Caenorhabditis eleganspathways that surveil and defend mitochondria
Iron is a valuable resource inside the cell. The mitochondrial electron transport chain is rich in haem and iron sulphur proteins, making it an attractive target upon bacterial infection. The authors show that disruption of mitochondrial function, through drugs such as antimycin or interference RNAs (RNAis), induces xenobiotic-detoxification, mitochondrial repair and pathogen response pathways in C. Elegans. They performed an RNAi screen to identify 45 RNAis that are involved in such pathways.
Thursday, 24 April 2014
Tuesday, 4 March 2014
Mitochondria from anoxia-tolerant animals reveal common strategies to survive without oxygen
Mitochondria from anoxia-tolerant animals reveal common strategies to survive without oxygen
Anoxia is the complete absence of oxygen, and various animal species have evolved to tolerate these environments for prolonged periods. The mechanisms allowing this adaptation may allow us to better understand how to combat the effects of reperfusion in cardiac tissue after myocardial infarction. The authors use examples, such as the painted turtle and the common frog, to demonstrate how adaptations to the mitochondria are important in avoiding the onset of cell death during anoxia. The overarching theme is that mitochondria must avoid the collapse of their membrane potential: failing this causes cytosolic calcium to be driven into the mitochondria during reperfusion, which leads to apoptotic signalling and cell death.
Some mechanisms which have been studied include: downregulation of respiratory chain activity; blocking of F1F0-ATPase; tighter membranes to avoid proton leak; blocking of mitochondrial calcium channels; reversal of F1F0-ATPase to maintain membrane potential; and increased ROS-scavenging enzymes. A final noteworthy example is the anoxic turtle brain, where it has been observed that the mitochondrial permeability transition pore can be transiently opened to release calcium from the mitochondria. This protective measure is not associated with mitochondrial swelling, nor release of apoptotic factors.
Anoxia is the complete absence of oxygen, and various animal species have evolved to tolerate these environments for prolonged periods. The mechanisms allowing this adaptation may allow us to better understand how to combat the effects of reperfusion in cardiac tissue after myocardial infarction. The authors use examples, such as the painted turtle and the common frog, to demonstrate how adaptations to the mitochondria are important in avoiding the onset of cell death during anoxia. The overarching theme is that mitochondria must avoid the collapse of their membrane potential: failing this causes cytosolic calcium to be driven into the mitochondria during reperfusion, which leads to apoptotic signalling and cell death.
Some mechanisms which have been studied include: downregulation of respiratory chain activity; blocking of F1F0-ATPase; tighter membranes to avoid proton leak; blocking of mitochondrial calcium channels; reversal of F1F0-ATPase to maintain membrane potential; and increased ROS-scavenging enzymes. A final noteworthy example is the anoxic turtle brain, where it has been observed that the mitochondrial permeability transition pore can be transiently opened to release calcium from the mitochondria. This protective measure is not associated with mitochondrial swelling, nor release of apoptotic factors.
Tuesday, 4 February 2014
Mitochondria supply membranes for autophagosome biogenesis during starvation
http://www.ncbi.nlm.nih.gov/pubmed/20478256
During starvation, autophagy is increased so that the cell can degrade its own components to retrieve nutrients. But where do the membranes that form the autophagosomes come from?
In this paper, they show that lipids for forming autophagosomes come from the outer membrane of mitochondria. The forming of autophagosomes is inhibited if cells lack MFN2, a protein necessary for mitochondrial fusion and also for tethering mitochondria to the ER. They think that the ER can resupply lipids to the mitochondrion (to make up for the lipids it lost to form the autophagosomal membrane (AM)). But doesn't the mitochondrion lose its outer membrane proteins by using part of his membrane to form AMs? Apparently it does not. Most outer membrane proteins of mitochondria are not seen in the AM, which is hypothesized to be the result of a diffusion barrier for proteins. Only proteins associated with the outer leaflet of the outer mitochondrial membrane can traverse the barrier.
