Mitochondria are often called the powerhouses of the cell. But their ancient origins may also make them drivers of inflammation.
Researchers at the University of Illinois Chicago have discovered that proteins released from mitochondria can activate the immune system in a similar way to invading bacteria. The findings suggest that remnants of mitochondria's evolutionary past may contribute to inflammation in infections and autoimmune disorders.
The research, published in eLife, sheds light on a longstanding question in biology: Why do immune cells continue to produce inflammation even after a threat has disappeared?
"Inflammation emerges when our immune cells fight off infections. However, many diseases have an excessive inflammation component," said Dr. Jalees Rehman , senior author of the study. "For example, even after antibiotics eliminate the bacteria causing pneumonia, patients can remain very sick because their immune system doesn't always switch off the inflammation."
The widely accepted scientific theory is that mitochondria originated billions of years ago, when an ancient cell engulfed a bacterium. Through evolution, the bacterium became the mitochondrion, an integrated part of a cell, but it kept some bacterial characteristics.
That evolutionary history inspired Rehman, the Benjamin J. Goldberg Professor and head of the Department of Biochemistry and Molecular Genetics at UIC, to ask if mitochondria could trigger inflammatory responses because parts of them still resemble bacteria.
One clue came from proteins produced by mitochondria. Mitochondrial proteins carry a chemical tag known as a formyl group. Bacterial proteins have the same feature.
"The only proteins our body makes that have these formyl groups are proteins produced in mitochondria," Rehman said. "The immune system uses formylated peptides as a signal that bacteria are present."
This signal draws the body's immune cells, particularly neutrophils, to the infection site to launch an attack.
Using mouse models of acute lung inflammation, the team found elevated levels of mitochondrial proteins circulating in the bloodstream even when no live bacteria were present. The researchers concluded that the proteins originated from the animals' own mitochondria.
Further experiments revealed that inflamed blood vessel cells, known as endothelial cells, were releasing the molecules through a process regulated by a protein called Pink1. That protein helps clean up and remove damaged mitochondria.
The team then exposed human neutrophils to the mitochondrial proteins. Even in the absence of bacteria, the immune cells became activated and generated high levels of oxidative stress, a hallmark of tissue injury.
"The reason we think they're so harmful is that these neutrophils create a lot of oxidative stress," Rehman said. "When bacteria are present, that response helps kill them. But if there are no bacteria, the same response can damage healthy tissues."
When the scientists removed Pink1 from endothelial cells, they produced lower levels of circulating mitochondrial proteins, less neutrophil accumulation in the lungs and better survival.
The findings identify endothelial cells as an unexpected source of inflammatory signals and suggest that mitochondria can act as messengers that amplify immune responses during disease. The work may help explain excessive inflammation seen in conditions ranging from severe infections to other inflammatory disorders.
The researchers hope that future studies will determine whether drugs that block the release or activity of mitochondrial proteins could help patients suffering from high inflammation.
The study also highlights how events that occurred billions of years ago continue to shape human health today, Rehman said.
"By understanding the evolution of cells, we can uncover new pathways to studying and treating diseases that are very impactful or detrimental for human health."
This project was supported by NIH grants P01HL160469, R01HL174916, R01HL152515, R01HL149300 and AHA grant 18PRE34070092.
Written by Tess Joosse
