Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As mitochondria play a key role in the commitment to cell death, we have investigated the mitochondrial consequences of resistance to doxorubicin (DOX) in K562 cells. We found that the permeability transition pore (PTP) inhibitor cyclosporine A (CsA) failed to inhibit PTP opening in the resistant clone. Moreover, the Ca2+ loading capacity in the resistant clone was identical to that observed in the parent cells in the presence of CsA, suggesting that the PTP was already inhibited in a CsA-like manner in the resistant cells. In agreement with this proposal, the mitochondrial target of CsA cyclophilin D (CyD) decreased by half in the resistant cells. The levels of adenine nucleotide translocator, voltage anion-dependent channel, Bax, Bcl-2, Bcl-xL, AIF and Smac/Diablo, were similar in both cell lines, whereas cytochrome c content was divided by three in the resistant cells. Since P-glycoprotein inhibition did not restore DOX toxicity in the resistant cells, while DOX-induced cell death in the parent cells was prevented by either PTP inhibition or siRNA-induced decrease in cytochrome c content, we conclude that the inhibition of PTP opening and the decrease in cytochrome c content participate in the mechanism that makes K562 cells resistant to DOX.
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PMID:Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562 cells. 1633 Dec 51

Mitochondria are important organelles for energy production, Ca2+ homeostasis, and cell death. In recent years, the role of the mitochondria in both apoptotic and necrotic cell death has received much attention. In apoptotic and necrotic death, an increase of mitochondrial membrane permeability is considered to be one of the key events, although the detailed mechanism remains to be elucidated. The mitochondrial membrane permeability transition (MPT) is a Ca2+-dependent increase in the permeability of the mitochondrial membrane that leads to loss of Deltapsi, mitochondrial swelling, and rupture of the outer mitochondrial membrane. The MPT is thought to occur after the opening of a channel, which is termed the permeability transition pore (PTP) and putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT), cyclophilin D (Cyp D: a mitochondrial peptidyl prolyl-cis, trans-isomerase), and other molecule(s). Our studies of mice lacking Cyp D have revealed that it is essential for occurrence of the MPT and that the Cyp D-dependent MPT regulates some forms of necrotic cell death, but not apoptotic death. We have also shown that two anti-apoptotic proteins, Bcl-2 and Bcl-x(L), block the MPT by directly inhibition of VDAC activity. Here we summarize a role of the MPT in cell death.
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PMID:Mitochondrial membrane permeability transition and cell death. 1671 47

In the intrinsic pathway of apoptosis, mitochondria play a crucial role by releasing cytochrome c from the intermembrane space into the cytoplasm. Cytochrome c release through Bax/Bak-dependent channels in mitochondria has been well documented. In contrast, cyclophilin D (CypD), an important component of permeability transition pore-dependent protein release, remains largely undefined, and no apoptogenic proteins that act specifically in a CypD-dependent manner have been reported to date. Here, we describe a novel and evolutionarily conserved protein, apoptogenic protein (Apop). Mouse Apop-1 expression induces apoptotic death by releasing cytochrome c from mitochondria into the cytosolic space followed by activation of caspase-9 and -3. Apop-1-induced apoptosis is not blocked by Bcl-2 or Bcl-xL, inhibitors of Bax/Bak-dependent channels, whereas it is completely blocked by cyclosporin A, an inhibitor of permeability transition pore. Cells lacking CypD were resistant to Apop-induced apoptosis. Moreover, inhibition of Apop expression prevented the cell death induced by apoptosis-inducing substances. Our findings, thus, indicate that the expression of Apop-1 induces apoptosis though CypD-dependent pathway and that Apop-1 plays roles in cell death under physiological conditions.
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PMID:Apop-1, a novel protein inducing cyclophilin D-dependent but Bax/Bak-related channel-independent apoptosis. 1678 8