Interestingly, lipids from mitochondria only play a role in forming AMs if forming of autophagosomes is induced by starvation. Other mechanisms that induce autophagy (e.g. ER stress and calcium perturbations) do not show mitochondrial outer membrane components colocalized with EM.
During starvation, autophagy is increased so that the cell can degrade its own components to retrieve nutrients. But where do the membranes that form the autophagosomes come from?
In this paper, they show that lipids for forming autophagosomes come from the outer membrane of mitochondria. The forming of autophagosomes is inhibited if cells lack MFN2, a protein necessary for mitochondrial fusion and also for tethering mitochondria to the ER. They think that the ER can resupply lipids to the mitochondrion (to make up for the lipids it lost to form the autophagosomal membrane (AM)). But doesn't the mitochondrion lose its outer membrane proteins by using part of his membrane to form AMs? Apparently it does not. Most outer membrane proteins of mitochondria are not seen in the AM, which is hypothesized to be the result of a diffusion barrier for proteins. Only proteins associated with the outer leaflet of the outer mitochondrial membrane can traverse the barrier.
Interestingly, lipids from mitochondria only play a role in forming AMs if forming of autophagosomes is induced by starvation. Other mechanisms that induce autophagy (e.g. ER stress and calcium perturbations) do not show mitochondrial outer membrane components colocalized with EM.
Stimulus-triggered fate conversion of somatic cells into pluripotency
Stimulus-triggered fate conversion of somatic cells into pluripotency
A surprising new way to generate stem cells has been presented by Obokata et al. The authors found that low-pH stress applied to cells from various tissues, when grown in a medium supplemented with leukaemia inhibtory factor (LIF) and B27, causes the formation of pluripotent cells which are named "stimulus-triggered acquisition of pluripotency" (STAP) cells. Other stress stimuli, such as physical damage, also induced the formation of STAP cells, but low-pH was the most efficient. They worked with Oct4-gfp transgene mouse lymphocytes, which allowed the monitoring of the expression levels of the pluripotency marker Oct4, according to the amount of observed fluorescence in the cells. They found extensive demethylation in Oct4 and another pluripotency gene Nanog, in STAP cells, suggesting substantial epigenetic modification during physical stress.
When STAP cells were grafted into mice they formed teratomas, which are non-malignant encapsulated tumors with tissue or organ components resembling normal derivatives of more than one germ layer. Once parental STAP cells were formed, if they were grown in a medium used to grow embryonic stem (ES) cells, STAP stem cells were formed. These have unlimited proliferative potential and behave very much like ES cells. After blastocyst injection, STAP stem cells efficiently contributed to chimeric mice, and in differentiation culture generated: ectodermal, mesodermal and endodermal derivatives in vitro, including beating cardiac tissue. The precise mechanism of how these somatic cells gained pluripotency after physical stress is still a mystery, but raises many questions such as: how is this reprogramming mechanism normally repressed? and what epigenetic mechanism unites such disparate physical stresses to cause this response?
This article was retracted on 03 July 2014
http://www.nature.com/nature/journal/v511/n7507/full/nature13598.html
A surprising new way to generate stem cells has been presented by Obokata et al. The authors found that low-pH stress applied to cells from various tissues, when grown in a medium supplemented with leukaemia inhibtory factor (LIF) and B27, causes the formation of pluripotent cells which are named "stimulus-triggered acquisition of pluripotency" (STAP) cells. Other stress stimuli, such as physical damage, also induced the formation of STAP cells, but low-pH was the most efficient. They worked with Oct4-gfp transgene mouse lymphocytes, which allowed the monitoring of the expression levels of the pluripotency marker Oct4, according to the amount of observed fluorescence in the cells. They found extensive demethylation in Oct4 and another pluripotency gene Nanog, in STAP cells, suggesting substantial epigenetic modification during physical stress.
