Wednesday, 25 February 2015

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

Mingkun Li, Roland Schröder, Shengyu Ni et al.

Currently, there is little evidence to support the role of positive selection for mutations in mtDNA; indeed there is evidence that in proliferative tissue, it is negative selection which is the greater force. In this large-scale study, the authors explore the prevalence of different mutations from post-mortem tissues across 152 individuals. They find that particular heteroplasmies occur at particularly high frequencies, based on their nucleotide position, the tissue and the consensus allele. In agreement with other studies, the authors find that the number of heteroplasmies correlates with age. 

The functional explanation for tissue-related and allele-related selection remains unknown, but the authors suggest that it is possibly the metabolic requirements of each tissue which generates a selective pressure. As a case-study, the authors show that there is a strong positive selection for heteroplasmies in the liver which decrease mitochondrial function. Since many metabolic processes in the liver generate damaging byproducts, mutations which result in reduced function may be a means to avoid further damage, dubbed as 'survival of the slowest'.


Tuesday, 24 February 2015

Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuit

Yiming Chen, Yen-Chu Liu, Tzu-Wei Kuo, Zachary A Knight

Summary: AgRP and POMC neurons have been observed via optogenetic methods with sub-second time resolution in actively behaving mice. Neural activity fluctuates in response to food presentation and feeding, and has characteristic dynamics within both meals and bouts. This represents a fast-responding, learning/knowledge-based modulation to the slower-fluctuating endocrine-mediated homeostatic regulation.

In this paper, the authors use optogenetic techniques to image hypothalamic activity during feeding behaviour, specifically activity of AgRP and POMC neurons. These share downstream POMC-activated/AgRP-inhibited melanocortin receptors. The paper addresses a particular knowledge gap: short-term dynamics of AgRP and POMC before, during and immediately following feeding.

AgRP neurons (which stimulate feeding) and POMC (which inhibit it) are both believed to have their activity modulated by endocrine signals encoding information about nutritional state, which is supported by this paper. A challenge with ghrelin (an endocrine indicator of hunger) led to AgRP activity almost doubling and POMC activity dropping to nearly half, and this change was reversed after food was consumed.

Surprisingly, AgRP & POMC can be strongly regulated simply by observing food, rather than longer-term endocrine-mediated homeostatic responses.  In fasted mice both POMC and AgRP neurons show a strong and rapid response to presentation of food, with most of the response having already taken place before the first bite occurs. In mice that were previously fed ad libitum this is not observed. Food removal was found to reverse the effects of food presentation, but on a slower timescale.

Detectable but inaccessible food (either in a cage or hidden from view) led to a much smaller and transient response, with the hidden food evoking a smaller change. The appeal of the food also influences the strength of the neural response, with highly appetising foods (peanut butter and chocolate) causing larger responses.

POMC and AgRP neurons also fluctuate within feeding bouts in a meal, with both AgRP and POMC having consistent fluctuations lasting approximately 30 seconds. These resemble the responses on first presentation of food, but at a much smaller level of variation.

Thursday, 19 February 2015

Trans-mitochondrial coordination of cristae at regulated membrane junctions

Martin Picard, Meagan J. McManus, György Csordás et al.

The existence of junctions which electrically couple adjacent mitochondria through their outer mitochondrial membranes, called inter-mitochondrial junctions (IMJs), has been known for almost three decades.  IMJs do not necessarily form when mitochondria come into contact, and the phenomenon is distinct from mitochondrial fusion, since the inner/outer mitochondrial membranes remain distinct when an IMJ is formed. Indeed, the authors note that the presence of IMJs tend to correlate with how dependent the cell is on oxidative phosphorylation. They are dynamically regulated, and can form on addition of electron donors to generate membrane potential.

The authors investigated the influence of IMJs on cristae structure, and found that cristae align themselves perpendicularly to IMJs, and at a higher density than other regions. Even after genetic perturbations to interfere with cristae structure, the cristae continued to align with IMJs. They observed that cristae would bend a great deal, so they could participate in IMJs, which suggests biological regulation. The authors present a novel drug-inducible system which can physically tether adjacent mitochondria. They show that both cristae and IMJ formation can be induced with this system, by stable juxtaposition of mitochondria. Their data suggest that such structures exist to promote information transfer inside the cytoplasm of eukaryotic cells.

Thursday, 12 February 2015

SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario

Luciana O. Almeida et al

SET is a protein that is accumulated in Alzheimer's disease and some types of cancer. It is hypothesized here that SET influences mitochondrial mechanisms.

In this paper they find that, in HEK293 cells overexpressing SET, levels of mitochondrial uncoupling proteins UCP2 and UCP3 are increased (uncoupling proteins allow for dissipation of the electrochemical gradient across the inner membrane of the mitochondrion). Cellular ATP content was decreased. Also, levels of mitochondrial fission were increased due to increased levels of the fission proteins Drp1 and Fis1.

Wednesday, 11 February 2015

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

Marco Archetti, Daniela A. Ferraro, and Gerhard Christofori

Significant heterogeneity exists in intratumour populations. At first glance, this appears to be at odds with the strong selective pressure for the most proliferative subclones. The authors explore this by considering neuroendocrine pancreatic cancer cells, which produce a growth factor called IGF-II. They mix populations of IGF-II positive (producer) cells and IGF-II knockout (nonproducer) cells, to explore under what circumstances heterogeneity can be supported. 

They find that, when cells are grown in nutrient-high conditions, the fraction of producer cells reduces to zero over time. This is because the nonproducer cells are able to free-ride on the IGF-II produced by the producer cells, in a tragedy of the commons. However, at low nutrient conditions, producer cells dominate over the nonproducer cells (at intermediate concentrations of nutrient there was no clear winner). The authors argue that this can be understood in terms of the nonlinear cost of generating IGF-II. When the cost/benefit ratio for producing IGF-II is low (i.e. in nutrient poor conditions), cells that can endogeneously produce the growth factor have an advantage. However, as nutrient availability increases, there is a diminishing return on generating the growth factor, so cells that are nonproducers have an advantage. The authors show via simulation that when such agents are spatially distributed on a lattice, coexistence between producers and nonproducers can occur due to heterogeneity in nutrient availability.

Monday, 2 February 2015

Breast-cancer-secreted ​miR-122 reprograms ​glucose metabolism in premetastatic niche to promote metastasis
Miranda Y. Fong, Weiying Zhou, Liang Liu et al.

The authors find that many breast cancer cell lines secrete the microRNA miR-122, in vesicles composed of both protein and microRNA. They show that this factor suppresses glucose metabolism by suppressing pyruvate kinase: the last step in glycolysis which generates pyruvate, which is the substrate for the citric acid cycle. The authors show that these vesicles are easily taken up by untransformed cells, and that glucose metabolism is then inhibited as a result. In vivo models show that mice receiving high levels of miR-122 developed significant metastatic colonisation, despite reduced primary tumour formation. The authors suggest that miR-122 is involved in preparing the pre-metastatic niche for tumour cell arrival, by suppressing nutrient uptake of other cells, to favour themselves.