The Role of Mitochondria in Cellular Stress and Disease

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The role of the mitochondria has been referred to most of the time as that of “powerhouses” in the cell, simply for the reason that these are organs responsible for generating energy in cells for proper working. However, their role extends far beyond energy production; simultaneously, they have strong implications for a number of cellular events related to the control of cellular stress responses, apoptosis-programmed cell death, and the maintenance of cellular health. Any defect in the mitochondria may initiate a serial event in which cellular stress is embedded and eventually culminates in a diversity of diseases. Knowing the interrelationship between the mitochondria and cellular stress may help in understanding the mechanisms behind a lot of pathological conditions at the moment, among them being neurodegenerative diseases, metabolic disorders, and inflammatory diseases.

Mitochondria: Guardians of Cellular Homeostasis

Mitochondria are organs having an independent, circular genome, which is maternally inherited and encodes basic constituents of the oxidative phosphorylation apparatus. This apparatus is responsible for generating adenosine triphosphate, the principal form of energy currency in the cell. Along with the generation of ATP, mitochondria take part in the synthesis of some molecules, like iron-sulfur clusters and heme, which play a vital role in various cellular processes.

In light of this fact, one of the most important functions of mitochondria is to maintain cellular redox balance. This balance between the generation of reactive oxygen species and antioxidant defenses within the cell has been considered a determinant of cellular homeostasis. In general, mitochondria slightly produce ROS as by-products during the process of oxidative phosphorylation. These ROS participate in cellular signaling and defense against pathogens. However, when ROS production becomes too large to be effectively cleared by these scavengers, usually triggered by mitochondrial dysfunction, excessive ROS production ensues, leading to oxidative stress that may cause damage to DNA, proteins, and lipids.

Mitochondrial Dysfunction and Oxidative Stress

One prominent feature of most diseases is mitochondrial dysfunction, which is often associated with increased oxidative stress. If mitochondria are damaged or their function is impaired, electron transport via the transport chain will not be so efficient, leading to electron leakage and, hence, overproduction of ROS. In excess, ROS then begins to overwhelm cellular antioxidant defenses, leading to the formation of oxidative stress. The latter, in turn, might further hit back at mitochondria, thus creating a vicious cycle and increasing cellular dysfunction.

Mitochondrial dysfunction and oxidative stress sit at the center of the pathogenesis of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. For example, in Parkinson’s disease, the accumulation of damaged mitochondria and subsequent oxidative stress contribute to dopaminergic neurodegeneration. Much the same, mitochondrial dysfunction in Alzheimer’s disease is believed to be responsible for the formation of amyloid-beta plaques and tau tangles that characterize the disease.

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Mitochondrial Dynamics: Fission, Fusion, and Mitophagy

The mitochondria are dynamic organelles in the sense that they continuously undergo fission (division) and fusion, merging to maintain their function and integrity. Collectively, these processes are referred to as mitochondrial dynamics and are involved in ensuring that mitochondria work correctly.

Mitochondrial fusion enables the mixing of mitochondrial contents to reduce mitochondrial damage by complementing defective mitochondria with functional ones. On the contrary, mitochondrial fusion has to occur for chaperone-mediated removal of damaged mitochondria by mitophagy, a specialized form of autophagy. This ensures that only healthy mitochondria are retained within the cell and thus prevents the buildup of dysfunctional mitochondria that accentuates cellular stress and subsequently leads to disease.

The disruption of mitochondrial dynamics may result in the accumulation of the damaged mitochondria, making them less efficient at producing ATP but more likely to generate ROS. Thus, the levels of oxidative stress would increase, with enhanced possibilities for cell death. More precisely, the balance between mitochondrial fusion and fission is changed in pathologies such as cancer, which subsequently changes cellular metabolism rates and cellular survival rates.

Mitochondria in Apoptosis and Cell Death

Mitochondria are one of the main regulators of apoptosis, a programmed cell death that prevents anomalies in tissue structure and maintains homeostasis by eliminating damaged or dangerous cells. During the process of apoptosis, mitochondria release some pro-apoptotic factors into the cytosol, which include cytochrome c; this initiates the activity of the caspases, enzymes executing programmed cell death.

The choice for apoptosis is tightly regulated by the quality control of mitochondrial dynamics and the fine balance of pro-apoptotic and anti-apoptotic signals in the cell. Under the influence of cellular stress, such as DNA damage, oxidative stress, or nutrient deprivation, this balance is titled towards apoptosis, and cells die. Nevertheless, this process is in fact compromised in some diseases, such as cancer, because it prevents the cells from undergoing apoptosis and, despite the damage, continues to proliferate.

