New pathway explains how zombie cells trigger chronic inflammation

Researchers have uncovered a previously unknown mechanism that helps aging cells drive the chronic inflammation linked to many age-related diseases. The findings reveal how dysfunctional mitochondria - the cell's energy-producing structures - work with the cell's epigenetic machinery to switch on inflammatory genes, opening the door to a new therapeutic approach for promoting healthier aging.

This persistent inflammation is thought to contribute to frailty, cardiovascular disease, cancer, neurodegeneration and other disorders of aging.

Helene Martini, Pharm.D., Ph.D., a Mayo Clinic researcher and first author of the studyWe found that inflammatory signaling alone isn't enough. The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on."

The researchers discovered that senescent cells increase production of acetyl-CoA, a molecule generated through mitochondrial metabolism. Acetyl-CoA enables epigenetic modifications - chemical changes that regulate whether genes are switched on or off without altering the DNA sequence itself. These modifications make inflammatory genes more accessible, allowing them to be robustly expressed.

In other words, mitochondrial DNA and RNA provide the inflammatory alarm, while mitochondrial metabolism grants the molecular "permission" needed to fully activate inflammatory genes.

"This is a completely new pathway," says Dr. Martini. "We found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on."

The team also identified a promising therapeutic target: a mitochondrial citrate transporter known as SLC25A1. Blocking this transporter reduced the supply of acetyl-CoA, limiting activation of inflammatory genes even though the initial immune signals remained present. Together, these findings reveal a previously unrecognized control point that could be exploited to promote healthier aging.

Source:

Mayo Clinic

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