When STAP cells were grafted into mice they formed teratomas, which are non-malignant encapsulated tumors with tissue or organ components resembling normal derivatives of more than one germ layer. Once parental STAP cells were formed, if they were grown in a medium used to grow embryonic stem (ES) cells, STAP stem cells were formed. These have unlimited proliferative potential and behave very much like ES cells. After blastocyst injection, STAP stem cells efficiently contributed to chimeric mice, and in differentiation culture generated: ectodermal, mesodermal and endodermal derivatives in vitro, including beating cardiac tissue. The precise mechanism of how these somatic cells gained pluripotency after physical stress is still a mystery, but raises many questions such as: how is this reprogramming mechanism normally repressed? and what epigenetic mechanism unites such disparate physical stresses to cause this response?
This article was retracted on 03 July 2014
http://www.nature.com/nature/journal/v511/n7507/full/nature13598.html
Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging
Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging
Mitochondrial reactive oxygen species (ROS) accumulation is thought to participate in a vicious cycle of oxidative damage in aging. Damaged mtDNA results in a faulty respiratory chain, causing ROS generation, which may further damage the mtDNA, and so on. In this review, the authors discuss some of the mechanisms of mitochondrial dysfunction in aging, and potential ways this may be regulated. In particular, calorie restriction has been observed to reduce age-related phenotypes. The authors present evidence supporting the claim that a family of deacetylases called sirtuins, which commonly modify mitochondrial proteins, are responsible for this. The authors also discuss how low-levels of ROS are important for autophagic signalling, a pro-cell survival response which recycles damaged organelles. Loss of this quality control has been shown in aging and aging-related disorders such as neurodegenerative diseases.
Mitochondrial reactive oxygen species (ROS) accumulation is thought to participate in a vicious cycle of oxidative damage in aging. Damaged mtDNA results in a faulty respiratory chain, causing ROS generation, which may further damage the mtDNA, and so on. In this review, the authors discuss some of the mechanisms of mitochondrial dysfunction in aging, and potential ways this may be regulated. In particular, calorie restriction has been observed to reduce age-related phenotypes. The authors present evidence supporting the claim that a family of deacetylases called sirtuins, which commonly modify mitochondrial proteins, are responsible for this. The authors also discuss how low-levels of ROS are important for autophagic signalling, a pro-cell survival response which recycles damaged organelles. Loss of this quality control has been shown in aging and aging-related disorders such as neurodegenerative diseases.
Monday, 27 January 2014
Amyloid β binds procaspase-9 to inhibit assembly of Apaf-1 apoptosome and intrinsic apoptosis pathway
Amyloid β binds procaspase-9 to inhibit assembly of Apaf-1 apoptosome and intrinsic apoptosis pathway
Amyloid-β (Aβ) is a family of 36-43 amino-acids which form aggregates in the brains of Alzheimer's patients. The expression of Aβ has been linked to apoptosis in other studies, although the precise mechanism is poorly understood. For the first time, however, the authors of this study report that Aβ42 can actually inhibit apoptosis. Their experiments found that caspase activation and cell death induced by stauroporine (which activates the intrinsic pathway) was inhibited by Aβ42 somewhere between cytochrome c release and procaspase-9 activation. The authors suggest the mechanism is Aβ42 competing with Apaf-1 for procaspase-9 binding, which causes inhibition of the apoptosome. The effect was time-dependent (longer incubation times resulting in apoptosis), which suggests an initial transient period where the cell attempts to resist cell death in the presence of Aβ42. The effect was most prevalent in HeLa cells, but was also observed to a lesser extent in MG63 and SHSY5Y cell lines.
Amyloid-β (Aβ) is a family of 36-43 amino-acids which form aggregates in the brains of Alzheimer's patients. The expression of Aβ has been linked to apoptosis in other studies, although the precise mechanism is poorly understood. For the first time, however, the authors of this study report that Aβ42 can actually inhibit apoptosis. Their experiments found that caspase activation and cell death induced by stauroporine (which activates the intrinsic pathway) was inhibited by Aβ42 somewhere between cytochrome c release and procaspase-9 activation. The authors suggest the mechanism is Aβ42 competing with Apaf-1 for procaspase-9 binding, which causes inhibition of the apoptosome. The effect was time-dependent (longer incubation times resulting in apoptosis), which suggests an initial transient period where the cell attempts to resist cell death in the presence of Aβ42. The effect was most prevalent in HeLa cells, but was also observed to a lesser extent in MG63 and SHSY5Y cell lines.
