Tissue injury and repair
C. Simon Herrington in Muir's Textbook of Pathology, 2020
The intrinsic pathway involves mitochondria. In normal cells, there are anti-apoptotic molecules present in the membranes of mitochondria. These belong to the Bcl-2 family of proteins, most notably Bcl-2 itself and Bcl-x. Their presence is stimulated by growth factors and other normal survival signals. Under circumstances of cellular stress or where the cell is deprived of its normal survival signals, there is a loss of the anti-apoptotic proteins and these are replaced by pro-apoptotic members of the same family such as Bax. A shift in the balance between pro- and anti-apoptotic Bcl-2 family members to favour apoptosis causes the mitochondrial membranes to become leaky (so-called mitochondrial permeability transition). One of the proteins that then escapes from the mitochondria is cytochrome C, an enzyme involved in respiration. In the cytosol, this protein binds to another protein Apaf-1 (apoptosis-activating factor 1), which is capable of activating caspases. Other proteins leak out from the mitochondria, which further encourages apoptosis.
Immunocytochemical Detection Systems
Lars-Inge Larsson in Immunocytochemistry: Theory and Practice, 2020
Many methods for conjugating HRP to IgG or to Fab fragments have been devised. These include the use of glutaraldehyde or other bifunctional reagents in one- or two-step procedures (cf. References 5, 6, 30, 52, 199, and 227) or takes advantage of the glycoprotein nature of HRP, which makes it possible (by periodate oxidation) to generate HRP-aldehyde, which subsequently reacts with primary amino groups on IgG.86,239,246 Careful attention must be paid to the molecular sizes, antibody reactivities, and enzyme activities of these and other antibody enzyme conjugates (for a recent extensive review see Ishikawa et al.158). The smaller the conjugate, the better the penetration into tissue, and much attention has been paid to preparation of HRP-Fab conjugates.192,199 In order to further minimize the size of conjugates, Gerber et al.106 have coupled the heme-octapeptide of cytochrome c to antibodies.
The Role of Mitochondrial Dysfunction in Mitophagy and Apoptosis and Its Relevance to Cancer
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Given that MOMP is the earliest irreversible step in apoptosis, this event is regarded as the point of no return in the execution of apoptosis. Since cytochrome c is an indispensable mobile carrier of electrons between Complexes III and IV during mitochondrial respiration, its mitochondrial release during MOMP triggers a sequence of events that eventually lead to the loss of mitochondrial function [61]. Although the initial decline in the levels of mitochondrial membrane potential induced by MOMP can be rescued by a compensatory mechanism, in which Complex V operates in reverse mode acting as a proton pump to re-establish the proton gradient at the expense of ATP, long-term activity of MOMP inevitably results in the deterioration of mitochondrial health. Under such circumstances, mitochondria are exposed to an inherent selection pressure imposed by the dependence of mitochondrial protein transport on membrane potential [62]. In this scenario, defective mitochondria are less likely to import protein constituents encoded by the nuclear genome. Since many of these proteins play essential roles in the maintenance of mitochondrial health, such mechanism may further contribute to the deterioration of mitochondrial respiration as well as OXPHOS resulting in the loss of mitochondrial membrane potential in a cyclic fashion (Figure 1). Moreover, given that mitophagy preferentially targets dysfunctional mitochondria, this paradigm could also explain the phenomenon of simultaneous activation of apoptosis and mitophagy by the same stress stimuli [63].
