Monday, 14 August 2017

Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell derivatives

Rajamani U, Gross AR, Ocampo C, Andres AM, Gottlieb RA, Sareen D

https://www.nature.com/articles/s41467-017-00254-8

  • Study of the effect of common man-made chemicals (specifically endocrine distrupting chemicals, or EDCs)  on human-induced pluipotent stem cells
  • The authors suggest that exposure to perfluoro-octanoic acid (found in cookware), tributyltin (found in house dust), and butylhydroxytoluene (found in food additives) can induce endoplasmic reticulum stress, perturb inflammatory and cell-death signalling pathways (NF-kB and p53), diminish mitochondrial respiratory gene expression, spare respiratory capacity and ATP levels in stem cells.
  • Consequently, normal secretion of appetite control hormones is affected.
  • The authors provide this as mechanistic evidence that repeated exposure to these "obesogenic" endocrine distrupting chemicals in utero can alter some genetically pre-disposed individuals' normal metabolic control, setting them up for long-term obesity.

In vivo imaging reveals mitophagy independence in the maintenance of axonal mitochondria during normal aging

Cao X, Wang H, Wang Z, Wang Q, Zhang S, Deng Y, Fang Y

http://onlinelibrary.wiley.com/doi/10.1111/acel.12654/epdf

  • Study of mitophagy and aging in Drosophila
  • Mitochondria become fragmented in aged mitochondria
  • Lack of Pink1 or Parkin does not lead to the accumulation of axonal mitochondria or axonal degeneration
  • Knockdown of core mitphagy genes Atg12 or Atg17 has little effect on turnover of axonal mitochondria or axonal integrity suggesting that mitophagy is not necessary for axonal maintainence, regardless of whether it is Pink1-Parkin dependent
  • Adult onset of neuronal downregulation of fission-fusion but not mitophagy genes dramatically accelerated features of aging
  • Thought: Is this partly because Drosophila generally has a short lifespan and, in some sense, die before they have the chance to get old? Are these results observable in other, longer-lived, species?

Tuesday, 8 August 2017

Interesting papers

The Mitochondrial Basis of Aging
Nuo Sun, Richard J. Youle and Toren Finkel
Molecular Cell 
http://www.sciencedirect.com/science/article/pii/S1097276516000812
  • An interesting review on the theory that mitochondrial decline contributes to ageing.
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype
Christopher D. Wiley, Michael C. Velarde, Pacome Lecot, ..., Akos A. Gerencser, Eric Verdin, Judith Campisi
Cell Metabolism 
http://www.sciencedirect.com/science/article/pii/S1550413115005781
  •  How mitochondrial dysfunction can induce senescence in proliferative cell types. Such cells have lower NAD+/NADH ratios. Progeroid mtDNA mutator mice accumulate sensescent cells with a mitochondrially-associated senescent secretory phenotype (MiDAS SASP).
Transit and integration of extracellular mitochondria in human heart cells
Douglas B. Cowan, Rouan Yao, Jerusha K. Thedsanamoorthy, David Zurakowski, Pedro J. del Nido, James D. McCully
Biorxiv
  • Transplanting isolated mitochondria from healthy tissue into ischaemic heart tissue can be internalised within minutes, fuse to the mitochondrial network, decrease cell death, increase energy production and improve contractile function

Mitochondrial DNA heteroplasmy is shared between human liver lobes
Manja  Wachsmuth, Alexander  Hübner, Roland  Schröder, ..., Mark Stoneking
Biorxiv
http://www.biorxiv.org/node/46200.full
  • Heteroplasmy distributions in multiple liver lobes from the same individual suggest sharing of heteroplasmy
Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders
Pauline Vachin, Elodie Adda-herzog, Gihad Chalouhi, ..., Julie Steffann
Journal Medical Genetics
  • Distribution of heteroplasmy for multiple samples per individual in the placenta
Mammalian Mitochondria and Aging: An Update
Timo E.S. Kauppila, Johanna H.K. Kauppila, Nils-Göran Larsson 
Cell Metabolism
  • Review on the mitochondrial theory of ageing 
Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins 
Tatiana Tkatch, Elisa Greotti, Gytis Baranauskas, ... and Israel Sekler
http://www.pnas.org/content/114/26/E5167.full
PNAS 
  • Reversible, tunable, optogenetic control of mitochondrial membrane potential using channelrhodopsins
 
Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence
Caterina Tezze, Vanina Romanello, Maria Andrea Desbats, Gian Paolo Fadin, ...,  Luca Scorrano, Marco Sandri
Cell Metabolism
  •   Disturbing the mitochondrial network through OPA1 deletion in muscle may induce faster ageing across distal organs

Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties
 Meriem Mahrouf-Yorgov, Lionel Augeul, Claire Crola Da Silva, Maud Jourdan, ..., Anne-Marie Rodriguez
Cell Death & Differentiation
  •   Mesenchymal cells can 'sense danger' by taking up and degrading mitochondria from stressed cells

The mitochondrial respiratory chain is essential for haematopoietic stem cell function
Elena Ansó,  Samuel E. Weinberg,  Lauren P. Diebold,  Benjamin J. Thompson, ..., Navdeep S. Chandel
Nature Cell Biology
  • OXPHOS is required for differentiation of haematopoietic stem cells 
Heteroplasmic Shifts in Tumor Mitochondrial Genomes Reveal Tissue-specific Signals of Relaxed and Positive Selection
Grandhi S, Bosworth C, Maddox W, Sensiba C, Akhavanfard S, Ni Y, LaFramboise T
https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddx172
Human Molecular Genetics
  •  Signs of positive selection for mitochondrial DNA mutations in certain cancers
 

Interesting papers

MitoNEET-dependent formation of intermitochondrial junctions
Alexandre Vernay, Anna Marchetti, Ayman Sabra, Tania N. Jauslin, Manon Rosselin, Philipp E. Scherer, Nicolas Demaurex, Lelio Orci, and Pierre Cosson 
PNAS
http://www.pnas.org/content/114/31/8277.full
  • MitoNEET, a factor which contributes to the formation of inter-mitochondrial junctions is knocked out. Network becomes more fragmented and there are fewer mitochondria.

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs
Yalin Zhang, Min Soo Kim, Baosen Jia, Jingqi Yan, Juan Pablo Zuniga-Hertz, Cheng Han & Dongsheng Cai
Nature
https://www.nature.com/nature/journal/v548/n7665/full/nature23282.html
  • Secretions from stem cells in the hypothalamus, consisting of exosomes containing miRNAs, can slow down ageing phenotypes. The hypothalamus becomes an inflammatory environment with age. Modifying stem cells to become resistant to inflammation (via the NF-kB pathway) and implanting them into brains of mid-aged mice can slow down ageing.

Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways
Snehal N. Chaudhari & Edward T. Kipreos
Nature Communications
https://www.nature.com/articles/s41467-017-00274-4
  • Mitochondrial fusion is permissive of extended lifespan, but not sufficient.

Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila
Nikolay P. Kandul, Ting Zhang, Bruce A. Hay & Ming Guo
Nature Communications
  • Mitophagy is able to alter heteroplasmy levels of a deleterious mtDNA deletion mutation in Drosophila. Overexpression of PINK1 and Parkin produce large reductions in the frequency of deleterious mutations.








Saturday, 10 June 2017

Mitochondrial heterogeneity, metabolic scaling and cell death


Juvid Aryaman, Hanne Hoitzing, Joerg P. Burgstaller, Iain G. Johnston and Nick S. Jones


Cells need energy to produce functional machinery, deal with challenges, and continue to grow and divide -- these activities and others are collectively referred to as "cell physiology". Mitochondria are the dominant energy sources in most of our cells, so we'd expect a strong link between how well mitochondria perform and cell physiology. Indeed, when mitochondrial energy production is compromised, deadly diseases can result -- as we've written about before.

The details of this link -- how cells with different mitochondrial populations may differ physiologically -- is not well understood. A recent article shed new light on this link by looking at a measure of mitochondrial functionality in cells of different sizes. They found what we'll call the "mitopeak" -- mitochondrial functionality peaks at intermediate cell sizes, with larger and smaller cells having less functional mitochondria. The subsequent interpretation was that there is an “optimal”, intermediate, size for cells. Above this size, it was suggested that a proposed universal relationship between the energy demands of organisms (from microorganisms to elephants) and their size predicts the reduction in the function of mitochondria. Smaller cells, which result from a large cell having divided, were suggested to have inherited their parent's low mitochondrial functionality. Cells were predicted to “reset” their mitochondrial activity as they initially grow and reach an “optimal” size.

We were interested in the mitopeak, and wondered if scientifically simpler hypotheses could account for it. Using mathematical modelling, our idea was to use the observation that as a cell becomes larger in volume, the size of its mitochondrial population (and hence power supply) increases in concert. We considered that a cell has power demands which also track its volume, as well as demands which are proportional to surface area and power demands which do not depend on cell size at all (such as the energetic cost of replicating the genome at cell division, since the size of a cell's genome does not depend on how big the cell is). Assuming that power supply = demand in a cell, then bigger cells may more easily satisfy e.g. the constant power demands. This is because the number of mitochondria increases with cell volume yet the constant demands remain the same regardless of cell size. In other words, if a cell has more mitochondria as it gets larger, then each mitochondrion has to work less hard to satisfy power demand.

To explain why the smallest cells also have mitochondria which do not appear to work hard, we suggested that some smaller cells could be in the process of dying. If smaller cells are more likely to die, and if dying cells have low mitochondrial functionality (both of these ideas are biologically supported), then, by combining this with the power supply/demand picture above, the observed mitopeak naturally emerges from our mathematical model.

As an alternative model, we also suggested that the mitopeak could come entirely from a nonlinear relationship between cell size and cell death, with mitochondrial functionality as a passive indicator of how healthy a cell is. This indicates the existence of multiple hypotheses which could explain this new dataset.




Interestingly, we also found that the mitopeak could be an alternative to one aspect of a model we used some time ago to explain a different dataset, looking at the physiological influence of mitochondrial variability. Then, we modelled the activity of mitochondria as a quantity that is inherited identically by each daughter cell from its parent, plus some noise -- noting that this was a guess at the true behaviour because we didn't have the data to make a firm statement. We needed this relationship because observed functionality varied comparatively little between sister cells but substantially across a population. The mitopeak induces this variability without needing random inheritance of functionality, and may thus be the refined picture we've been looking for. These ideas, and suggestions for future strategies to explore the link between mitochondria and cell physiology in more detail, are in our new BioEssays article here. Juvid, Nick, and Iain.

Mirrored from here

Monday, 27 March 2017

Dynamin-Related Protein 1-Dependent Mitochondrial Fission Changes in the Dorsal Vagal Complex Regulate Insulin Action

http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30216-4

Beatrice M. Filippi, Mona A. Abraham, Pamuditha N. Silva, Mozhgan Rasti, Mary P. LaPierre, Paige V. Bauer, Jonathan V. Rocheleau, Tony K.T. Lam
Type 2 diabetes is a condition where the body does not produce enough, or is resistant to, insulin. In this study, the authors investigated the role mitochondrial dynamics plays in insulin resistance and glucose regulation. As well as its clinical consequences, this study offers to shed light on the relationship between glucose homeostasis and mitochondrial functionality.
In healthy rodents, the hypothalamus and dorsal vagal complex (DVC) regulate glucose homeostasis in the liver (which is where excess glucose is stored). However, after a high fat diet (HFD) as short as 3 days, this regulation is disrupted. This link between the DVC and high-fat feeding has been poorly understood. 
The authors found that, after a HFD, DVC neuronal cells in rats had a higher density of mitochondria, and these mitochondria were less elongated, shorter and less branched. 
The authors tested the effect of providing the 3-day HFD rats with an infusion of  MDIVI-1, which is an inhibitor of the mitochondrial fission factor Drp-1 (by blocking its translocation from the cytosol into the mitochondria). The authors found that, upon infusion, mitochondrial morphology was restored to wild-type levels, the glucose infusion rate increased to normal levels, as well as the glucose production rate decreasing to normal levels. This was confirmed through molecular inhibition of Drp-1 via adenoviral-mediated inhibition. Furthermore, inducing overexpression of Drp-1 in the DVC of rats which were fed normally induced insulin resistance and recapitulated the effects of HFD.

The authors found that endoplasmic reticulum (ER) stress was necessary and sufficient  to induce DVC-mediated insulin resistance, and that ER stress was a consequence of mitochondrial fission.


----------------------------
Thoughts: Are these associations still observed on a long-term high-fat diet, rather than a 3-day alteration to diet?

Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU

http://www.cell.com/cell-reports/pdf/S2211-1247(17)30213-9.pdf

Paillard M, Csordás G, Szanda G, Golenár T, Debattisti V, Bartok A, Wang N, Moffat C, Seifert EL, Spät A, Hajnóczky G

Mitochondrial respiration is sensitive to the concentration of calcium in the cytoplasm, acting as an important control mechanism of respiration rate. It is known that different tissues have different responses to the presence of calcium. For instance, in the liver, calcium oscillations in the cytoplasm tend to be low frequency and are effectively propagated to intra-mitochondrial calcium concentrations. However, in the heart, oscillations are high frequency and are integrated into a more continuous intra-mitochondrial calcium signal.

Here, the authors investigated the difference in mitochondrial response to calcium concentration in different tissues by measuring the relative stoichiometry of two protein components of the mitochondrial calcium uniporter: MCU (a calcium pore unit) and MICU1 (a Calcium-sensing regulator). The authors found that, in heart tissue, a low MICU1 to MCU ratio is present, which results in a low cytoplasmic calcium threshold for mitochondrial accumulation of calcium, relative to liver tissue. Furthermore, heart tissue displayed a more shallow response curve to cytoplasmic calcium, suggesting lower cooperativity in cardiac tissue, relative to liver tissue. Therefore, the ratio of MICU1:MCU controls the tissue-specific response to cytoplasmic calcium.



Monday, 30 January 2017

Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells

https://www.ncbi.nlm.nih.gov/pubmed/28107184

Jinjin Lu, Xiufen Zheng, Fan Li, Yang Yu, Zhong Chen, Zheng Liu, Zhihua Wang, Hua Xu, Weimin Yang

In cell culture, cells have been observed to create long, thin, protrusions to connect to other cells and transfer material, including entire organelles such as mitochondria. These protrusions are called tunneling nanotubes (TNTs). In this study, the authors co-culture two kinds of urothelial bladder cancer cells: T24 (highly invasive) and RT4 (less invasive) cells. The authors observed the formation of TNTs between the two cell types and mitochondrial exchange between the cell types.

The authors found that the RT4 cells became more motile after intercellular mitochondria trafficking from T24 cells (RT4-Mito-T24) by around a factor of 2 relative to RT4 cells. Xenograft tumours from RT4-Mito-T24 cells were also around twice as large as T24 cells after ~30 days of growth.

This shows that transfer of material from a highly invasive cell type to a less invasive cell type results in increased invasive ability. It suggests that mitochondrial content may be the causal variable in determining invasive ability in this system.


------------------------------
Thoughts: This study adds to a growing body of evidence that mitochondrial content contributes to determining metastatic potential of cancer cells. What is it about these mitochondria that causes the increase in invasiveness? Are there other factors which are transferred through the TNTs? Is mitochondrial transfer necessary, or indeed sufficient, to see these effects? Interesting to note that the nuclear background of these cell types are presumably not the same -- to what extent can the nuclei be different between these cell types to observe the increase in invasiveness?