Damaged Mitochondria Seen to Be Targeted by a Protein, Preventing Excessive Inflammation

Damaged Mitochondria Seen to Be Targeted by a Protein, Preventing Excessive Inflammation

A protein called p62 acts as an anti-inflammatory molecular brake, helping to eliminate damaged mitochondria and preventing the onset of excessive inflammation that can harm healthy cells and tissues, leading to premature aging, autoimmunity, or worse. Besides elucidating how the body is able to turn off inflammation, the findings by researchers at the University of California, San Diego (UCSD) School of Medicine, could impact a series of age-related diseases.

The study, titled “NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria,” was published in the journal Cell.

Macrophages are immune cells with a major role in defending against foreign and harmful pathogens, particles and microbes. Besides detecting and swallowing these agents, macrophages also secrete cytokines that recruit and activate other immune cells. One of the most important cytokines, interleukin-1 beta (IL-1 beta), is produced by macrophages through molecular machines called inflammasomes. One such structure, the NLRP3-inflammasome, releases IL-1 when stimulated by harmful particles and toxins.

Researchers, working on a mouse model, found that harmful agents don’t act directly on the NLRP3-inflammasome, but instead damage the mitochondria that send out activation signals to the inflammasome. This process is necessary in case of potential infections; however, the continuous production of IL-1 beta when it is no longer necessary — signaled by the damaged mitochondria —  leads to an exacerbated inflammatory reaction that can result in multi-organ failure, septic shock, and death.

The scientists also discovered how the body turns off production of IL-1 beta by the NLRP3-inflammasome. The production of p62 is also increased when macrophages are responding to invading microbes or particles. This protein coats damaged mitochondria that send activating signals to the inflammasome, ensuring that these mitochondria are eliminated. Once the damaged mitochondria are eliminated, the inflammasome stops producing the pro-inflammatory IL-1 beta cytokine.

Dr. Zhenyu Zhong, the study’s co-lead author, said in a press release, “We’ve suspected for quite some time that damage to mitochondria caused by either genetic or environmental factors is the root cause of many age-related diseases, all of which are associated with chronic, low-grade inflammation. Therefore, p62 — and its part in eliminating damaged mitochondria — could provide a new target for preventing such diseases. Indeed, we already know that another protein that collaborates with p62 to eliminate damaged mitochondria is Parkin, which plays a role in a rare form of Parkinson’s disease.”

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