Tuesday, 14 January 2014
The Mitochondrial Proteome and Human Disease
The Mitochondrial Proteome and Human Disease
Defining the mitochondrial proteome is not a straightforward task: not all mitochondrial proteins possess a targeting sequence to direct their import into the organelle; abundance spans 6 orders of magnitude; and almost half of mitochondrial proteins are distributed in a tissue-specific manner. Surprisingly, it appears that complexes I, II, III and V are found in high abundance across many tissues but complex IV has a fair number of subunits which are expressed in a tissue-dependent manner, as well as many of the mitochondrial ribosome subunits. The most successful way of determining the mitochondrial proteome to date, has been with mass spectrometry by purifying mitochondrial extracts. It is believed that 1100-1400 distinct gene loci encode mitochondrial proteins, but these may also have splice isoforms. The authors also provide a list of useful online databases for mitochondrial proteins.
The authors discuss how the definition of mitochondrial disease has expanded from disorders of oxidative ATP production, to include diseases such as soft tissue tumours and diabetes mellitus. They suggest that a promising avenue to elucidate mitochondrial disorders is to combine disease genes, clinical features and biological pathways.
Defining the mitochondrial proteome is not a straightforward task: not all mitochondrial proteins possess a targeting sequence to direct their import into the organelle; abundance spans 6 orders of magnitude; and almost half of mitochondrial proteins are distributed in a tissue-specific manner. Surprisingly, it appears that complexes I, II, III and V are found in high abundance across many tissues but complex IV has a fair number of subunits which are expressed in a tissue-dependent manner, as well as many of the mitochondrial ribosome subunits. The most successful way of determining the mitochondrial proteome to date, has been with mass spectrometry by purifying mitochondrial extracts. It is believed that 1100-1400 distinct gene loci encode mitochondrial proteins, but these may also have splice isoforms. The authors also provide a list of useful online databases for mitochondrial proteins.
The authors discuss how the definition of mitochondrial disease has expanded from disorders of oxidative ATP production, to include diseases such as soft tissue tumours and diabetes mellitus. They suggest that a promising avenue to elucidate mitochondrial disorders is to combine disease genes, clinical features and biological pathways.
Homogeneous longitudinal profiles and synchronous fluctuations of mitochondrial transmembrane potential
http://www.sciencedirect.com/science/article/pii/S0014579300016835
What they did in this paper is measure the membrane potential along a mitochondrion, so along its longitudinal axis. They did this for about 80 mitochondria.
What they find is that within a mitochondrion, the membrane potential is more or less the same, the variations are around 5 mV. Interestingly, the points at the ends of the mitochondria were usually (in 78% of the cases) extrema. So it often occurred that the potential at the ends was either the minimum potential along the whole mitochondria, or the maximum. This maybe could have something to do with the ends being involved in fusion/fission processes.
They also find that the fluctuations in potential in mitochondria that are connected in the network occur simultaneously.
Another interesting thing is that they find that the potential does not depend on where in the cytosol the mitochondria are. This sort of contradicts other findings that the membrane potential depends on the localization of the mitochondrion in the cell (see e.g. http://www.pnas.org/content/88/9/3671.abstract)
Another thing that they mention (they don't measure this themselves) is that even if mitochondria don't have DNA, they still keep their membrane potential intact by using their ATP synthase in reverse. The ATP that is needed for this comes from glycolysis. But now the mitochondria are just things in the cell using up ATP and not generating anything at all, so I was wondering why they maintain their membrane potential at all. I guess the cell doesn't want to kill all its mitochondria if they don't work for a while..
What they did in this paper is measure the membrane potential along a mitochondrion, so along its longitudinal axis. They did this for about 80 mitochondria.
