No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Mitochondria and Apoptosis
Abstract
Apoptosis is an important biological process it plays critical role in cell growth differentiation as well as the response toward outside stimulus. Recently it was found that the mitochondrial transmembrane potential and mitochondrial permeability transition have a remarkable role in the process of apoptosis. Hypothesis of a permeability transition pore complex located in the mitochondrial membranes was postulated and had got extensive interest. This subject was introduced in the present minireview.
... In this pathway, apoptosis is initiated after the release of apoptogenic proteins from the intermembrane space of mitochondria into the cell cytoplasm. The key event in the mitochondrial apoptosis pathway is an increase in the permeability of the outer mitochondrial membrane [31,32]. The apoptotic Bcl-2 proteins, Bax and Bak, play a significant role in increasing MOMP. ...
The family of B-cell lymphoma-2 (Bcl-2) proteins exerts key functions in cellular health. Bcl-2 primarily acts in mitochondria where it controls the initiation of apoptosis. However, during the last decades, it has become clear that this family of proteins is also involved in controlling Ca²⁺ signaling in cells, a critical process for the function of most cell types, including neurons. Several anti- and pro-apoptotic Bcl-2 family members are expressed in neurons and impact neuronal function. Importantly, expression levels of neuronal Bcl-2 proteins are affected by age. In this review, we focus on the emerging roles of Bcl-2 proteins in neuronal cells. Specifically, we discuss how their dysregulation contributes to the onset, development, and progression of neurodegeneration in the context of Alzheimer's disease (AD). Aberrant Ca²⁺ signaling plays an important role in the pathogenesis of AD, and we propose that dysregulation of the Bcl-2-Ca²⁺ signaling axis may contribute to the progression of AD and that herein, Bcl-2 may constitute a potential therapeutic target for the treatment of AD.
TFAR19 TF-1 cell apoptosis related gene 19 is a novel apoptosis-related gene cloned from human leukemia cell line TF-1 cells undergoing apoptosis in 1999 (accession number AF014955 in GenBank). The human TFAR19 encodes a protein which shares significant homology to the corresponding proteins of species ranging from yeast to mice. TFAR19 exhibits a ubiquitous expression pattern and its expression is upregulated in tumor cells undergoing apoptosis. Overexpression of TFAR19 could enhance apoptosis of some tumor cells induced by growth factor withdrawal or serum deprivation. But the exact mechanism of TFAR19 is unclear. Mitochondria not only provides energy for the cell, but also plays a critical role on cell death or survival. The release of apoptosis promoting factor, such as cytochrome c from mitochondria, resulted by the damage of mitochondrial membrane integrity, is the key factor controlling apoptosis. The permeability transition pore (PTP) of mitochondria is a protein complex located between the mitochondrial membranes, and it plays an important role in regulating the integrity of mitochondrial membrane. In this study, the effect of recombinant TFAR19 on isolated mitochondrial PTP, membrane potential, and release of cytochrome c was investigated in vitro. The results indicated that recombinant TFAR19 facilitated the isolated mitochondrial PTP opening, decreased the membrane potential, and promoted the release of cytochrome c. The effect of TFAR19 on mitochondria is implemented by opening the mitochondrial PTP. Experimental results implicate that TFAR19 may positively feedback apoptosis signal of mitochondria, forming a positive loop to promote apoptosis.
Effects of mitochondrial permeability transition pore-specific inhibitor cyclosporine A (CsA) and highly expressed Bcl-2 on the apoptosis of HL-60 cells induced by EGTA were studied. Detection of apoptotic peak by flow cytometry, fluorescent microscope observation of chromatin condensation with double staining of PI and Hoechst33342 and DNA ladder analysis all demonstrated that CsA obviously enhanced the apoptosis of HL-60 cells induced by EGTA, while highly expressed Bcl-2 completely blocked it. It is revealed by mitochondrial membrane potential (deltapsi(m)) fluorescent probes rhodamine 123 and CMXRos that the deltapsi(m) decreased in the apoptosis of HL-60 cells induced by EGTA. CsA enhanced the decrease of deltapsi(m), but highly expressed Bcl-2 increased deltapsi(m) of HL-60 cells about 2-fold and completely blocked the decrease of deltapsi(m).
Mitochondrion is not only the major ATP manufacture center of animal cells, but also plays a key role, as a main switch, in the regulation of apoptos is. Opening of the mitochondrion permeability transition pore (MPTP), the life-or-death switch of cells, causes an increase of the permeability of mitochondrial membrane and the release of several types of apoptogenic factors from the intermembrane space, such as cytochrome c, apoptosis inducing factors (AIFs),procaspases and Ca(2+). These apoptotic factors can either activate caspases, the main member of apoptotic proteins, or destruct independently the intranuclear chromatin, or interact with other Ca(2+) -dependent proteins. These result in structural rupture and dysfunction of cells, and the cells are finally degraded into apoptotic bodies and died. Studies on the regulation mechanisms of mitochondrion in apoptosis will be of great value theoretically as well as potential practical usage in designing drugs for cancer, Parkinson's disease and so on, using mitochondria as targets. To understand the key role of the mitochondrion in the determination of life and death of the cells, recent findings in this field are reviewed in this article.
Various extracelluar stimulation, including those by growth factors and cytokines, can induce the bcl-2 gene expression. Bcl-2 protein induced by this stimulation seems to be essential for cell survival. In order to understand the regulations of bcl-2 transcription, recent advances at transcriptional and post-transcriptional levels in this field will be described.
Bcl-2 family proteins play key roles in apoptosis. They coordinate with other apoptotic proteins in apoptosis to control mitochondria stability both in structure and function, while mitochondria probably act as the main switch of apoptosis. Bcl-2 family proteins can be divided into two types, antiapoptotic proteins and pro-apoptotic proteins. During apoptosis, Bcl-2 family proapoptotic proteins can translocate to the outer membrane of mitochondrion after posttranslational modification by certain proteases such as caspases. Then cytochrome c (cyt.c), apoptosis-inducing factors (AIFs), and other proapoptotic factors are released from mitochondrion, triggering apoptosis. Bcl-2 family antiapoptotic proteins sequestered in mitochondrion have ability to inhibit the release of cyt.c and AIFs, and prevent apoptosis. When interacting with activated proapoptotic proteins, the antiapoptotic proteins lose inhibiting ability of pro-apoptotic factors' release, and again triggering apoptosis. Based on the newest research evolvements, types, structures, localizations, apoptosis regulating mechanisms of Bcl-2 family proteins are reviewed.
Apoptosis is usually accompanied by DNA fragmentation and up-regulation of reactive oxygen species, and it can be inhibited by overexpression of Bcl-2. Here, cadmium was found to induce apoptosis in BA/F3beta cells. MTT assay, Hochest 33258 staining, and transmission electron microscopy analysis were used to detect the apoptosis, however, neither DNA fragmentation nor up-regulation of reactive oxygen species were observed in this type of apoptosis. Furthermore, Bcl-2 overexpression had no effect on this type of apoptosis. In conclusion, these data suggested that cadmium induced a novel type of apoptosis in BA/F3beta cells.
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.