Reframing the Question: Does Mitochondrial Damage Set the Stage for Future Inflammation?

Abstract

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 nucleotide-binding 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

An inflammasome is a complex molecule made up of different proteins. Inflammasomes are activated by sensing the presence of viruses, bacteria, particulate matter, and molecules produced by tissue stress. On activation, they mediate the release of proinflammatory cytokines, which help the body clear foreign substances and repair tissue. Abnormal activation of inflammasomes is implicated in a variety of human diseases. Image: © RAMON ANDRADE 3DCIENCIA/Science Source.

“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 by-products 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 alter mitochondrial function.12^,13^,14^,15^,16^,17

One group of macrophages was activated, or primed, by exposure to bacterial lipopolysaccharide (LPS), and then both primed and unprimed groups were treated with tri-organotin compounds. Two known neurotoxicants, triethyltin bromide (TETBr) and trimethyltin hydroxide (TMTOH), enhanced formation of inflammasome aggregates and release of proinflammatory cytokines in LPS-primed macrophages. These compounds suppressed mitochondrial bioenergetics but did not alter ROS production, demonstrating that inflammasome activation can occur independently of ROS release. In the reverse scenario, however, pre-exposure to TETBr and TMTOH blunted the appropriate macrophage response to proinflammatory LPS.

“Overall, I think the study demonstrates that, rather than looking at apical end points, we should reframe the environmental and public health question: How does an exposure modify the system such that we may change a relative risk to something else coming down the pike later?” says Harry. The environmental toxicants were tested at sublethal levels—not high enough to elicit cell death, but sufficient to change the cells’ responses to a secondary insult. Harry says such changes could manifest as an earlier onset of disease, progression of a disease process, or—of particular interest in the context of the current global pandemic—reduced vaccine response. These effects may be seen as two sides of the same coin.

“On the one hand, having an underlying chronic inflammatory condition might change my susceptibility to [any] environmental exposures that might act upon the immune system,” Harry says. “On the other hand, a low-level environmental exposure could change how I respond to an immune challenge later.”

Matthew Havrda, an assistant professor at the Geisel School of Medicine at Dartmouth, cautions that the generalized suppression of metabolism observed in exposed macrophages may suggest general distress due to lack of adenosine triphosphate (ATP; the energy currency of the cell) and that inflammasome activation could therefore be part of a bigger stress response. Havrda, who was not involved in the current study, suggests that to find the direct link—the molecular smoking gun—scientists should look at whether the response elicited by tri-organotin exposure is specific to NLRP3. “[NLRP3] drugs and biomarker assays are out there, so if [NLRP3 activation is] specific for this type of toxic exposure, you could potentially screen and treat people to circumvent the deleterious effects,” he says.

Harry agrees, noting that inflammasome-blocking drugs currently in development may simply be blocking ATP release and that the specificity of the inflammasome response calls for further studies. She adds that the role of inflammasome aggregate formation should also be clarified. “These aggregates are very sticky and hard to break up, and they have a major stimulatory effect on [surrounding] macrophages, so the acute inflammatory response elicited by environmental exposures may have long-term consequences through the release of those aggregates,” she says. Recent studies18 have proposed these aggregates may act as scaffolds in the formation of plaques in Alzheimer’s disease, supporting the need for further investigation.

Biography

Florencia Pascual, PhD, is a freelance science writer based in Durham, North Carolina.