Author and Curator: Ritu Saxena, Ph.D.
Word Cloud By Danielle Smolyar
Role of mitochondria in cancer has long been speculated. Infact, Warburg in his 1956 publication talked about how cancer cells exhibit a different mechanism of mitochondrial respiration than normal cells and how this basic difference in glucose metabolism could be utilized to develop targeted therapies against cancer cells. Several decades later, mitochondrial defects, both genetic and functional have been detected and associated with cancer. Here is a brief overview of the mechanisms by which mitochondrial defects could be associated with cancer:
1. Alteration in energy metabolism- well documented function of mitochondria is ATP production through oxidative phosphorylation that involved both mitochondrial and nuclear proteins. Various complexes are involved in the process of electron transport through the respiratory chain. Some electrons might leak, leading to formation of ROS. Further, certain mutations in the ETC could tamper with the mechanism of electron transfer resulting in increased leakage of electrons finally leading to an increase in ROS production. ROS has been associated with cancer, however, the exact mechanism is not known.
2. Alteration of apoptotic machinery- Mitochondrial houses several pro-apoptotic proteins including cytochrome c, apoptosis induced factor (AIF), endonuclease G, and smac/DIABLO. However, when these are released into from mitochondrial, apoptotic signaling is triggered and the cell goes through programmed death. For example, release of cytochrome c into the cytosol triggers a set of proteins referred to as caspases leading to apoptosis of the cell. The exact role of mtDNA mutations in the cellular response to anticancer agents that target apoptotic machinery has not been defined and a lot of research is being done in this area.
3. Somatic mutations- While germline mutations of the mtDNA have implicated in several diseases such as Pearson Marrow syndrome Kearns-Sayre-CPEO, Leber’s hereditary optic neuropathy, Leigh’s syndrome and several others, somatic mutations have also been a associated with several diseases, especially cancer. High rate of mutations in the mtDNA, much more than that of the nuclear genome is the result of several factors – the absence of histone proteins, close proximity to the electron transport chain, reduced repair machinery, lack of introns. The mtDNA mutations could be induced by endogenous or exogenous agents such as ROS, chemical agents, and/or radiation. The mutations could either be detrimental to its survival in which case it would vanish eventually. In case it confers growth advantage to the cell, the mutation would eventually develop into a homoplasmic state where all the alleles of the different copies of the mtDNA harbor it. It may cause a functional change of the protein derived from the mutated gene resulting in the alterations of mitochondrial function. It might be speculated that the mutated mtDNA results in increase in endogenous ROS production further leading to DNA damage, genetic instability and cancer development.
Sources:
Warburg publication: http://www.ncbi.nlm.nih.gov/sites/entrez/13298683?dopt=Abstract&holding=f1000,f1000m,isrctn
Mitochondrial ROS bifurcation: http://informahealthcare.com/doi/abs/10.1080/10715760290021225
Mitochondria and apoptosis: http://www.ncbi.nlm.nih.gov/sites/entrez/11711427?dopt=Abstract&holding=f1000,f1000m,isrctn
Mitochondria and Cancer: http://www.molecular-cancer.com/content/1/1/9/#B7
Related posts:
http://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/
http://pharmaceuticalintelligence.com/2012/08/14/detecting-potential-toxicity-in-mitochondria/
[…] See original article: Mitochondria and Cancer: An overview « Pharmaceutical Intelligence […]
Dr. Ritu
Thank you for this post.
It only shows how cardinal to life Mitochondria actually is, respectively, we have already few posts on Mito on this Scientific Web site.
Please add to the sources ALL the Mito posts on this site.
We MUST cite related posts to provide emphasis to author’s record on this topic and to allow for MAX ping backs to the site which help with search engine optimization,
Thank you
Aviva
Sounds good!
Ritu
Sent from my iPhone
[…] of mitochondria in cancer has long been implicated. Post published on September 1, 2012 (http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/) presents a brief overview of the mechanisms by which mitochondrial defects could be associated […]
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[…] Mitochondria and Cancer: An overview of mechanisms (pharmaceuticalintelligence.com) […]
[…] http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/ […]
[…] Author: Ritu Saxena, PhD http://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/ […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette