Glucose feeds the TCA cycle via circulating lactate

https://www.nature.com/articles/nature24057

Sheng Hui, Jonathan M. Ghergurovich, Raphael J. Morscher, Cholsoon Jang, Xin Teng, Wenyun Lu, Lourdes A. Esparza, Tannishtha Reya, Le Zhan, Jessie Yanxiang Guo, Eileen White & Joshua D. Rabinowitz

• When oxygen is present, it is commonly thought that glucose (derived from the food we eat) is catabolised via glycolysis to pyruvate, which is then transported into mitochondria, fuelling the TCA cycle and oxidative phosphorylation. Alternatively, when oxygen is less available, glucose can be catabolised to lactate.
• Although traditionally thought of as a waste product, it is becoming increasingly clear that lactate can itself be used as a fuel molecule
• Here, the authors investigate the relative contribution of glucose and lactate to feeding the TCA cycle in mice, across various tissues
• In fasting mice, the contribution of glucose to the TCA cycle is primarily via circulating lactate in all tissues except the brain
• The circulatory turnover of lactate is the highest of all metabolites, exceeding that of glucose in both the fed and fasted state
• In tumours, lactate is a primary TCA substrate

Structural Basis of Mitochondrial Transcription Initiation

http://www.sciencedirect.com/science/article/pii/S009286741731262X?via%3Dihub

Hauke S.Hillen, Yaroslav I.Morozov, Azadeh Sarfallah, Dmitry Temiakov, Patrick Cramer

• Transcription of the mitochondrial DNA is a critical aspect of understanding mitochondrial physiology. Not only is this linked to the generation of protein, as per nuclear transcription, there is also a link with the actual replication of mtDNA. Many molecular players are involved in both of these processes. Yet, mitochondrial transcription is not well understood in its details.
• The authors report crystal structures of the protein responsible for mtDNA transcription (mtRNAP) when attached to mtDNA.
• TFAM tethers to mtRNAP to recruit the protein to the mtDNA promoter site.
• TFB2M induces structural changes in mtRNAP to enable it to open mtDNA

Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence

http://www.sciencedirect.com/science/article/pii/S1550413117306113

Song M, Franco A, Fleischer JA, Zhang L, Dorn II GW

• Mitochondrial fragmentation is often considered as harmful. This is often determined by inhibiting fusion fission proteins such as Mfn2 and Opa1. However, such conclusions are confounded by Mfn2 functioning in mitophagy and Opa1 functioning in cristae organisation. The authors sought to determine the role of fusion/fission dynamics in maintaining healthy heart function
• The authors overexpressed the pro-fission protein Drp1 in cardiomyocytes (10 & 25 wild-type expression levels). This induced fragmentation of the network without affecting the expression of other mitochondrial proteins. The fragmented mitochondria appeared healthy
• Through 93 weeks of age, Drp1 overexpression resulted in no phenotype
• Previous work by the authors found that overexpression of Mfn2 induces enlargement of mitochondria in the heart, without any other clear phenotype
• The authors conclude that increased or decreased mitochondrial size alone is not necessarily a mechanism of heart dysfunction
• The authors then investigated a mouse model where Mfn1, Mfn2 and Drp1 expression could be switched off in the adult heart (since knockouts of these proteins are embryonic lethal)
• Abolishing mitochondrial dynamics resulted in: fragmentation of the network, partial depolarisation of mitochondria, parkin aggregation and impaired mitophagy
• Surprisingly, such mice were able to survive 14 weeks after mitochondrial dynamics abrogation (whereas a cardiac knockout of any single one of the 3 genes is rapidly lethal in mice)
• The hearts of such mice were enlarged, and had a mitophagy defect resulting in suppressed elimination of defective mitochondria

Inertial picobalance reveals fast mass fluctuations in mammalian cells

https://www.nature.com/articles/nature24288

David Martínez-Martín, Gotthold Fläschner, Benjamin Gaub, Sascha Martin, Richard Newton, Corina Beerli, Jason Mercer, Christoph Gerber & Daniel J. Müller

• Use a highly sensitive balance to measure the mass of single or multiple adherent cells in culture conditions over days with millisecond time resolution and picogram mass sensitivity 
• The mass of living mammalian cells varies by around 1-4% over timescales of seconds throughout the cell cycle
• These mass fluctuations are linked to ATP synthesis and water transport
• The balance works by oscillating a microcantilever immersed in cell media at the microcantilever's natural frequency. A cell is grown at the tip of the microcantilever. The frequency and amplitude of the vibrations of the microcantilever can be measured using a laser. These data can be used to infer the mass of the cell growing at the tip.
• Blocking aquaporins reduced the amplitude of slow mass fluctuations (period ~17s) by a factor of 4
• Inhibition of ATP synthesis in starved cells reduced the amplitude of slow mass fluctuations by a factor of ~4, and reduced the amplitude of fast mass fluctuations by around 1/3. 

