Tag Archives: mitochondria

Metallic nanoparticles inside heart tissue mitochondria can cause damage

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With all the focus on COVID-19, viruses , and aerosols, it’s easy to forget that there are other kinds of contaminated air too. The last time I featured work on nanoparticles and air pollution was in a May 31, 2017 posting, “Explaining the link between air pollution and heart disease?” where scientists announced they may have discovered how air pollution (nanoparticles) were making their way from lungs to the heart. Answer: the bloodstream.

A July 3, 2020 Lancaster University press release (also on EurekAlert) announces research into how air made toxic by metallic nanoparticles affects the heart in very specific ways (Note: A link has been removed),

Toxic metallic air pollution nanoparticles are getting inside the crucial, energy-producing structures within the hearts of people living in polluted cities, causing cardiac stress – a new study confirms.

The research team, led by Professors Barbara Maher of Lancaster University and Lilian Calderón-Garcidueñas of The University of Montana and the Universidad del Valle de Mexico, found the metallic nanoparticles, which included iron-rich nanoparticles and other pollution-derived metals such as titanium, inside the damaged heart cells of a 26-year-old and even a three-year-old toddler.

The hearts had belonged to people who had died in accidents and who had lived in highly-polluted Mexico City.

The findings shed new light on how air pollution can cause the development of heart disease, as the iron-rich particles were associated with damage to the cells, and increased cardiac oxidative stress, even in these very young hearts.

The repeated inhalation of these iron-rich nanoparticles, and their circulation by the bloodstream to the heart, may account for the well-established associations between exposure to particulate air pollution and increased cardiovascular disease, including heart attacks. The study indicates that heart disease can start in very early age, before progressing to full-blown cardiovascular illness later in life. This type of air pollution may thus be responsible for the ‘silent epidemic’ of heart disease, internationally. By causing pre-existing heart conditions, it may also account for some of the increased death rates from Covid-19 seen in areas with high levels of particulate air pollution.

Professor Maher said: “It’s been known for a long time that people with high exposure to particulate air pollution experience increased levels and severity of heart disease. Our new work shows that iron-rich nanoparticles from air pollution can get right inside the millions of mitochondria inside our hearts…the structures which generate the energy needed for our hearts to pump properly.

“That we found these metal particles inside the heart of even a three-year old indicates that we’re setting heart disease in train right from the earliest days, but only seeing its full, clinical effects in later life. It’s really urgent to reduce emissions of ultrafine particles from our vehicles and from industry, before we give heart disease to the next generation too.”

The researchers, using high-resolution transmission electron microscopy and energy-dispersive X-ray analysis, found that the mitochondria containing the iron-rich nanoparticles appeared to be damaged, with some cells showing deformities and others with ruptured membranes. Professor Calderón-Garcidueñas stated that increased levels of markers of cardiac oxidative stress are present in the very young cases examined.

The iron-rich nanoparticles found inside the heart cells are identical in size, shape and composition to those emitted from sources such as the exhausts, tyres and brakes of vehicles. These air pollution nanoparticles are also emitted by industrial sources as well as open fires in homes.

Some of the iron-rich nanoparticles are also strongly magnetic. This raises concerns about what might happen when people with millions of these nanoparticles in their hearts are using appliances with associated magnetic fields, such as hair dryers and mobile phones. People who work in industries that mean they are exposed to magnetic fields such as welders and power line engineers may also be at risk. This kind of exposure could potentially lead to heart electrical dysfunction and cell damage.

The findings builds on the researchers’ previous findings that show that the hearts of city dwellers contain billions of these nanoparticles and can be up to ten times more polluted than the hearts of people living in less polluted places.

The researchers say their study underlines the need for governments across the world to tackle ultrafine particulate pollution in their cities.

Professor Calderón-Garcidueñas said: “Exposure to such air pollution is a modifiable risk factor for cardiovascular disease, on a global scale, reinforcing the urgent need for individual and government actions not just to reduce PM2.5 but to monitor, regulate and reduce emissions of these specific, ultrafine components of the urban air pollution ‘cocktail’.”

Here’s a link to and a citation for the paper,

Iron-rich air pollution nanoparticles: An unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress by B.A.Maher, A.González-Maciel, R.Reynoso-Robles, R.Torres-Jardón, L.Calderón-Garcidueñas. Environmental Research Volume 188, September 2020, 109816 DOI: https://doi.org/10.1016/j.envres.2020.109816 Available online 21 June 2020

This paper appears to be open access (just keep scrolling down).

