We often hear that stress can be unsettling as it could make us ill when it becomes chronic and overwhelming. However, is there really a biological ratification behind it? Is it scientifically founded? Apparently, independent studies hinted a biological connection indicating how stress can cause biological damage, and eventually lead to certain ailments. And, the mitochondrial DNA — the genome in the mitochondrion appears to play a role.
Biological features of mitochondria
The mitochondrion (plural: mitochondria) is an organelle that supplies molecular energy for various biological activities. In essence, this rod-shaped structure found within the cell accounts for the generation of ATP, the cell’s major energy source. Thus, the mitochondrion is known to be the “powerhouse of the cell“.
Through the process of cellular respiration, glucose (a monosaccharide) is “churned” to extract energy, primarily, in the form of ATP. Firstly, a series of reactions leads to the conversion of glucose to pyruvate. Then, it uses pyruvate, converting it into acetyl coenzyme A for oxidation via enzyme-driven cyclic reaction called Krebs cycle. Finally, a cascade of reactions (redox reactions) involving the electron transport chain leads to the production of ATPs (via chemiosmosis).
The mitochondria have their own genetic material, called mitochondrial DNA. Because of this, the mitochondrion is regarded as semi-autonomous and self-reproducing organelle. It means it can manufacture its own RNAs and proteins. Generally, we inherit the mitochondrial genome maternally, as opposed to the nuclear genome that we inherit from both parents.
Mitochondrial fate during stress
When confronted with a stressful situation, our body responds intrinsically. We tend to breathe fast. The heartbeat goes wild. Our muscles tense up. And, we sweat profusely. All these responses (so-called “fight-or-flight“) can be an arduous task as they abruptly demand energy. When triggered for so long, eventually, we feel exhausted. Sooner or later, stress sets in and it takes its toll on our health.
The mitochondria work for an extended time just to meet up the spike of demand for energy. In effect, they become vulnerable to damage from too much work. Inopportunely, the mitochondria have limited repair mechanisms unlike the nucleus.1 And in the end, it results in the disruption of the organelle, thereby, releasing the mitochondrial DNA into the cytoplasm. Eventually, the genetic material reaches the bloodstream where they become genetic cast-offs.
Mitochondrial DNA cast-offs
The ejected mitochondrial DNA, apparently, becomes genetic wastes and stress might have something to do with this outcome. This theory came about based on a series of studies. Firstly, Gong et al. found that chronic mild stress resulted in mitochondrial damage in hippocampus, hypothalamus, and cortex in mouse brains.2
Secondly, another team of researchers (Lindqvist et al.) reported that individuals who had recent suicide attempt had higher plasma level of freely circulating mitochondrial DNA in blood than those of healthy individuals.3
Thirdly, Martin Picard (a psychobiologist at Columbia University), together with his team, observed similar findings in their participants exposed to a stressful situation. Accordingly, their participants – healthy men and women – were asked to defend themselves against a false accusation. Their blood samples were taken before and after the interview. The researchers found that the mitochondrial DNA in the serum of the participants increased twice 30 minutes after the test. 1 Picard explained that the mitochondrial DNA might have acted like a hormone. Furthermore, he theorized that the ejection of these genetic cast-offs might have mimicked the adrenal gland cells releasing cortisol in response to stress. 1
Mitochondrial DNA as an inflammatory factor
Zhang et al. observed that circulating mitochondrial DNA triggered inflammatory responses. Accordingly, the genetic cast-offs can bind to TLR9 (a receptor) on the immune cell. This binding might have incited the immune cell to respond the same way as they do when reacting with antigens. It might have stimulated the cell to release cytokines that call for other immune cells to the site. 1
So far, these conjectures from independent studies disclose the possible direct biological damage due to stress. There could be a biological insinuation that stress could play a part in the manifestation of ill-health conditions. And, the upsurge of circulating mitochondrial DNA cast-offs is one of them. More information and studies on mitochondrial DNA are delineated on a report on mental health published in Scientific American.