Live imaging reveals the dynamics and regulation of mitochondrial nucleoids during the cell cycle in Fucci2-HeLa cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595809/

Taeko Sasaki, Yoshikatsu Sato, Tetsuya Higashiyama, Narie Sasaki

•  Authors investigate the dynamics of mitochondrial DNA replication through the cell cycle by labelling HeLa cells with Fucci markers (a fluorescent probe which changes color according to the cell cycle stage) and SYBR Green I (which stains mtDNA)
• Observe that mitochondrial nucleoids often attach/detach from each other
• Mitochondrial replication occurs throughout the cell cycle, but peaks during the S-phase

Mitochondrial fission facilitates the selective mitophagy of protein aggregates

Jonathon L. Burman, Sarah Pickles, Chunxin Wang, Shiori Sekine, Jose Norberto S. Vargas, Zhe Zhang, Alice M. Youle, Catherine L. Nezich, Xufeng Wu, John A. Hammer, Richard J. Youle

http://jcb.rupress.org/content/early/2017/09/11/jcb.201612106.long

• This study focuses on the interplay between mitophagy and mitochondrial fission. Whilst many studies have suggested that fission is required for mitophagy, there is mixed evidence on the issue
• Authors express a mutant form of ornithine transcarbamylase (ΔOTC) in HeLa cells, which creates insoluable protein aggregates which localise to the mitochondrial matrix, inducing the mitochondrial unfolded protein response
• This induces PINK1-Parkin-mediated mitophagy, to clear the ΔOTC aggregates
• Mitochondria associated with Parkin were observed to fragment and traffic away from their parental mitochondrion. These mitochondria remain coated in Parkin
• The authors overexpressed a dominant-negative mutant of the fission protein Drp1, effectively inhibiting fission. They found that, for both wild-type and ΔOTC, inhibition of fission did not reduce protein aggregate clearance. In fact, inhibition of mitochondrial fission fosters excessive PINK1-Parkin-mediated mitophagy of entire fused mitochondrial networks, even in the wild-type case. [The authors showed that Drp1-independent mitophagy was not dependent upon mitochondrial-derived vesicles (MDVs) through knockout of syntaxin 17, a protein involved in MDVs]
• The authors suggest that mitochondrial fission (via Drp1) restricts mitophagic activity (via PINK1-Parkin) to specific, dysfunctional, mitochondrial subdomains by localising the PINK1-Parkin positive feedback loop away from healthy mitochondria

Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster

Rana A, Oliveira MP, Khamoui AV, Aparicio R, Rera M, Rossiter HB, Walker DW

https://www.nature.com/articles/s41467-017-00525-4 

• Transient induction of Drp1-mediated fission for 7 days during midlife of the fruit fly D. melanogaster is sufficient to extend lifespan. (Note that Drp-1 upregulation in early life had no significant impact on longevity)
• Short-term midlife Drp1 induction gave increased day-time physical activity levels, suggesting an extension of healthy lifespan, rather than prolonging frailty. These flies also had improved starvation resistance, improved fertility, and delayed intestinal aging.
• In flight muscle, elongated mitochondrial morphology was associated with lowered mitochondrial membrane potential, accumulation of dysfunctional mitochondria, lowered OXPHOS complex activity, increased ROS and lowered respiration with aging. These phenotypes are reversed upon short-term midlife Drp1 induction.
• These effects were not mediated by the mitochondrial unfolded protein response. 
• Short-term midlife Drp1 induction reduced levels of protein aggregates in aged muscle and aged brain tissue
• Disruption of mitophagy, via Atg1 inhibition, inhibits the anti-aging effects of midlife Drp1 induction.

Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions

Wong HS, Dighe PA, Mezera V, Monternier PA, Brand MD

http://www.jbc.org/content/early/2017/08/24/jbc.R117.789271

• Relative contributions of mitochondrial superoxide/ hydrogen peroxide production by different sites in the electron transport chain, under different conditions

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?

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

http://www.biorxiv.org/content/early/2017/06/28/157164?ct

• 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

http://jmg.bmj.com/content/early/2017/07/27/jmedgenet-2017-104615

• 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

http://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30502-2?elsca1=etoc&elsca2=email&elsca3=1550-4131_20170110_25_1_&elsca4=Cell%20Press

• 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

http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30227-9?elsca1=etoc&elsca2=email&elsca3=1550-4131_20170606_25_6_&elsca4=Cell%20Press%3Chttp://www.cell.com/cell-metabolism/fulltext/S1550-4131%2817%2930227-9?elsca1=etoc&elsca2=email&elsca3=1550-4131_20170606_25_6_&elsca4=Cell%20Press

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

https://www.nature.com/cdd/journal/v24/n7/full/cdd201751a.html

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

https://www.nature.com/ncb/journal/v19/n6/full/ncb3529.html 

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

https://www.nature.com/articles/ncomms13100

• 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.

Mitochondrial heterogeneity, metabolic scaling and cell death

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

http://onlinelibrary.wiley.com/doi/10.1002/bies.201700001/full

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

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.

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?