Fight Aging!

Mitochondria are the power plants of the cell, producing the chemical energy store molecule ATP, but are also integrated into a wide range of fundamental cellular processes. Mitochondrial function declines with age, likely an important contribution to age-related declines in energy-hungry tissues such as the brain and muscles. It is also known that mitochondrial dysfunction can provoke chronic inflammation via the mislocation of mitochondrial DNA into parts of the cell where it will act as a damage-associated molecular pattern. This upregulation of inflammatory signaling is a reasonable proposal for the way in which mitochondrial aging can contribute meaningfully to atherosclerosis.

Atherosclerosis is considered an inflammatory condition. Fundamentally, atherosclerosis results from the dysfunction of the macrophage cells responsible for clearing excess cholesterol from blood vessel walls. Greater inflammatory signaling reduces the ability of macrophages to undertake repair-related activities, encouraging them to instead enter an inflammatory mode of activity. Once a tipping point is reached in the establishment of toxic deposits of excess cholesterol in blood vessels walls, the lesions will grow over time as ever more macrophages are attracted to the problem, become overwhelmed, and die. Greater inflammatory signaling causes that tipping point to occur more readily.

The second plausible pathway for mitochondrial aging to contribute to atherosclerosis is via the increased generation of oxidative molecules observed to take place in the mitochondrial of cells in aged tissues. Oxidation of cholesterol, other lipids, and lipid carriers such as LDL particles can produce additional stress on the macrophages responsible for cleaning up this metabolic waste. Again, the tipping point in fatty lesions present in blood vessel walls occurs more readily given greater oxidative stress and consequent production of toxic lipids.

Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

The atherosclerotic process is very often responsible for several cardiovascular and cerebrovascular diseases. It is now well accepted and documented that atherosclerosis starts from endothelial dysfunction and lipid deposition, which progresses through macrophage infiltration, smooth muscles://en.wikipedia.org/wiki/Smooth_muscle">smooth muscle cell migration, and blood borne material deposition, and becomes clinically relevant due to complications, eventually leading to local intravascular thrombus formation. Modified lipoproteins, mainly oxidized low-density lipoproteins (oxLDL), are considered the major contributors to the genesis, progression, and immunological response occurring during the atherosclerotic process.

The first report linking mitochondria to atherosclerosis is from 1970. However, only in the last few years has increasing evidence really underlined the key role of mitochondrial dynamics in the pathogenesis of atherosclerosis. Vascular cells, such as endothelial and smooth muscle cells, due to their metabolic functions and their barrier role are the main targets of mitochondrial dysfunction. In the atherosclerosis process, dysfunctional mitochondria might cause alterations in cellular metabolism and respiration resulting in the excessive production of reactive oxygen species (ROS), leading to oxidative stress. While low levels of ROS exert important signaling functions, elevated ROS production induces the damage of cellular structures, alters DNA, proteins, and other molecules. These conditions can become chronic, thereby favoring atherosclerosis progression and destabilization.

Atherosclerosis is a multifactorial disease. Multiple clinical trials and basic studies have clearly demonstrated that the management of the known risk factors only is not enough to limit the burden of this condition which underlies most cardiovascular diseases. Increasing evidence suggests an important role for mitochondria in the initial steps of this process. They regulate the inflammatory response and oxidative stress, two key steps that, once dysfunctional, might modulate initiation and progression of the atherosclerotic lesion. Thus, the modulation of mitochondrial function could delay the development of endothelial dysfunction, which represents the primum movens of the atherosclerotic process. In this context, it will be important for research, at both preclinical and clinical levels, to define the precise therapeutic interventions focusing on mitochondrial functions.