1,721,074 research outputs found
The mitochondrial permeability transition pore and its adaptive responses in tumor cells
No full textThis review covers recent progress on the nature of the mitochondrial permeability transition pore (PTP) - a key effector in the mitochondrial pathways to cell death - and on the adaptive responses of tumor cells that desensitize the PTP to Ca2+ and reactive oxygen species (ROS), thereby playing an important role in the resistance of tumors to cell death. The discovery that the PTP forms from dimers of F-ATP synthase; and the definition of the Ca2+- and ROS-dependent signaling pathways affecting the transition of the F-ATP synthase from an energy-conserving to an energy-dissipating device open new perspectives for therapeutic intervention in cancer cells
Calcium and cell death: the mitochondrial connection
No full textCurrent research on the mitochondrial permeability transition pore (PTP) and its role in cell death faces a paradox. Initially considered as an in vitro artifact of little pathophysiological relevance, in recent years the PTP has received considerable attention as a potential mechanism for the execution of cell death. The recent successful use of PTP desensitizers in several disease paradigms leaves little doubt about its relevance in pathophysiology; and emerging findings that link the PTP to key cellular signalling pathways are increasing the interest on the pore as a pharmacological target. Yet, recent genetic data have challenged popular views on the molecular nature of the PTP, and called into question many early conclusions about its structure. Here we review basic concepts about PTP structure, function and regulation within the framework of intracellular death signalling, and its role in disease pathogenesis
Apoptosis and Disease: Unbalancing the Survival Equilibrium
No full textContrary to what might be common sense, the ordered development and maintenance of
multicellular organisms not only requires adequate nutrient supply and a flourishing growth
potential, but also relies on complex mechanisms of cell suicide. In fact, both tissue sculpting
during embryogenesis and their homeostatic regulation in adulthood are the outcome of a dynamic
competition between cell proliferation and death, and a network of signals has evolved to induce
and keep under a tight control the process of cell elimination. In addition, cells damaged by diverse
noxious agents must be efficiently cleared away through a regulated death program to avoid lethal
dysfunctions. Accordingly, cells have developed a variety of molecular controllers that sense every
potentially harmful metabolic change, damage or genetic abnormality. The unifying response to all
these unbalancing or stressful conditions is the activation of a form of programmed cell death
termed apoptosis. Apoptotic cells utilize a well-defined biochemical machinery to orderly dismantle
their architecture, and become endowed with stereotypical morphological changes which ultimately
lead to their engulfment by phagocytic cells. Apoptosis signaling can be grossly subdivided in an
initiator phase, which depends either on death receptor activation or on intracellular insults, and in
an execution phase, whose biochemical hallmark is the activation of proteases termed caspases. In
between these two extremes, a sophisticated system composed by molecular checks and balances
determines whether a cell is committed to survive or to die. This final output depends on several
integrated parameters, such as the transcriptional regulation of apoptosis inducers or brakes and
their subcellular distribution and interactions. In recent years, the comprehension of the molecular
bases of apoptosis allowed the identification of an articulated network of crosstalks between the
death regulators and signaling pathways that coordinate biological processes such as cell cycle and
proliferation. Disturbances in the fine tuning of this intricate death/survival equilibrium result either
in an uncontrolled growth or in an excessive degeneration of tissues, leading to a variety of
diseases, including cancer, neurodegenerative and autoimmunity disease. Further layers of
complexity are added by the finding that other forms of cell death, spanning from autophagy to
necrosis through a variety of ill-defined intermediate conditions, are relevant in defined physiologic
and pathologic settings. A deep understanding of the mechanisms that regulate the apoptotic
machinery, its interactions with other transduction pathways and how these orchestrate the fate of
the cell is therefore pivotal for the development of drugs that reinstate the appropriate apoptotic
response, either where it is lacking, as in cancer, or where it is exacerbated, as in neurodegenerative
diseases
Induction of the permeability transition pore in cells depleted of mitochondrial DNA
