Today's open access research implicates an imbalance of mitochondrial dynamics in the direction of too much mitochondrial fission in the age-related chronic inflammation observed in endothelial cells of the cardiovascular system. Every cell carries a herd of hundreds of mitochondria, the distant descendants of symbiotic bacteria now integrated as cellular components. The primary task of mitochondria is to generate adenosine triphosphate (ATP), a chemical energy store used to power cellular operations, but they are involved in many core cellular processes. Mitochondria are removed when damaged by the quality control mechanism of mitophagy, and replicate by fission in order to make up their numbers. Mitochondria are very dynamic structures: they pass around component parts, fuse together, and split apart constantly.
A balance between mitochondrial fission and fusion is necessary for optimal cellular function. A sizable portion of the age-related decline in mitochondrial function may be due to an imbalance in the direction of excessive fusion, leading to large mitochondria that become worn and damaged but are resistant to recycling via mitophagy. The proximate cause of this issue appears to be changes in gene expression and protein levels, such as NAD+, or MFF and PUM2, but links to deeper, more fundamental causes of aging remain to be established in a concrete way. It isn't as simple as just a matter of too much fusion, however, as the research here illustrates. Certainly, changes in mitochondrial dynamics are involved in a number of important issues in aging, and imbalance in either direction can be problematic.
The vast majority of cells in the human body contain tiny power plants known as mitochondria that generate much of the energy cells use for day-to-day activities. Like a dynamic renewable resource, these little power plants are constantly dividing and uniting in processes called fission and fusion. The balance between fission and fusion is critical for health - especially cardiovascular health. Now, scientists have uncovered a novel mechanism by which abnormalities in mitochondrial fission in endothelial cells - the cells that line the inner surface of blood vessels - 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.
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 fission-fusion balance. When cells are stressed by inflammation, however, it steps up fission activity, resulting in mitochondrial fragmentation. Researchers stimulated inflammatory pathways that produced mitochondrial fragmentation. They then examined the effects of blocking Drp1 activity and expression. These experiments showed that in cells, 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.
Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses.
In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 deficient mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB.
In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.