Cutting into a cell with a nanoblade

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A May 11, 2016 news item on Nanotechnology Now features a type of surgery that could aid in cell engineering,

To study certain aspects of cells, researchers need the ability to take the innards out, manipulate them, and put them back. Options for this kind of work are limited, but researchers reporting May 10 [2016] in Cell Metabolism describe a “nanoblade” that can slice through a cell’s membrane to insert mitochondria. The researchers have previously used this technology to transfer other materials between cells and hope to commercialize the nanoblade for wider use in bioengineering.

Caption: This diagram illustrates the process of transferring mitochondria between cells using the nanoblade technology. Credit: Alexander N. Patananan Courtesy UCLA

Caption: This diagram illustrates the process of transferring mitochondria between cells using the nanoblade technology.
Credit: Alexander N. Patananan Courtesy UCLA

A May 10, 2016 Cell Press news release on EurekAlert, which originated the news item, expands on the theme,

“As a new tool for cell engineering, to truly engineer cells for health purposes and research, I think this is very unique,” says Mike Teitell, a pathologist and bioengineer at the University of California, Los Angeles (UCLA). “We haven’t run into anything so far, up to a few microns in size, that we can’t deliver.”

Teitell and Pei-Yu “Eric” Chiou, also a bioengineer at UCLA, first conceived the idea of a nanoblade several years ago to transfer a nucleus from one cell to another. However, they soon delved into the intersection of stem cell biology and energy metabolism, where the technology could be used to manipulate a cell’s mitochondria. Studying the effects of mutations in the mitochondrial genome, which can cause debilitating or fatal diseases in humans, is tricky for a number of reasons.

“There’s a bottleneck in the field for modifying a cell’s mitochondrial DNA,” says Teitell. “So we are working on a two-step process: edit the mitochondrial genome outside of a cell, and then take those manipulated mitochondria and put them back into the cell. We’re still working on the first step, but we’ve solved that second one quite well.”

The nanoblade apparatus consists of a microscope, laser, and titanium-coated micropipette to act as the “blade,” operated using a joystick controller. When a laser pulse strikes the titanium, the metal heats up, vaporizing the surrounding water layers in the culture media and forming a bubble next to a cell. Within a microsecond, the bubble expands, generating a local force that punctures the cell membrane and creates a passageway several microns long that the “cargo”–in this case, mitochondria–can be pushed through. The cell then rapidly repairs the membrane defect.

Teitell, Chiou, and their team used the nanoblade to insert tagged mitochondria from human breast cancer cells and embryonic kidney cells into cells without mitochondrial DNA. When they sequenced the nuclear and mitochondrial DNA afterwards, the researchers saw that the mitochondria had been successfully transferred and replicated by 2% of the cells, with a range of functionality. Other methods of mitochondrial transfer are hard to control, and when they have been reported to work, the success rates have been only 0.0001%-0.5% according to the researchers.

“The success of the mitochondrial transfer was very encouraging,” says Chiou. “The most exciting application for the nanoblade, to me, is in the study of mitochondria and infectious diseases. This technology brings new capabilities to help advance these fields.”

The team’s aspirations also go well beyond mitochondria, and they’ve already scaled up the nanoblade apparatus into an automated high-throughput version. “We want to make a platform that’s easy to use for everyone and allow researchers to devise anything they can think of a few microns or smaller that would be helpful for their research–whether that’s inserting antibodies, pathogens, synthetic materials, or something else that we haven’t imagined,” says Teitell. “It would be very cool to allow people to do something that they can’t do right now.”

The pipette being used is measured at the microscale but it’s called a nanoblade? Well, perhaps the tip or the edge of the pipette is measured at the nanoscale.

Getting back to the research, here’s a link to and a citation for the paper,

Mitochondrial Transfer by Photothermal Nanoblade Restores Metabolite Profile in Mammalian Cells by Ting-Hsiang Wu, Enrico Sagullo, Dana Case, Xin Zheng, Yanjing Li, Jason S. Hong, Tara TeSlaa, Alexander N. Patananan, J. Michael McCaffery, Kayvan Niazi, Daniel Braas, Carla M. Koehler, Thomas G. Graeber, Pei-Yu Chiou, Michael A. Teitell. Cell Metabolism Volume 23, Issue 5, p921–929, 10 May 2016  DOI: http://dx.doi.org/10.1016/j.cmet.2016.04.007

This paper appears to be open access.

Titanium dioxide nanoparticles and the brain

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This research into titanium dioxide nanoparticles and possible effects on your brain should they pass the blood-brain barrier comes from the University of Nebraska-Lincoln (US) according to a Dec. 15, 2015 news item on Nanowerk (Note: A link has been removed),

Even moderate concentrations of a nanoparticle used to whiten certain foods, milk and toothpaste could potentially compromise the brain’s most numerous cells, according to a new study from the University of Nebraska-Lincoln (Nanoscale, “Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles”).

