent, caspase 8-independent pathway, we hypothesized that vaccinia virus would encode a mechanism to directly modulate the mitochondrial apoptotic pathway. In support of this, we observed that Jurkat cells, which undergo Fas-mediated apoptosis exclusively through the mitochondrial route, were resistant to Fas-induced death following infection with a crmA/Spi-2-deficient strain of vaccinia virus. In addition, vaccinia virus-infected cells subjected to the proapoptotic stimulus staurosporine exhibited decreased levels of both cytochromec released from the mitochondria and caspase 3 activation. In all cases we found that the loss of the mitochondrial membrane potential, which occurs as a result of opening the multimeric permeability transition pore complex, was prevented in vaccinia virus-infected cells. Moreover, vaccinia virus infection specifically inhibited opening of the permeability transition pore following treatment with the permeability transition pore ligand atractyloside and t-butylhydroperoxide. These studies indicate that vaccinia virus infection directly impacts the mitochondrial apoptotic cascade by influencing the permeability transition pore.
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Mollinedo, Faustino, and Consuelo Gajate. "Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine." Pharmaceutics 13, no. 5 (May 20, 2021): 763. http://dx.doi.org/10.3390/pharmaceutics13050763.
Abstract:
The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated with the recruitment of F1FO–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the FO sector of the F1FO–ATP synthase, which contains the membrane-embedded c-subunit ring that constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death. Taking together, the evidence shown here suggests that the ether lipid edelfosine could modulate cell death in cancer cells by direct interaction with mitochondria, and the reorganization of raft-located mitochondrial proteins that critically modulate cell death or survival. Here, we summarize and discuss the involvement of mitochondria in the antitumor action of the ether lipid edelfosine, pointing out the mitochondrial targeting of this drug as a major therapeutic approach, which can be extrapolated to other alkylphospholipid analogs. We also discuss the involvement of cholesterol transport and cholesterol-rich lipid rafts in the interactions between the organelles as well as in the role of mitochondria in the regulation of apoptosis in cancer cells and cancer therapy.
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Karbowski, Mariusz, Yang-Ja Lee, Brigitte Gaume, Seon-Yong Jeong, Stephan Frank, Amotz Nechushtan, Ansgar Santel, Margaret Fuller, Carolyn L. Smith, and Richard J. Youle. "Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis." Journal of Cell Biology 159, no. 6 (December 23, 2002): 931–38. http://dx.doi.org/10.1083/jcb.200209124.
Abstract:
We find that Bax, a proapoptotic member of the Bcl-2 family, translocates to discrete foci on mitochondria during the initial stages of apoptosis, which subsequently become mitochondrial scission sites. A dominant negative mutant of Drp1, Drp1K38A, inhibits apoptotic scission of mitochondria, but does not inhibit Bax translocation or coalescence into foci. However, Drp1K38A causes the accumulation of mitochondrial fission intermediates that are associated with clusters of Bax. Surprisingly, Drp1 and Mfn2, but not other proteins implicated in the regulation of mitochondrial morphology, colocalize with Bax in these foci. We suggest that Bax participates in apoptotic fragmentation of mitochondria.
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Alves, Sara, Cátia Santos-Pereira, Cláudia S. F. Oliveira, Ana Preto, Susana R. Chaves, and Manuela Côrte-Real. "Enhancement of Acetate-Induced Apoptosis of Colorectal Cancer Cells by Cathepsin D Inhibition Depends on Oligomycin A-Sensitive Respiration." Biomolecules 14, no. 4 (April 12, 2024): 473. http://dx.doi.org/10.3390/biom14040473.
Abstract:
Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors.