Mitochondrial DNA Damage in the Context of Atherosclerosis
Mitochondria swarm by the hundreds in every cell, acting much like power plants by generating chemical energy store molecules (adenosine triphosphate, ATP) to power cellular operations. The progressive loss of mitochondrial ATP production that occurs with age is harmful to cell and tissue function. One way in which mitochondrial dysfunction leads to tissue damage is through stochastic damage to mitochondrial DNA. Some forms of damage, such as large deletions, can change mitochondrial function in ways that allow them to both malfunction and outcompete their functional peers. A cell becomes overtaken by broken mitochondria, and pollutes the surrounding tissue with damaging, reactive molecules. These can cause cholesterol and other lipids to become oxidized, and this contributes to the development of atherosclerosis, as oxidized lipids cause macrophages to become dysfunctional and falter in their task of keeping blood vessel walls free from fatty lesions. This may not be the only relevant mechanism, however.
The link between mitochondrial dysfunction and atherosclerosis has been the subject of extensive research. A model that could link the mitochondrial DNA (mtDNA) mutation-induced mitochondrial dysfunction and deficient autophagy may help understanding of the importance of these events in the age-related nature of inflammation and identifying potential points of therapeutic intervention. Based on the available data, we propose a plausible mechanism, according to which, phagocytosis stimulation by circulating large associates of modified LDL activate the pro-inflammatory response of the innate immune system.
According to this hypothesis, atherogenic modified LDL circulating in the blood of atherosclerotic patients induces lipid accumulation in the arterial wall cells. Modified LDL particles form self-associates that penetrate the cell by nonspecific phagocytosis, stimulation of which by LDL associates activates the pro-inflammatory response of macrophages in the form of secretion of inflammatory cytokines. Secretion of cytokines leads to increased accumulation of intracellular lipids. If the innate immunity functions normally, the pro-inflammatory reaction resolves rather quickly and further lipid accumulation does not occur. However, when macrophages contain mtDNA mutations, the pro-inflammatory response does not arrest, but rather intensifies with each repeated pro-inflammatory stimulation. Local inflammation in the vascular wall becomes chronic and accompanied by uncontrolled lipid accumulation giving rise to an atherosclerotic lesion.
Another intriguing possibility is that cells may recognize the dysfunctional mitochondrion as a pathogen that presents foreign epitopes, therefore triggering the immune response. This may be a consequence of the bacterial origin of mitochondria, due to which defective mitochondria could be recognized by immune cells as pathogens triggering the innate immunity response.
The proposed concept allows speculation that atherogenesis is due to two errors made by the cell of the arterial wall. The first one is that the cell perceives the associates of modified LDL as a pathogen that is taken up by phagocytosis, which causes an inflammatory response and the accumulation of intracellular lipids, which in turn is a trigger of atherogenesis at the cellular level. The second is that due to mutations, the mitochondria becomes dysfunctional and due to a defect in mitophagy, the cell cannot free itself from this mitochondrion and perceives it as a bacterium-like pathogen. This triggers an ongoing inflammatory signaling that may lead to inflammasome activation.
Does this mean that engineering macrophages to digest the oxydized LDL will not cure atherosclerosis, since the inflammatory response will still happen?
@Antonio - the oxisidised LDL will get removed by macrophages genetically engineered to break it down. Those same macrophages could also have the mitochondrial genes expressed in the nucleus. Or have their epigenetics reset to a younger state.