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
  • 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
AUG 11, 2021
Genetics & Genomics
Modified CRISPR Corrects Cystic Fibrosis Mutations in Organoid Model
AUG 11, 2021
Modified CRISPR Corrects Cystic Fibrosis Mutations in Organoid Model
Over 70,000 around the world have cystic fibrosis (CF), one of the world's most common genetic diseases. People with ...
AUG 19, 2021
Immunology
Immune Enzyme Kills Viruses but Makes Tumors Stronger
AUG 19, 2021
Immune Enzyme Kills Viruses but Makes Tumors Stronger
Robert Louis Stevenson’s 1886 novel Strange Case of Dr. Jekyll and Mr. Hyde describes a man who is a kind, respect ...
AUG 30, 2021
Health & Medicine
For the love of java: Researchers find association, not causation, between excessive coffee consumption, brain size, and dementia
AUG 30, 2021
For the love of java: Researchers find association, not causation, between excessive coffee consumption, brain size, and dementia
Researchers find association, not causation, between excessive coffee consumption, brain size, and dementia
SEP 10, 2021
Cell & Molecular Biology
New Artificial Cells Can Ingest, Process & Expel Material
SEP 10, 2021
New Artificial Cells Can Ingest, Process & Expel Material
Better research models can help us solve some biological mysteries. In recent years, scientists have developed a variety ...
SEP 20, 2021
Genetics & Genomics
Clinical Trial of CRISPR-Based HIV Treatment Set to Begin
SEP 20, 2021
Clinical Trial of CRISPR-Based HIV Treatment Set to Begin
Human immunodeficiency virus (HIV) is a retrovirus, which is a type of virus that can write its genetic material into th ...
SEP 22, 2021
Health & Medicine
Genetic Mutation Improving Protein Translation Found to Slow Aging
SEP 22, 2021
Genetic Mutation Improving Protein Translation Found to Slow Aging
A study from University College London found a genetic mutation in a gene encoding for more accurate translation of prot ...
Loading Comments...