No full textAbstractRespiratory complexes are believed to play a role in the function of the mitochondrial permeability transition pore (PTP), whose dysregulation affects the process of cell death and is involved in a variety of diseases, including cancer and degenerative disorders. We investigated here the PTP in cells devoid of mitochondrial DNA (ρ0 cells), which lack respiration and constitute a model for the analysis of mitochondrial involvement in several pathological conditions. We observed that mitochondria of ρ0 cells maintain a membrane potential and that this is readily dissipated after displacement of hexokinase (HK) II from the mitochondrial surface by treatment with either the drug clotrimazole or with a cell-permeant HK II peptide, or by placing ρ0 cells in a medium without serum and glucose. The PTP inhibitor cyclosporin A (CsA) could decrease the mitochondrial depolarization induced by either HK II displacement or by nutrient depletion. We also found that a fraction of the kinases ERK1/2 and GSK3α/β is located in the mitochondrial matrix of ρ0 cells, and that glucose and serum deprivation caused concomitant ERK1/2 inhibition and GSK3α/β activation with the ensuing phosphorylation of cyclophilin D, the mitochondrial target of CsA. GSK3α/β inhibition with indirubin-3′-oxime decreased PTP-induced cell death in ρ0 cells following nutrient ablation. These findings indicate that ρ0 cells are equipped with a functioning PTP, whose regulatory mechanisms are similar to those observed in cancer cells, and suggest that escape from PTP opening is a survival factor in this model of mitochondrial diseases. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012)
Targeting apoptosis in cancer therapy
No full textDefects in apoptosis, a complex cell death program that controls tissue homeostasis, play important roles in tumorigenesis. Conventional anticancer treatments trigger the apoptotic response in cancer cells. Drawbacks of these approaches are the lack of selectivity towards the tumor and treatment resistance. In the last few years, the recognition of the molecular events that promote and regulate the apoptotic program allowed the development of more rational anticancer strategies. These therapies are aimed at reinstating apoptosis in tumor cells by targeting the core components of cell death machinery and a broad array of apoptosis regulators
Receptor tyrosine kinases as targets for cancer therapy
No full textReceptor tyrosine kinases (RTKs) transduce into the cell a complex network of environmental signals, orchestrating in a tightly regulated fashion mandatory processes for the development of multicellular organisms, such as cell growth, differentiation, migration and survival. Perturbation of RTK signaling caused by genetic or functional alterations results in development and progression of cancer. Therefore, strategies aimed at targeting RTKs are under intensive investigation in order to achieve highly selective anti-tumor devices. In this review we summarize the different approaches directed towards the interception of aberrant RTK activation in cancer therapy
Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis
No full textA variety of stimuli utilize an increase of cytosolic free Ca(2+) concentration as a second messenger to transmit signals, through Ca(2+) release from the endoplasmic reticulum or opening of plasma membrane Ca(2+) channels. Mitochondria contribute to the tight spatiotemporal control of this process by accumulating Ca(2+), thus shaping the return of cytosolic Ca(2+) to resting levels. The rise of mitochondrial matrix free Ca(2+) concentration stimulates oxidative metabolism; yet, in the presence of a variety of sensitizing factors of pathophysiological relevance, the matrix Ca(2+) increase can also lead to opening of the permeability transition pore (PTP), a high conductance inner membrane channel. While transient openings may serve the purpose of providing a fast Ca(2+) release mechanism, persistent PTP opening is followed by deregulated release of matrix Ca(2+), termination of oxidative phosphorylation, matrix swelling with inner membrane unfolding and eventually outer membrane rupture with release of apoptogenic proteins and cell death. Thus, a rise in mitochondrial Ca(2+) can convey both apoptotic and necrotic death signals by inducing opening of the PTP. Understanding the signalling networks that govern changes in mitochondrial free Ca(2+) concentration, their interplay with Ca(2+) signalling in other subcellular compartments, and regulation of PTP has important implications in the fine comprehension of the main biological routines of the cell and in disease pathogenesis
Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells
No full textMany tumors undergo a dramatic metabolic shift known
as the Warburg effect in which glucose utilization is
favored and oxidative phosphorylation is downregulated,
even when oxygen availability is plentiful. However,
the mechanistic basis for this switch has remained
unclear. Recently several independent groups identified
tumor necrosis factor receptor-associated protein 1
(TRAP1), a mitochondrial molecular chaperone of the
heat shock protein 90 (Hsp90) family, as a key modulator
of mitochondrial respiration. Although all reports agree
that this activity of TRAP1 has important implications for
neoplastic progression, data from the different groups
only partially overlap, suggesting that TRAP1 may have
complex and possibly contextual effects on tumorigenesis.
In this review we analyze these recent findings and
attempt to reconcile these observations
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