What they find is that within a mitochondrion, the membrane potential is more or less the same, the variations are around 5 mV. Interestingly, the points at the ends of the mitochondria were usually (in 78% of the cases) extrema. So it often occurred that the potential at the ends was either the minimum potential along the whole mitochondria, or the maximum. This maybe could have something to do with the ends being involved in fusion/fission processes.
They also find that the fluctuations in potential in mitochondria that are connected in the network occur simultaneously.
Another interesting thing is that they find that the potential does not depend on where in the cytosol the mitochondria are. This sort of contradicts other findings that the membrane potential depends on the localization of the mitochondrion in the cell (see e.g. http://www.pnas.org/content/88/9/3671.abstract)
Another thing that they mention (they don't measure this themselves) is that even if mitochondria don't have DNA, they still keep their membrane potential intact by using their ATP synthase in reverse. The ATP that is needed for this comes from glycolysis. But now the mitochondria are just things in the cell using up ATP and not generating anything at all, so I was wondering why they maintain their membrane potential at all. I guess the cell doesn't want to kill all its mitochondria if they don't work for a while..
Wednesday, 11 December 2013
Appetite regulation is controlled in part by neurons in the lateral hypothalamus, which secrete neuropeptides in response to signals from the body about its energy reserves. In particular, a pair of neuron populations called AGRP (agouti-gene related protein) and POMC (pro-opiomelanocortin) appear to have an opposing effect, with AGRP stimulating feeding and POMC inhibiting it. In this month's issue of Cell, the effect of mitochondrial dynamics on both neuronal populations has been investigated by Dietrich et al and Schneeberger et al. In AGRP neurons, food deprivation leads to a breakup of the mitochondrial network established in the normal-chow diet, whereas feeding of a high fat diet leads to greater aggregation of the mitochondrial network. This effect appears to be population-specific, and has the effect of causing weight gain by increased fat mass.
Knockout of mfn1 does not lead to phenotypic variation on standard chow diet, but leads to fat mass gain in female mice on a high fat diet. No effect is observed in males. Mfn2 knockout leads to decreased weight gain in female mice fed ad libitum on normal chow, with the only observed compensating factor being an increase in respiratory exchange ratio (a measurement of the use of glucose instead of fat in metabolism, which AGRP neurons are believed to play a role in regulating). Both genders gained less weight on a high fat diet if mfn2 was knocked out.
Knockout of mfn1 does not lead to phenotypic variation on standard chow diet, but leads to fat mass gain in female mice on a high fat diet. No effect is observed in males. Mfn2 knockout leads to decreased weight gain in female mice fed ad libitum on normal chow, with the only observed compensating factor being an increase in respiratory exchange ratio (a measurement of the use of glucose instead of fat in metabolism, which AGRP neurons are believed to play a role in regulating). Both genders gained less weight on a high fat diet if mfn2 was knocked out.
Tuesday, 12 November 2013
The regulation of mitochondrial DNA copy number in glioblastoma cells
The regulation of mitochondrial DNA copy number in glioblastoma cells
Embryonic stem cells and cancer cells share a number of similarities. Both are highly proliferative (stem cells needing to find a tissue to differentiate at, and cancers are malignant by their nature), glycolytic and have a low copy number of mtDNA. This study compares human neuronal stem cells (hNSCs) and a highly malignant brain cancer called glioblastoma multiforme (GBM). It was shown that hNSCs increase their mtDNA copy number in a cell-specific way during differentiation to a mtDNA "setpoint". When induced to differentiate, GBM fails to match hNSCs expansion in copy number, patterns of gene expression and increased respitatory capacity. However, if mtDNAs are depleted from a GBM and transferred to a mouse, if a tumour manages to form, it is observed that the mtDNA copy number is recovered to in vitro levels, indicating GBM also has an mtDNA setpoint. It is interesting to note that, once mtDNA was depleted from GBM cells and allowed to form a tumour in nude mice, the survival time from largest to smallest was the following: 0.2% (>100 days), 3% (~95 days), 100% (~85 days), 20% (~81 days) and 50% (~78 days), where the percentage indicates the amount of mtDNA remaining in the GBM cells before transfer.
Embryonic stem cells and cancer cells share a number of similarities. Both are highly proliferative (stem cells needing to find a tissue to differentiate at, and cancers are malignant by their nature), glycolytic and have a low copy number of mtDNA. This study compares human neuronal stem cells (hNSCs) and a highly malignant brain cancer called glioblastoma multiforme (GBM). It was shown that hNSCs increase their mtDNA copy number in a cell-specific way during differentiation to a mtDNA "setpoint". When induced to differentiate, GBM fails to match hNSCs expansion in copy number, patterns of gene expression and increased respitatory capacity. However, if mtDNAs are depleted from a GBM and transferred to a mouse, if a tumour manages to form, it is observed that the mtDNA copy number is recovered to in vitro levels, indicating GBM also has an mtDNA setpoint. It is interesting to note that, once mtDNA was depleted from GBM cells and allowed to form a tumour in nude mice, the survival time from largest to smallest was the following: 0.2% (>100 days), 3% (~95 days), 100% (~85 days), 20% (~81 days) and 50% (~78 days), where the percentage indicates the amount of mtDNA remaining in the GBM cells before transfer.
The regulatory role of mitochondria in capacitative calcium entry.
The regulatory role of mitochondria in capacitative calcium entry.
Mitochondria can uptake calcium by using a uniport in the mitochondrial inner membrane. This uniport is driven by the membrane potential. The uniport has a low affinity for calcium. This implies that mitochondria are not able to take up calcium very efficiently. It is observed, however, that mitochondria do take up calcium and this happens more efficiently than one would expect based on the low affinity of the uniport. This can be explained by the discovery that locally there can be high concentrations of calcium (much higher than the global concentration of calcium in the cytoplasm) which enables the mitochondria to efficiently uptake calcium. Local high concentrations of calcium appear close to calcium channels in the endoplasmic reticulum (ER) and the plasma membrane (PM).
The ER is the cell's biggest calcium store and the calcium concentration in the ER can be 3-4 orders of magnitude larger than the concentration in the cytosol. The opening of calcium channels in the ER, which enables calcium to passively flow into the cytosol, depends on the concentration of calcium in the cytosol ([Cacyt]). A higher [Cacyt] induces the opening of the calcium channels in the ER. This positive feedback system is called Calcium-Induced Calcium Release (CICR). If the [Cacyt] rises above a certain value, however, there is a negative feedback on IP_3-receptor calcium channels (which let calcium flow from the ER into the cytoplasm). This negative feedback inhibits the release of calcium from the ER and consequently decreases the capacitative calcium entry (CCE). This eventually stops the calcium signal in the cell.
Mitochondria in the vicinity of calcium channels of the ER will take up calcium. This lowers the local [Cacyt] and can prevent the [Cacyt] from reaching the level at which it starts to give negative feedback to calcium channels in the ER. Mitochondria can therefore inhibit negative feedback on IP_3-receptor calcium channels. This stimulates the depletion of calcium stores and also stimulates CCE.
A concentration of calcium in the mitochondrial matrix that is too high can lead to damaged mitochondrial function consequently stops mitochondrial calcium uptake. This will lead to an increase in [Cacyt] and this stimulates negative feedback to the calcium channels. By forming mitochondrial networks, the concentration of calcium inside the mitochondria can be kept at a lower level since the calcium will spread throughout the network. This means that more calcium can be taken up by the mitochondria and less negative feedback will be given to the calcium channels. The formation of mitochondrial networks can therefore lead to a longer effectiveness of the calcium signal.
A concentration of calcium in the mitochondrial matrix that is too high can lead to damaged mitochondrial function consequently stops mitochondrial calcium uptake. This will lead to an increase in [Cacyt] and this stimulates negative feedback to the calcium channels. By forming mitochondrial networks, the concentration of calcium inside the mitochondria can be kept at a lower level since the calcium will spread throughout the network. This means that more calcium can be taken up by the mitochondria and less negative feedback will be given to the calcium channels. The formation of mitochondrial networks can therefore lead to a longer effectiveness of the calcium signal.
Tuesday, 5 November 2013
Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis): Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell
Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis):
Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell
When mitochondria are faulty, what is often observed is mitochondrial autophagy or mitophagy, where a subset of the mitochondrial population are digested by autophagosomes. In this paper, another pathway is observed after damage to the whole mitochondrial population. As a model, highly glycolytic HeLa cells are studied. Respiratory chain inhibitors and uncouplers (which induce ROS production and hydrolyse ATP in mitochondria) were applied. This was observed to cause fission of the mitochondrial network, migration of mitochondria to the perinuclear space, accumulation of mitochondria into a vesicle and then its subsequent expulsion by fusing to the plasma membrane.
Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell
When mitochondria are faulty, what is often observed is mitochondrial autophagy or mitophagy, where a subset of the mitochondrial population are digested by autophagosomes. In this paper, another pathway is observed after damage to the whole mitochondrial population. As a model, highly glycolytic HeLa cells are studied. Respiratory chain inhibitors and uncouplers (which induce ROS production and hydrolyse ATP in mitochondria) were applied. This was observed to cause fission of the mitochondrial network, migration of mitochondria to the perinuclear space, accumulation of mitochondria into a vesicle and then its subsequent expulsion by fusing to the plasma membrane.
Wednesday, 30 October 2013
The Role of Mitochondrial Electron Transport in Tumorigenesis and Metastasis
The Role of Mitochondrial Electron Transport in Tumorigenesis and Metastasis
The role of electron transport in metastasis (formation of secondary tumors) and tumorigenesis (the creation of cancer cells) is poorly understood. This review collects evidence to suggest that there exists a bioenergetic landscape (bell curve) for malignancy in tumors, which must optimise glycolysis versus oxidative phosphorylation (OXPHOS) as a means of energy production. Glycolysis is an anaerobic respiration pathway, which produces less energy than mitochondrial oxidative phosphorylation, but produces many reactive oxygen species and activates malignancy pathways. On the other hand, OXPHOS correlates with more differentiated tumor cells but also anchorage independent cell growth (anoikis resistance) and metastatic potential. This highlights the need for a cancer cell to balance OXPHOS and glycolytic energy production.
The role of electron transport in metastasis (formation of secondary tumors) and tumorigenesis (the creation of cancer cells) is poorly understood. This review collects evidence to suggest that there exists a bioenergetic landscape (bell curve) for malignancy in tumors, which must optimise glycolysis versus oxidative phosphorylation (OXPHOS) as a means of energy production. Glycolysis is an anaerobic respiration pathway, which produces less energy than mitochondrial oxidative phosphorylation, but produces many reactive oxygen species and activates malignancy pathways. On the other hand, OXPHOS correlates with more differentiated tumor cells but also anchorage independent cell growth (anoikis resistance) and metastatic potential. This highlights the need for a cancer cell to balance OXPHOS and glycolytic energy production.
Tuesday, 22 October 2013
Coastal Physical Features in West Africa Shape the Genetic Structure of the Bonga Shad
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793960/
In this paper the genetic diversity of the fish E. Fimbriata that lives along the west coast of Africa is studied. In total 480 fish are sampled and their nuclear DNA is extracted. They then studied the variability in seven loci using an EPIC (exon-primed, intron-crossing polymerase chain reaction) method and used MCMC methods to find the number of parental populations.
The results they found were somewhat different from earlier studies on these fish in the same regions. In an earlier study, they had looked at variability in mtDNA. This study using mtDNA found three genetically different groups: 1) a northern group extending from Mauritania to Guinea, 2) a central group distributed from Côte d’Ivoire to Cameroon, and 3) a southern group with populations extending from Gabon to Angola. Also, they found a correlation between geographical distance and genetic differentation (the larger the geographical distance, the more genetic differences).