A Dec. 14, 2015 University of Nebraska-Lincoln news release, which originated the news item, provides more detail (Note: Links have been removed),

The researchers examined how three types of titanium dioxide nanoparticles [rutile, anatase, and commercially available P25 TiO2 nanoparticles], the world’s second-most abundant nanomaterial, affected the functioning of astrocyte cells. Astrocytes help regulate the exchange of signal-carrying neurotransmitters in the brain while also supplying energy to the neurons that process those signals, among many other functions.

The team exposed rat-derived astrocyte cells to nanoparticle concentrations well below the extreme levels that have been shown to kill brain cells but are rarely encountered by humans. At the study’s highest concentration of 100 parts per million, or PPM, two of the nanoparticle types still killed nearly two-thirds of the astrocytes within a day. That mortality rate fell to between half and one-third of cells at 50 PPM, settling to about one-quarter at 25 PPM.

Yet the researchers found evidence that even surviving cells are severely impaired by exposure to titanium dioxide nanoparticles. Astrocytes normally take in and process a neurotransmitter called glutamate that plays wide-ranging roles in cognition, memory and learning, along with the formation, migration and maintenance of other cells.

When allowed to accumulate outside cells, however, glutamate becomes a potent toxin that kills neurons and may increase the risk of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The study reported that one of the nanoparticle types reduced the astrocytes’ uptake of glutamate by 31 percent at concentrations of just 25 PPM. Another type decreased that uptake by 45 percent at 50 PPM.

The team further discovered that the nanoparticles upset the intricate balance of protein dynamics occurring within astrocytes’ mitochondria, the cellular organelles that help regulate energy production and contribute to signaling among cells. Titanium dioxide exposure also led to other signs of mitochondrial distress, breaking apart a significant proportion of the mitochondrial network at 100 PPM.

“These events are oftentimes predecessors of cell death,” said Oleh Khalimonchuk, a UNL assistant professor of biochemistry who co-authored the study. “Usually, people are looking at those ultimate consequences, but what happens before matters just as much. Those little damages add up over time. Ultimately, they’re going to cause a major problem.”

Khalimonchuk and fellow author Srivatsan Kidambi, assistant professor of chemical and biomolecular engineering, cautioned that more research is needed to determine whether titanium dioxide nanoparticles can avoid digestion and cross the blood-brain barrier that blocks the passage of many substances. [emphasis mine]

However, the researchers cited previous studies that have discovered these nanoparticles in the brain tissue of animals with similar blood-brain barriers. [emphasis mine] The concentrations of nanoparticles found in those specimens served as a reference point for the levels examined in the new study.

“There’s evidence building up now that some of these particles can actually cross the (blood-brain) barrier,” Khalimonchuk said. “Few molecules seem to be able to do so, but it turns out that there are certain sites in the brain where you can get this exposure.”

Kidambi said the team hopes the study will help facilitate further research on the presence of nanoparticles in consumer and industrial products.

“We’re hoping that this study will get some discussion going, because these nanoparticles have not been regulated,” said Kidambi, who also holds a courtesy appointment with the University of Nebraska Medical Center. “If you think about anything white – milk, chewing gum, toothpaste, powdered sugar – all these have nanoparticles in them.

“We’ve found that some nanoparticles are safe and some are not, so we are not saying that all of them are bad. Our reasoning is that … we need to have a classification of ‘safe’ versus ‘not safe,’ along with concentration thresholds (for each type). It’s about figuring out how the different forms affect the biology of cells.

I notice the researchers are being careful about alarming anyone unduly while emphasizing the importance of this research. For anyone curious enough to read the paper, here’s a link to and a citation for it,

Mitochondrial dysfunction and loss of glutamate uptake in primary astrocytes exposed to titanium dioxide nanoparticles by Christina L. Wilson, Vaishaali Natarajan, Stephen L. Hayward, Oleh Khalimonchuk and   Srivatsan Kidambi. Nanoscale, 2015,7, 18477-18488 DOI: 10.1039/C5NR03646A First published online 31 Jul 2015

This is paper is open access although you may need to register on the site.

Final comment, I note this was published online way back in July 2015. Either the paper version of the journal was just published and that’s what’s being promoted or the media people thought they’d try to get some attention for this work by reissuing the publicity. Good on them! It’s hard work getting people to notice things when there is so much information floating around.