APR 21, 2019 11:21 AM PDT

Getting Rid of Damaged Mitochondria Relieves Autoimmune Disease in Mice

WRITTEN BY: Carmen Leitch

Inflammation is a vital process in the body. It helps protect us from invading pathogens and helps us heal after wounds occur. But when inflammation gets out of control, it can cause significant harm and lead to many types of chronic disease. One way the immune system can keep the process regulated is through protein complexes called inflammasomes. The one we might know the most about is the NLRP3 inflammasome, which is active when mitochondria, the cell’s powerhouses, are stressed or have been damaged. An overactive NLRP3 inflammasome has been linked to a variety of chronic inflammatory disorders. New work reported in Cell Metabolism has shown that in mice, cells can be induced to eliminate damaged mitochondria before the NLRP3 inflammasome is activated.

Image credit: Pixabay

The leader of this work, senior author Michael Karin, Ph.D., a Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine, reported in 2018 that damaged mitochondria can activate the NLRP3 inflammasome. In a process called mitophagy, cellular recycling machinery removes damaged mitochondria. The NLRP3 inflammasome, the researchers found, is deactivated during that process.

"After that, we wondered if we could reduce harmful excess inflammation by intentionally inducing mitophagy, which would eliminate damaged mitochondria and should in turn pre-emptively inhibit NLRP3 inflammasome activation," explained Karin. "But at the time we didn't have a good way to induce mitophagy."

A postdoctoral researcher in the Karin lab, Elsa Sanchez-Lopez, Ph.D., was investigating how cells control the uptake of a nutrient called choline. She found that an inhibitor of an enzyme choline kinase or ChoK is able to initiate mitophagy. With ChoK inhibited, choline is not added to mitochondrial membranes, and cells can sense that mitochondria are damaged. The mitochondria are then disposed of, through mitophagy.

"Most importantly, by getting rid of damaged mitochondria with ChoK inhibitors, we were finally able to inhibit NLRP3 inflammasome activation," Karin added.

Muckle-Well syndrome mouse spleens after treatment with a ChoK inhibitor; inflammation is reduced as shown by the smaller spleens (right), compared to large, mock-treated mice (left). / Credit: UC San Diego

The scientists used a mouse model to test the effects of  ChoK inhibitors. Treatment with the inhibitor stopped acute inflammation when the mice were exposed to uric acid, which mimics gout flares. The ChoK inhibitor also reversed symptoms of chronic inflammation seen in a model of Muckle-Well Syndrome, a genetic disorder caused by NLRP3 gene mutations. Enlarged spleens are seen with increased inflammation, and in Muckle-Well Syndrome mice, spleens are about twice the normal size. After treatment with ChoK inhibitor, the spleens returned to normal size.

While the NLRP3 inflammasome exerts its effects through two cytokines (IL-1β and IL-18) that promote inflammation, existing drugs only block one of those two cytokines. ChoK inhibitors, however, block both cytokines.

"There are several diseases, including lupus and osteoarthritis, whose treatment will likely require dual inhibition of both IL-1β and IL-18," Karin explained.

Learn more about the inflammasome from the video.

Sources: AAAS/Eurekalert! Via UCSD, Cell Metabolism

About the Author
BS
Experienced research scientist and technical expert with authorships on over 30 peer-reviewed publications, traveler to over 70 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
SEP 25, 2022
Cell & Molecular Biology
New Imaging Tools Provide Insights Into Cell Stress
SEP 25, 2022
New Imaging Tools Provide Insights Into Cell Stress
In cells, active genes are transcribed into mRNA molecules, which can be edited and processed in a variety of ways, to u ...
SEP 28, 2022
Genetics & Genomics
Microprotein Mutations May Significantly Increase Alzheimer's Risk
SEP 28, 2022
Microprotein Mutations May Significantly Increase Alzheimer's Risk
The mitochondrion, commonly called the powerhouse of the cell, might be one of the best known organelles. This special o ...
OCT 13, 2022
Immunology
SARS-CoV-2 Can Infect Fat Cells, Promoting Infection & Inflammation
OCT 13, 2022
SARS-CoV-2 Can Infect Fat Cells, Promoting Infection & Inflammation
SARS-CoV-2, the virus that causes COVID-19, is generally known to infect cells in the nose and respiratory tract by latc ...
OCT 09, 2022
Immunology
A Gel Treatment for Gum Disease is in Development
OCT 09, 2022
A Gel Treatment for Gum Disease is in Development
Scientists have developed a gel that can relieve multiple symptoms of gum disease, and brings better health to the oral ...
OCT 21, 2022
Plants & Animals
Were Neandertals carnivores?
OCT 21, 2022
Were Neandertals carnivores?
A new study uses zinc isotope analysis to determine whether Neandertals from the Iberian peninsula were carnivores.
NOV 08, 2022
Neuroscience
Does Nose-Picking Really Increase Alzheimer's Risk?
NOV 08, 2022
Does Nose-Picking Really Increase Alzheimer's Risk?
Researchers have found that a bacterium that travels via the olfactory nerve from the nose to the brain may lead to Alzh ...
Loading Comments...