The Link Between Mitochondrial Fission and Inflammation

The vast majority of human cells contain mitochondria—the organelles that generate the energy cells need to carry out their functions. Like a dynamic renewable resource, these tiny organelles are constantly dividing and uniting in processes called fission and fusion. The balance between fission and fusion is critical for health.

In a study published today in Hypertension, scientists at Temple University uncovered a novel mechanism by which abnormalities in mitochondrial fission in endothelial cells contribute to inflammation and oxidative stress in the cardiovascular system. They further show how the fission–fusion balance can be stabilized to lower inflammation using salicylate, the main active ingredient in everyday pain-relieving drugs like aspirin.

“It was already known that in cardiovascular disease the function of endothelial cells and mitochondria are impacted by inflammation, but we were unsure whether there was a link between the two,” says senior author Satoru Eguchi.

In endothelial cells, chronic inflammation causes mitochondria to become smaller and fragmented. This damaging process is mediated by a molecule known as dynamin-related protein 1 (Drp1). Normally, Drp1 plays a helpful role in maintaining the fission–fusion balance. But when cells are stressed by inflammation, it steps up fission activity, resulting in mitochondrial fragmentation.

“How Drp1 acts to increase mitochondrial fragmentation when endothelial cells are inflamed has been unclear,” Eguchi explains. “But we wondered whether it might interact with nuclear factor (NF)-κB, which oversees the regulation of inflammatory processes and is involved in endothelial dysfunction.”

In endothelial cells, the team stimulated inflammatory pathways that produced mitochondrial fragmentation. They then examined the effects of blocking Drp1 activity and expression. These experiments showed Drp1 inhibition suppresses mitochondrial fission, NF-κB activation, and inflammation. Reductions in fission and inflammation were also observed in cells following NF-κB inhibition, as well as in follow-up studies in mice genetically engineered to have less Drp1.

The researchers next determined whether the anti-inflammatory drug salicylate could also reduce mitochondrial fragmentation. Salicylate works by blocking the activity of multiple inflammatory molecules, including NF-κB. As anticipated, in mice, treatment with salicylate attenuated inflammation and mitochondrial fragmentation via its effects on NF-κB and downstream pathways.

“Our findings suggest that salicylate may be able to maintain the balance between mitochondrial fission and fusion under inflammatory conditions,” Eguchi says. “This observation could have real clinical impact, since salicylate is already used in aspirin and related pain-relievers.”