— written by Maria Victoria Gonzaga
1 Sheikh, K. (2018 Sept 13). Brain’s Dumped DNA May Lead to Stress, Depression. Scientific American. Retrieved from https://www.scientificamerican.com/article/brain-rsquo-s-dumped-dna-may-lead-to-stress-depression/
2 Gong, Y. Chai, Y., Ding, J. H., Sun, X. L., & Hu, G. (2011).Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neuroscience Letters, 488 (1): 76-80. https://doi.org/10.1016/j.neulet.2010.11.006
3 Lindqvist, D., Fernström, J., Grudet, C., Ljunggren, L., Träskman-Bendz, L., Ohlsson, L., & Westrin, Å. (2016). Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity. Translational Psychiatry, 6 (12), e971–. http://doi.org/10.1038/tp.2016.236
The alphaproteobacteria have been widely cited as the closest relative– and possibly the prokaryotic ancestor — of the powerhouse of the eukaryotic cell, mitochondria. A team of researchers from Uppsala University in Sweden aimed to identify its prokaryotic ancestral origin. However, their recent findings seemed to contradict this notion.1 The mitochondria may have taken an evolutionary fate that is quite different from the one previously thought. Debates on the endosymbiotic theory remain fierce.
Mitochondria, the cell’s powerhouse
The mitochondria are best known as the powerhouse of eukaryotic cells. Through cellular respiration, the mitochondrion (single form of the plural, mitochondria) is the organelle responsible for generating and supplying energy (e.g. adenosine triphosphate) needed in various metabolic activities of the cell. It is semi-autonomous as it has its own genome. Referred to as mitochondrial DNA, the genetic material contained in the mitochondrion enables the manufacturing of its own RNAs and proteins. The genome of the mitochondrion is distinct from the nuclear genome and this paved the idea that this organelle is possibly derived from a prokaryote through endosymbiosis (endosymbiotic theory).
Mitochondria and the endosymbiotic theory
An endosymbiosis is a form of symbiosis wherein the endosymbiont lives within the body of its host. In terms of evolution, endosymbiosis was used as a basis of the origin of semi-autonomic organelles, such as mitochondria. Referred to as the Endosymbiotic theory, this theory suggests that mitochondria within the eukaryotic cell came about as a result of early endosymbiosis between prokaryotic endosymbionts and the eukaryotic host cell. The proponents of this theory posited that the mitochondria arose from the prokaryotes (particularly, alphaproteobacteria). One of the proofs raised is based upon the ability of the mitochondria to reproduce via a process similar to the prokaryotic binary fission. Another is the mitochondrial DNA being more akin to the prokaryotic genome (as a single circular DNA) than the nuclear genome.2
Ancestral endosymbiont of the mitochondria
To lay further evidence to the endosymbiotic theory, the research team from Uppsala University in Sweden aimed to uncover the identity of the mitochondrial ancestor. They analyzed large amounts of environmental sequencing data from the Pacific and the Atlantic Ocean and found several species that had not yet been identified. They were able to reconstruct the genomes of over 40 alphaproteobacteria.1 These bacteria include the Rickettsiales group, which is commonly cited as the closest relative among other alphaproteobacteria based on genomic studies 3, and possibly where the mitochondria originated from. Also, the Rickettsiales is a group of parasitic prokaryotes. As such, they depend highly on their host cell to survive. However, the Uppsala University research team was unable to pinpoint the mitochondrial ancestor from their recent analyses on the present-day alphaproteobacteria, including Rickettsiales. And based on what their current data suggest, the evolutionary position of the mitochondria would lie outside of the alphaproteobacteria. This means that this group is not the closest relative, and the ancestor from where the mitochondria evolved could have also given rise to the presently-identified alphaproteobacteria.1
Laying a firm basis for the endosymbiotic theory remains a challenging feat at this time. Nevertheless, we cannot simply rest the case just because the new data said otherwise. Researchers should not be disheartened in finding more decisive and fully comprehensive evidence as to the ancestral origin of the mitochondria. Reaching a consensus may still be far off. However, a disparity in evidence-based viewpoints is better than a clash of unfounded words.
— written by Maria Victoria Gonzaga
1 Uppsala University. (2018, April 25). “Redefining the origin of the cellular powerhouse”. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2018/04/180425131841.htm
2 “Endosymbiotic theory”. (n.d.). Biology-Online.org. Retrieved from https://biology-online.org/dictionary/Endosymbiotic_theory
3 Andersson, S. G., Zomorodipour, A., Andersson, J. O., Sicheritz-Pontén, T., Alsmark, U. C., Podowski, R. M., Näslund, A. K., Eriksson, A. S., Winkler, H. H., and Kurland, C. G. (1998). “The genome sequence of Rickettsia prowazekii and the origin of mitochondria”. Nature 396 (6707): 133–140. doi:10.1038/24094