In recent years, the role of the mitochondria in both apoptotic and necrotic cell death has received considerable attention. An increase of mitochondrial membrane permeability is one of the key events in apoptotic or necrotic death, although the details of the mechanism involved remain to be elucidated. The mitochondrial membrane permeability transition (MPT) is a Ca(2+)-dependent increase of mitochondrial membrane permeability that leads to loss of Deltapsi, mitochondrial swelling, and rupture of the outer mitochondrial membrane. The MPT is thought to occur after the opening of a channel that is known as the permeability transition pore (PTP), which putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT), cyclophilin D (Cyp D: a mitochondrial peptidyl prolyl-cis, trans-isomerase), and other molecule(s). Recently, significant progress has been made by studies performed with mice lacking Cyp D at several laboratories, which have convincingly demonstrated that Cyp D is essential for the MPT to occur and that the Cyp D-dependent MPT regulates some forms of necrotic, but not apoptotic, cell death. Cyp D-deficient mice have also been used to show that the Cyp D-dependent MPT plays a crucial role in ischemia/reperfusion injury. The anti-apoptotic proteins Bcl-2 and Bcl-x(L) have the ability to block the MPT, and can therefore block MPT-dependent necrosis in addition to their well-established ability to inhibit apoptosis.
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PMID:Role of the mitochondrial membrane permeability transition in cell death. 1713 22

Previous reports have shown that honokiol induces apoptosis in numerous cancer cell lines and showed preclinical efficacies against apoptosis-resistant B-cell chronic lymphocytic leukemia and multiple myeloma cells from relapse-refractory patients. Here, we show that honokiol can induce a cell death distinct from apoptosis in HL60, MCF-7, and HEK293 cell lines. The death was characterized by a rapid loss of integrity of plasma membrane without externalization of phosphatidyl serine. The broad caspase inhibitor z-VAD-fmk failed to prevent this cell death. Consistently, caspase activation and DNA laddering were not observed. The death was paralleled by a rapid loss of mitochondrial membrane potential, which was mechanistically associated with the mitochondrial permeability transition pore regulated by cyclophilin D (CypD) based on the following evidence: (a) cyclosporin A, an inhibitor of CypD (an essential component of the mitochondrial permeability transition pore), effectively prevented honokiol-induced cell death and loss of mitochondrial membrane potential; (b) inhibition of CypD by RNA interference blocked honokiol-induced cell death; (c) CypD up-regulated by honokiol was correlated with the death rates in HL60, but not in K562 cells, which underwent apoptosis after being exposed to honokiol. We further showed that honokiol induced a CypD-regulated death in primary human acute myelogenous leukemia cells, overcame Bcl-2 and Bcl-X(L)-mediated apoptotic resistance, and was effective against HL60 cells in a pilot in vivo study. To the best of our knowledge, this is the first report to document an induction of mitochondrial permeability transition pore-associated cell death by honokiol.
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PMID:Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore. 1751 Apr 19

Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of beta-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or beta-adrenergic receptor antagonists, demonstrating a proximal relationship among beta-adrenergic receptor function, Ca2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx and acute beta-adrenergic receptor stimulation. This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca2+ handling and beta-adrenergic receptor signaling.
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PMID:Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. 1769 79

The mitochondrial permeability transition (MPT) pore complex is a key participant in the machinery that controls mitochondrial fate and, consequently, cell fate. The quest for the pore identity has been ongoing for several decades and yet the main structure remains unknown. Established "dogma" proposes that the core of the MPT pore is composed of an association of voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT). Recent genetic knockout experiments contradict this commonly accepted interpretation and provide a basis for substantial revision of the MPT pore identity. There is now sufficient evidence to exclude VDAC and ANT as the main pore structural components. Regarding MPT pore regulation, the role of cyclophilin D is confirmed and ANT may still serve some regulatory function, although the involvement of hexokinase II and creatine kinase remains unresolved. When cell protection signaling pathways are activated, we have found that the Bcl-2 family members relay the signal from glycogen synthase kinase-3 beta onto a target at or in close proximity to the pore. Our experimental findings in intact cardiac myocytes and neurons indicate that the current "dogma" related to the role of Ca2+ in MPT induction requires reevaluation. Emerging evidence suggests that after injury-producing stresses, reactive oxygen species (but not Ca2+) are largely responsible for the pore induction. In this article we discuss the current state of knowledge and provide new data related to the MPT pore structure and regulation.
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PMID:The identity and regulation of the mitochondrial permeability transition pore: where the known meets the unknown. 1837 92

