Cell: Mitochondria initiate a new type of cell death, from pyrotic to necrosis

As researchers gain a deeper understanding of the dynamic world inside the human immune system, it is becoming increasingly clear that mitochondria are key regulators of our body's
response to disease.

In addition to their traditional work as the "powerhouse of the cell," mitochondria play a key role in the life of the cell – and more importantly, in the death of the cell to guide inflammation and antimicrobial
defenses.
This means that mutations in mitochondria-related genes may affect the immune system's ability to fight disease and even trigger an overreaction that leads to inflammatory diseases
such as cancer or Crohn's disease.
Although it is increasingly understood how mitochondria regulate the immune system, how they regulate is still relatively unknown
.
Figuring out how mitochondrial mutations interfere with the immune response could be key to understanding disease mechanisms such as tuberculosis, leprosy and Parkinson's disease, and 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 published a study in the journal Cell that solved some of the mystery
.
Watson and Patrick studied mutations
in the LRRK2 protein in macrophages or leukocytes from animal models.
When mutated macrophages are exposed to bacteria that cause tuberculosis, mitochondria initiate a new type of cell death, from pyrotic to necrosis
.

When cells die of necrosis, they release chemical signals that cause an aggressive inflammatory immune response
.
For animal models with LRRK2 mutations, switching to necrotic cell death made them more susceptible to tuberculosis infection and triggered excessive inflammation of infected tissue, leading to worse outcomes
.

Although this research has focused on macrophage and tuberculosis infection, the newly discovered disease mechanisms may have broader implications
.

"Mutations in the LRRK2 protein have been linked to a variety of important human diseases that, ostensibly, have little link between them — Parkinson's, leprosy, inflammatory bowel disease and Crohn's disease, and cancer
," Patrick said.
"Our work shows that a common mutation in LRRK2 triggers a new type of cell death, triggering a high inflammatory response
to infection.
Cell death and inflammation may be what
links LRRK2 to all these different human diseases.
”

The team's findings have potential real-world applications to provide much-needed relief to patients, and Patrick and Watson are poised to move on to the next phase of research, using LRRK2 inhibitors already developed by pharmaceutical companies to test their theory
.

"Our study is geared towards taking these drugs and studying them
in the context of the immune response.
We are about to begin research to see if drugging LRRK2 and other proteins involved in this new cell death pathway can improve outcomes for
TB infection.
”

The team's findings underscore the critical role
of basic science in developing new treatment options for patients with life-changing diseases.
In Patrick's words, "It's exciting
to see basic science research digging deeper into how molecules work to identify unexpected connections between seemingly unrelated diseases and open up new avenues for therapeutic intervention.
" ”