They are also implicated in the process of necrosis, a type of cell death that is basically attributed to the uncontrolled release of cellular contents that subsequently leads to inflammation and tissue damage. In contrast to apoptosis, which is a regulated process, necrosis is usually a consequence of severe mitochondrial dysfunction and the collapse of cellular energy-producing machinery.

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Mitochondria and Inflammation

The mitochondria not only have a role in cell death but also participate in the regulation of inflammation. In the process of self-destruction, mitochondria can release damage-associated molecular patterns, such as mitochondrial DNA, into the cytosol or extracellular space. These DAMPs may induce innate immune responses to activate the production of pro-inflammatory cytokines and activate immune cells.

These organelles have been implicated in a variety of inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, an illness that combines characteristics of rheumatism and erythema, and inflammatory bowel disease. In these conditions, continuous activation of the immune system by mitochondrial DAMPs promotes inflammation and tissue damage.

Furthermore, mitochondrially produced ROS are signaling molecules that can modulate the activity of inflammatory pathways, thus further linking dysfunction to inflammation. Interplay between mitochondria and inflammation is thus another critical frontier in research, since it indicates potential therapeutic targets for treating inflammatory diseases.

Mitochondrial Transfer and Therapeutic Implications

The most fascinating discovery of recent studies is the phenomenon of mitochondrial intercellular transmission. In what became known as horizontal mitochondrial transfer, mitochondria move through various mechanisms, such as tunneling nanotubes, from cell to cell. Mitochondrial transfer rescued mitochondrial function in recipient cells and thus holds some potential for therapeutic applications in conditions characterized by mitochondrial dysfunction.

In neurodegenerative disease models, the transfer of healthy mitochondria to damaged neurons restored cellular function and decreased disease pathology. Likewise, in disorders such as myocardial infection, it has been suggested that mitochondrial transfer might be a means of restoring mitochondrial activity in damaged heart tissue.

Research on the possible therapeutic potential of mitochondrial transfer is still underway, but it nonetheless signals a very promising way forward in combining diseases that are a result of mitochondrial malfunction. Understanding this process better with regard to which molecules are transferred between cells will enable new therapies that use the process to improve the health of cells and eventually cure many diseases.

Conclusion

Mitochondria are key to cell health, and their failure can lead to a host of diseases. Although the roles of mitochondria in processes such as energy production and the maintenance of redox balance appear very isolated, they place them squarely at the center of a host of cellular functions, particularly in apoptosis, inflammation, and cellular stress responses. The interwoven complex relationship of mitochondrial function with disease will hold the key to a new therapeutic strategy that will mitigate the consequences of mitochondrial dysfunction and improve cellular health.

With further research into the intricate mechanisms of how the mitochondria act on cellular stress and disease, there is growing potential to target mitochondria in therapeutic interventions. In the near future, mitochondrial medicine may yield great promise for some of the most challenging diseases of our time by modulating mitochondrial dynamics, preventing oxidative stress, and promoting mitochondrial transfer.

References

  1. Youle, R.J., 2019. Mitochondria—Striking a balance between host and endosymbiont. Science, 365(6454), p.eaaw9855.
  2. Torralba, D., Baixauli, F. and Sánchez-Madrid, F., 2016. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Frontiers in cell and developmental biology, 4, p.107.
  3. Shneyer, B.I., Ušaj, M. and Henn, A., 2016. Myo19 is an outer mitochondrial membrane motor and effector of starvation-induced filopodia. Journal of cell science, 129(3), pp.543-556.
  4. Wilson, C. and González-Billault, C., 2015. Regulation of cytoskeletal dynamics by redox signaling and oxidative stress: implications for neuronal development and trafficking. Frontiers in cellular neuroscience, 9, p.381.
  5. Davis, C.H.O., Kim, K.Y., Bushong, E.A., Mills, E.A., Boassa, D., Shih, T., Kinebuchi, M., Phan, S., Zhou, Y., Bihlmeyer, N.A. and Nguyen, J.V., 2014. Transcellular degradation of axonal mitochondria. Proceedings of the National Academy of Sciences, 111(26), pp.9633-9638.
  6. Sheng, Z.H., 2014. Mitochondrial trafficking and anchoring in neurons: new insight and implications. Journal of Cell Biology, 204(7), pp.1087-1098.
  7. Hoppins, S. and Nunnari, J., 2012. Mitochondrial dynamics and apoptosis—the ER connection. Science, 337(6098), pp.1052-1054.
  8. Youle, R.J. and Van Der Bliek, A.M., 2012. Mitochondrial fission, fusion, and stress. Science, 337(6098), pp.1062-1065.

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