Electronic cigarettes, often targeted to youth and pregnant women, cause a stress response in neural stem cells, critical cells in the brain, reports a research team at the University of California, Riverside.

Using cultured mouse neural stem cells, the UC Riverside researchers identified the mechanism underlying electronic cigarette-induced stem cell toxicity as “stress-induced mitochondrial hyperfusion,” or SIMH.

“SIMH is a protective, survival response. Our data show that exposure of stem cells to e-liquids, aerosols, or nicotine produces a response that leads to SIMH,"

said Prue Talbot, a professor in the Department of Molecular, Cell and Systems Biology who led the research.

Not Harmless

Present throughout life, stem cells become specialized cells with more specific functions, such as brain cells, blood cells, or bone. Far more sensitive to stress than the specialized cells they become, stem cells provide a model to study exposure to toxicants, such as cigarette smoke.

[caption id=“attachment_99041” align=“aligncenter” width=“680”]e-cigarette neural stem cell damage diagram Credit: Atena Zahedi et al. CC-BY[/caption]

Electronic cigarettes, or ECs, are nicotine-delivery devices that aerosolize nicotine and flavor chemicals through heating. Researchers do not yet understand how the chemicals in ECs might affect neural stem cells, particularly their mitochondria — organelles that serve as the cell’s powerhouses and are critical in regulating cell health.

“Although originally introduced as safer, ECs, such as Vuse and JUUL, are not harmless. Even short-term exposure can stress cells in a manner that may lead, with chronic use, to cell death or disease. Our observations are likely to pertain to any product containing nicotine,"

said Atena Zahedi, the first author of the research paper who received her doctoral degree in bioengineering this year.

Stress-induced Mitochondrial Hyperfusion

Zahedi explained that during SIMH, round punctate mitochondria fuse together to form long hyperfused networks in order to rescue each other — making them less vulnerable to degradation.

“The high levels of nicotine in ECs lead to a nicotine flooding of special receptors in the neural stem cell membrane,” Zahedi said. “Nicotine binds to these receptors, causing them to open up. Calcium and other ions begin to enter the cell. Eventually, a calcium overload follows."

[caption id=“attachment_99042” align=“aligncenter” width=“680”]Exposure to EC Liquid or Aerosol Causes Superoxide Production and an Antioxidant Response Exposure to EC Liquid or Aerosol Causes Superoxide Production and an Antioxidant Response
Credit: Atena Zahedi et al. CC-BY[/caption]

Too much calcium in the mitochondria is harmful. The mitochondria then swell, changing their morphology and function. They can even rupture and leak molecules that lead to cell death.

“If the nicotine stress persists, SIMH collapses, the neural stem cells get damaged and could eventually die. If that happens, no more specialized cells—astrocytes and neurons, for example—can be produced from stem cells,"

Zahedi said.


Zahedi noted that damaged stem cell mitochondria could accelerate aging and lead to neurodegenerative diseases.

Neural stem cells can get exposed to nicotine through the olfactory route, she explained. Users inhale the fumes, which can travel through the olfactory tracks to reach the brain.

[caption id=“attachment_99043” align=“aligncenter” width=“680”]Atena Zahedi Atena Zahedi (seated) is seen here with Prue Talbot.
Credit: I. Pittalwala, UC Riverside[/caption]

The researchers stress that youth and pregnant women need to pay especially close attention to their results.

“Their brains are in a critical developmental stage. Nicotine exposure during prenatal or adolescent development can affect the brain in multiple ways that may impair memory, learning, and cognition. Furthermore, addiction and dependence on nicotine in youth are pressing concerns. It’s worth stressing that it is nicotine that is doing damage to neural stem cells and their mitochondria. We should be concerned about this, given that nicotine is now widely available in ECs and their refill fluids,"

said Talbot, the director of the UCR Stem Cell Center.

Atena Zahedi, Rattapol Phandthong, Angela Chaili, Sara Leung, Esther Omaiye, Prue Talbot Mitochondrial Stress Response in Neural Stem Cells Exposed to Electronic Cigarettes iScience (2019). DOI: 10.1016/j.isci.2019.05.034

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