The Alternate Version of Kreb's Cycle Underlying Cellular Identity
News Release, World Mitochondria Society, Berlin - Germany – March 16, 2022
Mitochondria and the Krebs cycle were discovered in the race to find causes and treatments for cancer and those pathways are learned by every student.
A new research, published in nature, that turned down the Krebs breakthrough that won him a Nobel Prize, says there is a complete alternative to this canonical cycle, also called the citric acid and tricarboxylic acid (TCA) cycle, with the downside the work is only in cells, not animals, so it remains exploratory.
Through several converging lines of evidence, the paper posits that an alternate version of the Krebs cycle takes place partly in the mitochondria and partly in the cytosol. Rather than burning sugar for energy, this alternate version allows cells to use the carbons in sugar to build important molecules such as lipids for cell membranes.
Not only that, but a cell’s use of one or the other version of the TCA cycle is associated with changes in its identity, the team found. The new results came out of a collaboration in the Finley lab between Gerstner Sloan Kettering graduate student Paige Arnold and Tri-Institutional MD-PhD student Benjamin Jackson. Arnold had been using carbon-tracing techniques to study the flow of carbons through the TCA cycle in different cell types. She had noticed, for example, that there seemed to be variation in the extent to which cells put their carbons into the TCA cycle versus skipping one part of it.
Around the same time, Jackson was using computational methods to analyze publicly available data from experiments in which the genome-editing tool CRISPR had been used to systematically knock out genes for various enzymes, one at a time, to see what effect this had on cells.
“You would hypothesize that if the TCA cycle were one functional module, then any one of those enzymes should have a relatively similar effect when you remove it,” Dr. Finley points out. “What Ben noticed is that’s not actually the case.”
“The metabolic enzymes seemed to form two separate modules,” Jackson says. “This backed up the anecdotal evidence that we were accumulating that there were different parts of the TCA cycle that cells could use or not use.”
The CRISPR studies Jackson analyzed were performed in cancer cell lines — in other words, cells that aren’t “normal.” Arnold wanted to know if normal also engage in this alternative or noncanonical cycle. The Finley lab often works with embryonic stem cells, so Arnold had easy access to these normal cells. Arnold traced the flow of carbons through them and found that they also engaged in the noncanonical TCA cycle.
These two sets of experiments seemed to confirm that there really was an alternate way to perform the TCA cycle, one that is not in textbooks. But why had Krebs missed it?
To try to answer that question, Arnold decided to review Krebs’ original papers from the 1930s and 40s. She found, to her surprise, that Krebs had made his pivotal discoveries in one particular type of tissue: pigeon breast muscle.
“Nobody really talks about that,” Arnold says. “But it made us wonder if maybe different cell types have distinct preferences for whether they use the traditional TCA cycle or this alternate version.”
She decided to reconstruct Krebs’ original experiments, only in a dish rather than in pigeon muscle. She used mouse stem-like muscle cells to grow a muscle fiber precursor called a myotube and then traced the carbons. When she did this, she saw something interesting: “When the cells were still in a more stem-like stage, they seemed to be doing a lot of this noncanonical TCA cycle, similar to embryonic stem cells and cancer cells,” Arnold says. “But as soon as the cells had differentiated into myotubes, they immediately switched to the more traditional TCA cycle. This is in keeping with what Krebs saw in pigeon muscle tissue.”
To the team, this result suggested a clear link between changes in cell identity and usage of particular biochemical pathways. To test whether the changes in cell fate required use of the different pathways, the team performed additional experiments in which they chemically or genetically blocked certain enzymes in the cycles and asked whether the cells could still change their fate. They could not. This finding implied that changes in cell fate required different biochemical pathways.
To Burn or To Build
Why would a cell opt for a different form of the TCA cycle at all? According to Dr. Finley, the Krebs cycle is really good at maximizing ATP production. It helps cells combust all their nutrients down to carbon dioxide.
“That’s great if what you really care about is making ATP,” Dr. Finley says. “But if you want to grow, ATP is actually not the limiting reagent. You actually need to retain those carbons to make new biomass. That’s what the noncanonical TCA cycle does: It allows you to take carbons from glucose and export them to the cytosol, where they can be used to build other molecules. So, instead of burning the carbon, you get to keep it.”
This growth-oriented cycle may have particular relevance to cancer, whose signature characteristic is unlimited growth.
Dr. Finley cautions that their laboratory experiments were all done in a dish rather than in animals. The team is keenly interested in understanding whether and when it occurs in vivo, both in normal animals and in tumors.
“That will help us know whether it might be a good cancer drug target,” Dr. Finley says.
Join us in Targeting Mitochondria 2022 and stay updated about the most recent studies in cell biology. Keep in mind that professional speakers like Dr. Jessica Spinelli will boost your knowledge on the latest discoveries on the the mitochondria.
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Mitochondrial Transfer in Obesity
News Release, World Mitochondria Society, Berlin - Germany – March 14, 2022
Researchers from the Brestoff and Teitelbaum Labs have demonstrated that adipose-tissue resident macrophages acquire mitochondria from adjacent adipocytes using Heparan Sulfate (HS). This process occurs in healthy conditions but is impaired in obesity. Further, they have shown that genetic disruption of mitochondria uptake by macrophages reduces energy expenditure and increases diet-induced obesity in mice, indicating that intercellular mitochondria transfer to macrophages mediates systemic metabolic homeostasis.
Obesity is an increasingly common metabolic disease that affects over 40% of adults and 18% of children and adolescents in the United States and is an independent risk factor for the development of many other disorders such as type 2 diabetes, cardiovascular diseases, and cancer.
Head of the group - Professor Jonathan Brestoff commented “Mitochondria are the power plants of cells, and it has long been assumed that they are made in one cell and never leave. We discovered that is not the case and found that fat cells give some of their mitochondria to an immune cell type called macrophages. In obesity, this transferring of mitochondria between cells goes awry, contributing to faster weight gain and worse metabolism. Using a tool called CRISPR, we screened the entire genome and figured out that cells trade mitochondria using a special type of sugar called heparan sulfate, which we think acts as a loading dock for receiving cargo like mitochondria. When we delete heparan sulfates on macrophages, mice get fat. This suggests to us that it is probably good for cells to trade mitochondria with each other. Our team is now trying to figure out how this mysterious and surprising process of mitochondria transfer works because we believe we can harness this biology to treat some human diseases.”
Dr. Wentong Jia, a postdoctoral fellow at the Brestoff lab added “The cell surface expression of heparan sulfate, a glycosaminoglycan required for mitochondria uptake in macrophages, depends on a key glycosyltransferase named EXT1. The 10E4 antibody from AMSBIO has helped us verify that we’ve successfully prevented Heparan Sulfate from being synthesized in cells that lack EXT1.”
“I find it fascinating that cells use heparan sulfates to take up mitochondria,” says Rocky Giwa, a Ph.D. candidate in the Brestoff Lab. “I wonder if there’s a correlation between the amount or composition of heparan sulfates and a cell’s ability to efficiently take up mitochondria from other cells. Since the various HS antibodies have unique specificities, the different clones can help us start to attack that question.”
Join us in Targeting Mitochondria 2022 where a whole session will be dedicated to Mitochondria Transplantation and Transfer; and professional researchers like, Dr. Camilla Bean, will introduce you to the importance of mitochondria in adipose tissue biology.
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Mitochondria Rich Extracellular Vesicles & Ageing: What is the Link?
Electron microscopy showed EVs of typical size and morphology
News Release, Wolrd Mitochondria Society, Berlin - Germany – March 10, 2022
The accumulation of oxidative damage to mitochondria and mitochondrial DNA (mtDNA) plays a major role in aging, "the mitochondrial free radical theory of aging". Circulating cell-free mtDNA (ccf-mtDNA) in blood can be considered as disease biomarkers.
Extracellular vesicles (EVs), the small lipid-bound vesicles capable of shuttling cargo, take part in intercellular communication systems.
In thier fascinating research, Lazo et al.:
- Reported that a portion of ccf-mtDNA in plasma is encapsulated in EVs.
- Studied whether EV mtDNA levels vary upon aging by analyzing mtDNA in EVs from individuals aged 30–64 years cross-sectionally and longitudinally.
They reported the following:
- EV mtDNA levels decreased with age.
- The maximal mitochondrial respiration of cultured cells was differentially affected by EVs from old and young donors.
In conclusion, their results suggested that plasma mtDNA is present in EVs, that the level of EV-derived mtDNA is associated with age, and that EVs affect mitochondrial energetics in an EV age-dependent manner.
In Targeting Mitochondria 2022, a whole session will be dedicated to Extracellular Vesicles & Mitochondria: The Target, in which Dr. Marc Germain and Dr. Devika S. Manickam will share with us their
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Regulatory Role of Extracellular Vesicles on Mitochondria Under Hypoxia
News Release, World Mitochondria Society, Berlin - Germany – March 10, 2022
Mitochondria are indispensable organelles for maintaining cell energy metabolism, and also are necessary to retain cell biological function by transmitting information as signal organelles. Hypoxia, one of the important cellular stresses, can directly regulates mitochondrial metabolites and mitochondrial reactive oxygen species (mROS), which affects the nuclear gene expression through mitochondrial retrograde signal pathways, and also promotes the delivery of signal components into cytoplasm, causing cellular injury. In addition, mitochondria can also trigger adaptive mechanisms to maintain mitochondrial function in response to hypoxia.
Extracellular vesicles (EVs), as a medium of information transmission between cells, can change the biological effects of receptor cells by the release of cargo:
- Nucleic acids
- Proteins
- Lipids
- Mitochondria and their compositions
The secretion of EVs increases in cells under hypoxia, which indirectly changes the mitochondrial function through the uptake of contents by the receptor cells.
This article focuses on the mitochondrial regulation indirectly through EVs under hypoxia, and the possible mechanisms that EVs cause the changes in mitochondrial function. It also discusses the significance of this EV-mitochondria axis in hypoxic diseases.
You will have the chance to know more about extracellular vesicle-mitochondrial relationships and many more mitochondria related topics in Targeting Mitochondria 2022.
Dr. Marc Germain and Dr. Devika S. Manickam will both join us in October to cover this EV-mitochondria relationship, so don't forget to reserve your spot!
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Mitochondria As Microlenses: Strategic Role In Eyesight
News Release, World Mitochondria Society, Berlin - Germany – March 7, 2022
A study by Researchers at the National Eye Institute (NEI) on ground squirrels shows a fascinating phenomenon that mitochondria appear to have a dual purpose: their well-established metabolic role producing energy, as well as this optical effect. This was revealed by their act as micro-lenses that redirect light to the tapering outer reaches of these cells where light is converted into electrical signals.
Once light reaches the retina, it must pass through several neural layers to reach the outer segment of photoreceptors, where light’s physical energy is converted into neural signals through a process called phototransduction. Between the inner and outer segment of the cone photoreceptors lie a dense bundle of mitochondria that light must traverse to be transduced. Although it might appear these mitochondria pose an obstacle to the process of vision by either scattering or absorbing light, the current study shows they serve a unique function to facilitate vision.
Those bundles of mitochondria would seem to work against the process of vision either by scattering light or absorbing it. So, Li’s team set out to investigate their purpose by studying cone photoreceptors from the 13-lined ground squirrel.
Using a modified confocal microscope to observe the optical properties of living cone mitochondria exposed to light, the researchers observed that instead of scattering light, the tightly packed mitochondria concentrated light along a pencil-like trajectory onto the light-sensitive outer segment. High-resolution mitochondrial reconstructions corroborated the live-imaging findings. In addition, the authors show remodeling mitochondrial architecture affects this concentration of light.
In this study, Li found that the lens-like effect of mitochondria followed a similar directional light intensity profile. That is, depending on light source location, the mitochondria focused light into the outer segment of the cell along trajectories that mirrored those observed from the Stiles-Crawford effect.
The study also sheds new light on how our eyes may have evolved. Within the photoreceptors of birds and reptiles, tiny oil droplets at the junction of the inner and outer segments that may play an optical role are reminiscent of the lipid-rich mitochondria of cones in the current study on ground squirrels. Moreover, the mitochondrial “microlens” in mammalian cone photoreceptors is functionally like the biological effect achieved by the compound eye in insects.
“This insight conceptually bridges compound eyes in arthropods with the camera eyes of vertebrates, two independently evolved image-forming systems, demonstrating the power of convergent evolution,” Li said.
More interesting studies on the hidden functions of mitochondria will be introduced in Targeting Mitochondria 2022.
Read more about the micro-lense function of mitochondria.
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