Cell (2022). DOI: 10.116/j.cell.2022.06.038″ width=”800″ height=”530″/>

Graphic abstract. Credit: Cell (2022). DOI: 10.116/j.cell.2022.06.038

As researchers gain new insights into the dynamic inner world of the human immune system, it is becoming increasingly clear that mitochondria are crucial regulators of how our bodies respond to disease.

In addition to their traditional job as “powerhouses of the cell”, mitochondria play a key role in the life – and more importantly, the death – of cells to direct inflammation and antimicrobial defense mechanisms. This means that mutations in mitochondrial genes can affect the immune system’s ability to fight disease or even cause an overreaction, leading to cancer or inflammatory conditions such as Crohn’s disease.

While there is a growing understanding of what mitochondria do to regulate the immune system, how they do it is still relatively unknown. Figuring out how mitochondrial mutations disrupt the immune response could hold the key to understanding mechanisms for diseases such as tuberculosis, leprosy and Parkinson’s disease, potentially opening the door to new treatments.

A team of researchers led by Robert O. Watson and Kristin L. Patrick of Texas A&M University School of Medicine recently unlocked some of that mystery in research published in the journal Cell

. Watson and Patrick studied mutations in the protein LRRK2 in macrophages, or white blood cells, of animal models. When the mutated macrophages were exposed to the bacteria that cause tuberculosis, the mitochondria triggered a new type of cell death, switching from pyroptosis to necroptosis.

When cells die from necroptosis, they release chemical signals that trigger an aggressive inflammatory immune response. For the animal models with LRRK2 mutations, the switch to necroptotic cell death made them more susceptible to tuberculosis infection and caused excessive inflammation in the infected tissues, causing worse outcomes.

While the study focused primarily on macrophages and tuberculosis infection, the newly discovered mechanism of disease may have much broader implications.

“Mutations in the LRRK2 protein have been linked to multiple major human diseases that appear to have little to do with each other — Parkinson’s disease, leprosy, inflammatory bowel and Crohn’s disease and cancer,” Patrick said. “Our work shows that a common mutation in LRRK2 causes a new type of cell death that triggers hyperinflammation in response to infection. Cell death and inflammation may be the thing linking LRRK2 to all of these disparate human diseases.”

The team’s discovery has potential real-world applications that could provide patients with much-needed relief, and Patrick and Watson are poised to dive into the next phase of research by testing their theory using LRRK2 inhibitors already marketed by pharmaceuticals. companies have been developed.

Related Post

“Our research has positioned us to take these drugs and study them in the context of the immune response,” Patrick said. “We are about to begin investigating whether drugging LRRK2, as well as other proteins involved in this novel cell death pathway, can improve tuberculosis infection outcomes.”

The team’s discovery highlights the critical role of basic science in the bench-to-bedside pathway for developing new treatment options for patients suffering from life-changing diseases. In Patrick’s words, “It’s exciting to see how basic science research that digs deep into how molecules work can identify unexpected links between seemingly unrelated diseases and open up new avenues for therapeutic intervention.”


Parkinson’s disease mutation leads to the wrong direction of iron in the brain


More information:
Chi G. Weindel et al, Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis, Cell (2022). DOI: 10.116/j.cell.2022.06.038
Journal information:
Cell

Provided by Texas A&M University

Quote: Unlocking Hidden Links Between Cell Death and Inflammation (2022, Oct. 21) Retrieved Oct. 21, 2022 from https://phys.org/news/2022-10-hidden-cell-death-inflammation.html

This document is copyrighted. Other than fair dealing for personal study or research, nothing may be reproduced without written permission. The content is provided for informational purposes only.