The study in this paper found genetic differentiation at finer scale, so within the three groups found in the mtDNA study, they found genetically distinct samples whereas these samples appeared genetically the same using the mtDNA markers. Also, this paper found no correlation between the geographical distance and genetic differentation. Sam suggested that this might be because maybe only the male fish move away from where they are born. If the females of a certain population tend not to migrate then the mtDNA of that population will not mix with that of a different population and so you expect to see more difference in mtDNA as the geographical distances become larger. The nuclear DNA of different populations then does mix because of the migrating males.
In this paper the genetic diversity of the fish E. Fimbriata that lives along the west coast of Africa is studied. In total 480 fish are sampled and their nuclear DNA is extracted. They then studied the variability in seven loci using an EPIC (exon-primed, intron-crossing polymerase chain reaction) method and used MCMC methods to find the number of parental populations.
The results they found were somewhat different from earlier studies on these fish in the same regions. In an earlier study, they had looked at variability in mtDNA. This study using mtDNA found three genetically different groups: 1) a northern group extending from Mauritania to Guinea, 2) a central group distributed from Côte d’Ivoire to Cameroon, and 3) a southern group with populations extending from Gabon to Angola. Also, they found a correlation between geographical distance and genetic differentation (the larger the geographical distance, the more genetic differences).
The study in this paper found genetic differentiation at finer scale, so within the three groups found in the mtDNA study, they found genetically distinct samples whereas these samples appeared genetically the same using the mtDNA markers. Also, this paper found no correlation between the geographical distance and genetic differentation. Sam suggested that this might be because maybe only the male fish move away from where they are born. If the females of a certain population tend not to migrate then the mtDNA of that population will not mix with that of a different population and so you expect to see more difference in mtDNA as the geographical distances become larger. The nuclear DNA of different populations then does mix because of the migrating males.
The Role of Dynamin-Related Protein 1, a Mediator of Mitochondrial Fission, in Apoptosis
The Role of Dynamin-Related Protein 1, a Mediator of Mitochondrial Fission, in Apoptosis
Apoptosis is a form of programmed cell-death, where a cell decides to kill itself in a controlled manner following a stress signal. A number of physiological changes occur inside the cell during apoptosis, one of which is the fragmentation of the mitochondrial network. Drp1 is an important protein involved in mitochondrial fission and can be seen to translocate from the cytosol to the outer membrane of mitochondria before fission. This paper finds that, in the COS-7 immortalized monkey kidney cell line, blocking the function of Drp1 prevents: mitochondrial fragmentation; the loss of mitochondrial membrane potential; the leaking of cytochrome c into the cytoplasm; and crucially, can block apoptosis itself.
Apoptosis is a form of programmed cell-death, where a cell decides to kill itself in a controlled manner following a stress signal. A number of physiological changes occur inside the cell during apoptosis, one of which is the fragmentation of the mitochondrial network. Drp1 is an important protein involved in mitochondrial fission and can be seen to translocate from the cytosol to the outer membrane of mitochondria before fission. This paper finds that, in the COS-7 immortalized monkey kidney cell line, blocking the function of Drp1 prevents: mitochondrial fragmentation; the loss of mitochondrial membrane potential; the leaking of cytochrome c into the cytoplasm; and crucially, can block apoptosis itself.
Tuesday, 15 October 2013
Evolution of mitochondrial gene content: gene loss and transfer to the nucleus
Evolution of mitochondrial gene content: gene loss and transfer to the nucleus
adams2003mitochondrialhttp://www.ncbi.nlm.nih.gov/pubmed/14615181
Eukaryotic relationships with mitochondria are largely accepted to be the result of an endosymbiotic event between an ancestral eukaryote and a "proto-mitochondrion". Since this event, genes encoding functional aspects of the mitochondrion have been transferred to the eukaryotic nucleus -- for reasons that are unclear but may be related to increased genetic control and/or stability. This review describes current understanding of this process, including the different extents to which it has occurred in different lineages across life. Rickettsia looks perhaps a bit like a precursor mitochondrion; Reclinomonas americana has retained more (67) mitochondrial protein genes than other organisms; animals seem to have stabilised at 13 protein and 22 tRNA genes.
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