Extracellular vesicles derived from natural killer cells use multiple cytotoxic proteins and killing mechanisms to target cancer cells
Published in Journal of Extracellular Vesicles, 2019
Chun-Hua Wu, Jingbo Li, Li Li, Jianping Sun, Muller Fabbri, Alan S. Wayne, Robert C. Seeger, Ambrose Y. Jong
Granzyme B is the granzyme family member with the strongest apoptotic activity as a result of its caspase-like ability to cleave substrates at aspartic acid residues, thereby activating procaspases directly and cleaving downstream caspase substrates [22]. GzmB prominently induces damage to mitochondria, a central hallmark of apoptosis [36]. Cytochrome C is a well-conserved electron-transport protein and is part of the respiratory chain localized to mitochondrial intermembrane space [37]. Upon apoptotic stimulation, cytochrome C released from mitochondria associates with procaspase-9 [38]. The complex then processes caspase-9 from an inactive proenzyme to its active form. This event further triggers activation of caspase-3 and −7, and eventually leads to apoptosis (Figure 8). We observed the release of cytochrome C (Figure 6) and the activation of caspase-3, −7, and −9 in NK-EV-treated cells [19], suggesting damage to mitochondria and a role for GzmB (Figure 8). The release of AIF (apoptosis inducing factor) may cause DNA damage and induce necrosis. It has also been reported that both GzmA and GNLY may damage mitochondria to induce cell death. Thus, multiple cytotoxic actions may centre at the mitochondrial death pathway.
CYCS gene variants associated with thrombocytopenia
Published in Platelets, 2019
Elizabeth C Ledgerwood, Caitlin Dunstan-Harrison, Lily Ong, Ian M Morison
It remains unclear how cytochrome c contributes to normal megakaryopoiesis and thrombopoiesis, and therefore which function of the mutated cytochromes c drives the release of atypical platelets into the bone marrow space. Cytochrome c has an essential role in mitochondria as a component of the electron transport chain, transferring electrons from complex III to complex IV. As no symptoms associated with abnormal mitochondrial respiratory function have been reported in association with the CYCS variants, and a low platelet phenotype is not associated with disorders of mitochondrial electron transport, it seems unlikely that the thrombocytopenia involves a defect in electron transport. In addition, the ability of G42S cytochrome c to sustain oxygen consumption has been shown to be either normal, when using isolated rat mitochondria, or slightly reduced, in G42S-overexpressing cytochrome c knockout mouse lung fibroblasts [1,2]. Both G42S and Y49H cytochromes c complemented a cytochrome c knockout yeast strain, although this complementation was slightly decreased when yeast was cultured under a heat stress [2]. There was no change in the steady state reduction of G42S cytochrome c by rat mitoplasts, and G42S cytochrome c has a normal redox potential [1].
Cytochrome c injection induced embryo loss
Published in Drug and Chemical Toxicology, 2021
Tonghui Xu, Qiuhong Yang, Banqin Wang, Wenfu Wang, Jingxin Li, Yuyan Ma, Xiaolin Gao
Cytochrome c plays an important role in electron transfer between cytochrome c oxidase and reductase (Margalit and Schejter 1973). Normally, cytochrome c resides between the inner and outer mitochondrial membrane. At present, cytochrome c has been used as first-aid in the clinic for organs which are lacking oxygen. However, intriguingly based on more recent evidence, injection of cytochrome C has been shown to result in selective suicide of dendritic cells (DCs) (Lin et al.2008) and failure of self-tolerance (Qiu et al.2009). It is widely believed that decidual antigen-presenting cells (APCs), especially DCs, are critical for fetomaternal tolerance (Blois et al.2004, Blois et al.2007). In vivo DCs depletion affects implantation and early placental development in mice (Krey et al.2008). Cross talk between DCs and natural killer cells at the feto-maternal interface is also believed to be pivotal for pregnancy (Laskarin et al.2007). As a failure of self-tolerance result, recurrent spontaneous abortion (RSA) occurs in pregnant women. This type of abortion has been related to a shift in the T helper 2 (Th2) cell response of normal pregnancy to a Th1 response, where cytokines such as interferon-γ (INF-γ) and tumor necrosis factor-α (TNF‐α) can destroy trophoblasts (Raghupathy 1997). Therefore, we hypothesized that transient ablation of decidual DCs by cytochrome c injection may result in failed fetomaternal tolerance induction and Th1/Th2 imbalances, triggering embryo loss and abortion.
Related Knowledge Centers
- Cellular Respiration
- Cytochrome C Oxidase
- Inner Mitochondrial Membrane
- Iron
- Oxygen
- Apoptosis
- Hemoprotein
- Mitochondrion
- Coenzyme Q – Cytochrome C Reductase
- Redox