Mitochondria And Inflammation

Mitochondria are a type of cell organelle that has a lot of different and important functions.

Some of those are the various mechanisms through which our body treats an infection: namely, inflammation. 

This occurs when perfect homeostasis exists (a process mediated by mitochondria-endoplasmic reticulum contact sites), but can be deregulated, as mitochondria not only serve as an agent of acute and benign inflammation, but also contribute to the maintenance of a proinflammatory state, when this is not what our body needs. 

Damage-Associated Molecular Patterns (DAMPs)

During an infection, mitochondria release DAMPs, which detect and fight infections in an early stage.        

When some condition leads to damaged or dysfunctional mitochondria, they release the same components, and these, through pattern recognition receptors (PRRs), induce an undesired inflammatory response. 

These DAMPs may arise from their membrane (cardiolipin); from de mitochondrial DNA; and from their proteins; and they act when released into cytosol, the extracellular space or the circulation:

-       Cardiolipin: usually not oxidized, but, in sick individuals, it becomes oxidized, which promotes its exit from the mitochondria, and acts as a toll-like receptor 4 agonist (TLR4 - TLRs are a group of proteins that mediate the inflammatory process), and promotes pro-inflammatory cytokine production, production of leukotrienes in macrophages and the activation of endothelial cells;

-       Mitochondrial DNA: also activates different TLR, with a pro-inflammatory effect.

Even without contacting the TLR, these components can directly activate inflammasomes (also inflammatory molecules).

When the mitochondrial mechanisms that regulate homeostasis break, as it happens when we have a massive cell damage (with important traumatic injuries, or cardiac disease, for example); some processes become impaired, such as mitophagy (that eliminates defective mitochondria), and our body senses the DAMPs of the impaired organelles and promotes an unwanted inflammation.

Mitophagy

Mitochondrial quality control relies on different pathways: scavenging of bi-products of its metabolism (reactive oxygen species - ROS); DNA repair; and mitophagy, for example. 

In addition, there is also mitochondrial fusion and fission.

Fusion promotes content mixing between healthy and partially dysfunctional organelles; while fission separates damaged mitochondrial components from  the mitochondrial pool.

Mitophagy is a selective form of macro-autophagy, in which mitochondria are degraded in the autophagolysosome. It eliminates mitochondria that have become dysfunctional: by destroying mitochondria with excessive production of DAMPs, and also limiting the production of molecules that can become harmful, such as reactive oxygen species (ROS). When there is hypoxia, or nutrient deprivation, mitophagy also reduces overall mitochondrial mass, in order to ensure efficient use of scarce metabolites and oxygen, as an adaptive process.

Reactive Oxygen Species

Mitochondria have a main function: ATP production (energy), through oxidative phosphorylation. This process creates a bi-product known as ROS. The main sources of these molecules are the complex I and III, that make the oxidative phosphorylation possible, but complex II also contributes to their production. 

Through continuous stress, or major aggression, this production can be significatively increased, and the inflammatory response can be maintained in a deletary way. This is why there are some trials evaluating the use of anti-oxidants to fight this phenomenom, but its efficacy is still unclear.

Elevated levels of ROS have also been linked to some neurological diseases, namely Parkinson’s disease. It was proposed that reduced levels of dopamine lead to an increased production of ROS, which leads us to think that there can be an inflammatory pathway to the progression of this pathology.

The various pathways that were explained show us the importance of mitochondria as regulators of inflammation, when it is essential to fight some kind of infection; but also underlines their potential to become a trigger of inflammation when it does not need to happen, leading to its nephast consequences in the living organisms. 

04/08/2023