Mitochondrial Dysfunction in Atherosclerosis
Atherosclerosis is the build up of fatty plaques in blood vessels, narrowing and weakening them. This leads to heart failure, heart attack, and stroke when vessels or plaques rupture. The core problem is that the macrophage cells responsible for clearing lipids from blood vessel walls become dysfunctional with age. Contributing factors that increase with age include chronic inflammatory signaling that shifts macrophage behavior away from repair activities, and the presence of oxidized lipids that macrophages are poorly equipped to handle. Once a plaque is established, these mechanisms ensure that it becomes an inflammatory hot spot that attracts and kills ever more macrophages, growing as a result.
Mitochondria, the power plants of the cell, become dysfunctional with age. This dysfunction can be connected, at least in principle, to the important contributing mechanisms of atherosclerosis. This is the topic of discussion in today's open access review paper. Whether mitochondrial aging makes inflammation worse in ways that matter to atherosclerosis is an interesting question; as is usually the case, the mechanisms exist, but one can certainly debate the degree to which they matter versus other mechanisms. More defensible is the rising level of oxidative stress with age, largely the result of mitochondria generating ever more oxidizing molecules as a side-effect of changes in their operation. This leads to increased oxidization of lipids, and thus more of a burden of toxicity due to those oxidized lipids, falling heavily on macrophages.
How much of a benefit can one obtain in the case of atherosclerosis by rejuvenating mitochondrial function? That is hard to say, as ever, without a proof of concept study. On the inflammation side of the house, there is evidence to suggest that broad suppression of inflammatory signaling produces little more benefit to patients than does the lowering of blood cholesterol, however. That might indicate that oxidized lipids are responsible for a larger fraction of the problem of cardiovascular mortality, but again, until someone (such as the Underdog Pharmaceuticals or Repair Biotechnologies teams) provides evidence based on specifically and only removing oxidized lipids, it is hard to do more than hypothesize.
Cardiovascular disease (CVD) is the main cause of death worldwide. Atherosclerosis is the underlying pathological basis of CVD. Mitochondrial homeostasis is maintained through the dynamic processes of fusion and fission. Mitochondria are involved in many cellular processes, such as steroid biosynthesis, calcium homeostasis, immune cell activation, redox signaling, apoptosis, and inflammation, among others. Under stress conditions, mitochondrial dynamics, mitochondrial cristae remodeling, and mitochondrial reactive oxygen species (ROS) production increase, mitochondrial membrane potential (MMP) decreases, calcium homeostasis is imbalanced, and mitochondrial permeability transition pore (mPTP) open and release of mitochondrial DNA (mtDNA) are activated.
mtDNA recognized by TLR9 can lead to NF-κB pathway activation and pro-inflammatory factor expression. At the same time, TLR9 can also activate NLRP3 inflammasomes and release interleukin, an event that eventually leads to tissue damage and inflammatory responses. In addition, mitochondrial dysfunction may amplify the activation of NLRP3 through the production of mitochondrial ROS, which together aggravate accumulating mitochondrial damage.
In addition, mtDNA defects or gene mutation can lead to mitochondrial oxidative stress. Mitochondria are highly dynamic organelles that constantly produce adenosine triphosphate (ATP). Events, such as mtDNA mutation, imbalance in calcium homeostasis, accumulation of oxidative stress products, and metabolic dysfunction are hallmarks of mitochondrial damage. When mitochondria are damaged or dysfunctional, energy production is limited and large quantities of ROS are produced. Increased ROS levels induce endothelial dysfunction, vascular inflammation, and accelerated accumulation of oxidized low density lipoprotein (ox-LDL) in the arterial wall, a phenomenon that promotes atherosclerosis.
Finally, obesity, diabetes, hypertension, and aging are risk factors for the progression of CVD, which are closely related to mitochondrial dynamics. Mitochondrial dynamics may represent a new target in the treatment of atherosclerosis. Antioxidants, mitochondrial inhibitors, and various new therapies to correct mitochondrial dysfunction represent a few directions for future research on therapeutic intervention and amelioration of atherosclerosis.