Mitochondria-mediated apoptosis represents a central process driving age-related muscle loss. However, the temporal relation between mitochondrial apoptotic signaling and sarcopenia as well as the regulation of release of pro-apoptotic factors from the mitochondria has not been elucidated. In this study, we investigated mitochondrial apoptotic signaling in skeletal muscle of rats across a wide age range. We also investigated whether mitochondrial-driven apoptosis was accompanied by changes in the expression of Bcl-2 proteins and components of the mitochondrial permeability transition pore (mPTP). Analyses were performed on gastrocnemius muscle of 8-, 18-, 29- and 37-month-old male Fischer344 x Brown Norway rats (9 per group). Muscle weight declined progressively with advancing age, concomitant with increased apoptotic DNA fragmentation. Cytosolic and nuclear levels of apoptosis inducing factor (AIF) and endonuclease G (EndoG) increased in old and senescent animals. In contrast, cytosolic levels of cytochrome c were unchanged with age. Mitochondrial Bcl-2, Bax and Bid increased dramatically in 37-month-old rats, with no changes in the Bax/Bcl-2 ratio in any of the age groups. Finally, expression of cyclophilin D (CyPD) was enhanced at very old age. Our findings indicate that the mitochondrial caspase-independent apoptotic pathway may play a more prominent role in skeletal muscle loss than caspase-mediated apoptosis.
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PMID:Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle. 1857 79

Retention of bile acids within the liver is a primary factor in the pathogenesis of cholestatic liver disorders, which are more common in human infants. The objective of this study was to evaluate developmental changes in mitochondrial factors involved in bile acid-induced hepatocyte injury. Hepatic mitochondria from adult rats (aged 9 wk) underwent a mitochondrial permeability transition (MPT) and release of cytochrome c upon exposure to glycochenodeoxycholic acid. In contrast, mitochondria from young rats (age 6-36 d) were resistant to MPT induction and cytochrome c release. Neither mitochondrial levels of MPT-associated proteins (voltage-dependent anion channel, cyclophilin D, or adenine nucleotide translocase), Bcl-2 family proteins, nor antioxidant enzymes explained this resistance. Mitochondria from young rats contained 2- to 3-fold higher alpha-tocopherol (alpha-TH). In vivo alpha-TH enrichment of adult hepatic mitochondria increased their MPT resistance. Tetra-linoleoyl cardiolipin (TL-CL), the primary molecular species of CL, was reduced in mitochondria of the young rat; however, enrichment with CL and TL-CL only modestly increased their MPT susceptibility. In conclusion, we observed an unexpected resistance in young rats to bile acid induction of mitochondrial cell death pathways, which may be related to developmental differences in membrane composition.
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PMID:Resistance of young rat hepatic mitochondria to bile acid-induced permeability transition: potential role of alpha-tocopherol. 1859 69

In nonmyeloid cells, Shigella hijacks the mitochondrial checkpoint of cell death, thereby inducing a regulated form of necrosis depending on Bnip3 and cyclophilin D. Carneiro et al. (2009) describe the interplay between this program and a prosurvival response transmitted via the Nod1/Rip2/NF-kappaB/Bcl-2 axis, which determines the fate of infected cells.
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PMID:Shigella targets the mitochondrial checkpoint of programmed necrosis. 1921 84


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