In the 1970s, evidence emerged that environmental exposures could damage mitochondria, the primary regulators of cellular energetics. (1,2) More recently, researchers are studying how stressed mitochondria may initiate a signaling cascade that culminates in inflammation. At the center of this increased investigation is a multiprotein complex called the NLRP3 inflammasome. (3,4) The elusive link between environmentally induced mitotoxicity and inflammasome activation is the subject of a new study published in Environmental Health Perspectives. (5)
Inflammation is a vital physiological response to invading agents or stressors, and inflammasomes are major players in this response. These multiprotein complexes sense pathogen- or damage-associated molecular patterns and trigger the release of proinflammatory cytokines that enhance and sustain inflammation. (3) Most inflammasomes contain proteins in the nucleotidebinding oligomerization domain (NOD)-like receptor (NLR) family; among these, the NLRP3 inflammasome is sensitive to the broadest variety of stimuli and has therefore sparked the most research interest. (6) Abnormal activation of NLRP3 has been implicated in disorders such as Alzheimer's and Parkinson's diseases, diabetes, and atherosclerosis, (4) raising huge clinical interest as a drug development target. (7)
"This study may lay the foundation for new directions in research examining agents that contribute to disease via mitochondrial function and inflammasome modulation," says EHP deputy editor B. Paige Lawrence, a professor at the University of Rochester Medical Center. "Being able to connect exposures with specific, measurable molecular pathways helps to inform our understanding of pathways that lead from exposure to disease."
Previous research has linked inflammasome activation to byproducts of mitochondrial damage, such as production of reactive oxygen species (ROS) and loss of membrane potential. (8,9,10) However, it remains unclear whether pollutant exposures directly alter mitochondria or indirectly affect them by other injury to the cell. (11)
National Institute of Environmental Health Sciences (NIEHS) neurotoxicologist Jean Harry, senior author of the present report, says her team set out to clarify this link. "We wanted to separate biological responses from toxicological ones by looking at a specific shift in the ability of the cell to respond to a secondary hit," she says. To do this, the investigators exposed specialized immune cells called macrophages to tri-organotins, which are prevalent environmental contaminants that have been shown to...