Mitochondrial DNA: The Living Legacy Within Us
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Since time-immemorial, conventional wisdom has dictated that humans are strictly creatures of sexual reproduction. Broadly speaking, our genetic composition is a dyad, with half from each parent, and the mechanisms of crossing over, independent assortment as well as genetic recombination have been deeply ingrained within our collective memory since high school. Yet, little do many realise that a vital organelle within our cellular architecture has been constitutively undergoing asexual reproduction for hundreds of millenia. This is the curious case of the mitochondrion, which has, for all intents and purposes, been passed down across generations as a virtually impeccable carbon copy.
Why does this happen?
This phenomenon is put down to a unique hereditary pathway: humans inherit their mitochondria, with their DNA inclusive, exclusively from the maternal oocyte. At the maternal end, the ovum stands out as the most voluminous cell within the human body, equipped with far and away a whole set of organelles as well as cytoplasm in its arsenal as a result of asymmetric cell division. In this sense, resources are disproportionately allocated to a singular egg, whereas the three diminutive polar bodies are discarded later on. Switching gears to the paternal end, sperms turn out to be the tiniest cells within the human body, with most organelles ditched to conserve energy for locomotion. While a sperm does harbour mitochondria within its midpiece, only the nucleus in the head penetrates into and fuses with the ovum, thereby contributing to the zygote’s nuclear DNA.
Mitochondrial Eve
Owing to this unidirectional inheritance, mitochondrial DNA (mtDNA) circumvents the genetic shuffling of paternal recombination, passing down unaltered from mother to offspring. Consider an example: our mitochondrial DNA is an exact replica of our mum’s, which in turn mirrors our maternal grandmother’s. By extension, this means that we share the same mitochondrial DNA with our maternal ancestors. It is exactly this unbroken lineage that enables geneticists to trace the deep matrilineal heritage of the global population back to a single ancestor. In 1987, a group of researchers led by geneticist Rebecca Cann found that global human mtDNA diversity coalesces to one African female, dubbed Mitochondrial Eve, in the region of 145 years back. And, this revelation has now formed part of the cornerstones in favour of the theory that humans originate from Africa.
It is easy to fall into the trap of getting hold of the wrong end of the stick by surmising that Mitochondrial Eve was the primordial female of our species. Nonetheless, this is simply an evolutionary fallacy. In effect, our Mitochondrial Eve is merely one of the many women living in Africa at her time. Nevertheless, she is the sole figure whose unbroken maternal line of descendants managed to survive to the present day. On the other hand, the mtDNA of all other female counterparts were eventually wiped out after falling victim to natural selection.
Mitochondrial DNA
Just the same as any of our typical nuclear DNA, mitochondrial DNA has a double-helix structure comprising the bases adenine (A), thymine (T), guanine (G) and cytosine (C). Yet, it stands out by forming a closed loop or circle in lieu of long, straight lines of chromosomes. At first glance, this might remind us of plasmids in bacteria, which are also small pieces of circular DNA separated from the main nuclear DNA. Nonetheless, mitochondrial DNA are not considered plasmids, in part accounting for the essential roles mitochondrial DNA plays in regulating vital processes of cellular respiration, unlike bacterial plasmids which carry no vital essentiality aside from being a retrofitment. Additionally, a mitochondria has its own ribosomes, called mitoribosomes, to translate specific proteins encoded by mtDNA. Interestingly, mitochondria synthesise enzymes for electron transport chain independently, yet a vast majority of its own proteins are still dependent on nuclear DNA, and have to be imported inside.
Endosymbiosis
The existence of an independent organellar genome remains one of the most intriguing chapters in our evolution. As such, the endosymbiotic theory posits that mitochondria were prokaryotic bacteria of yore, which got ingested by an eukaryotic cell and co-evolved within its lineage for millions of years. Proponents have laid out a few plausible pieces of evidence in support of such a theory. Well, mitochondria are about the same size as prokaryotic cells to start with, and they divide by binary fission - a feature shared with bacteria. Additionally, mitochondria has a DNA which is circular in lieu of linear, which consolidates the proposition that mitochondria carries the direct remnants of their bacterial ancestors. Perhaps the strongest evidence after all is that mitochondria have ribosomes that deploy 30S and 50S subunits, which are traditionally reserved for only the prokaryotes. Conversely, all eukaryotes have evolved to have ribosomes with 40S and 60S subunits.
This has prompted the scientific community to carry out further investigation. Interestingly, there has been a general consensus that mitochondria can neither survive as an independent organism nor reproduce outside its host cell in spite of their remarkable resemblance to ancient organisms. For instance, research by Raval et al. has demonstrated that mitochondria have lost a vast majority of their DNA in their process of transformation because they were not of benefit to the host cell. By connecting the dots, this explains why mitochondria remains dependent on the nucleus despite having its own DNA. Nonetheless, such a postulation remains wobbly owing to a dearth in empirical evidence. Theories aside, it remains highly promising when recent studies have proven that mitochondria can, unlike other organelles, somewhat function outside the cell. In practice, the functional independence of mitochondria has shed light on new therapeutic solutions to treat congenital mitochondrial disorders.
Three-parents embryo
By way of statistics, an estimated 1 in 5000 individuals carries a congenital mitochondrial disease, many of which carry devastating risks of morbidity and mortality. This clinical urgency sparks a new quest in genetic technology, to swap a faulty, fatal mitochondria for a healthy, viable replacement within an embryo. In brief, the new embryo produced will constitute the genetic makeup of three individuals: a father contributing 50% of nuclear DNA, a mother contributing another 50% of nuclear DNA, and another female donor donating a mitochondria, along with the mtDNA. In 2015, the world’s first three-parent baby was born, turning this idea into life. He was evaluated to grow healthily without traces of genetic disorder, and that marked the first instance when mitochondrial replacement therapy was successfully adopted. To date, at least 15 children have been born globally using such a technique. This cutting-edge bio-technological breakthrough has heralded a new era of which we can potentially eradicate fatal congenital mitochondrial disorders from our genetic pool. However, as with any other intervention targeting human subjects, such a technique demands incredible care and caution in compliance with medicoethics.
Conclusion
Taken together, the intricacy of our mitochondria is more than meets the eye, transcending its functions as the powerhouse of the cell. It is the living testament of an ancient curiosity that weather through the test of time. And, it stands as a subtle nexus that links all of us to our common origins, besides serving as a beacon for consolidating the future of healthcare. From ancient endosymbiosis to the modern reality of three-parent embryos, this unique organelle has time and again challenged our traditional understanding of heredity. Ultimately, unravelling the mysteries beneath this tiny cellular engine will enable us to understand our own biology even more.
Citations
Raval, P.K., Martin, W. and Gould, S.B. (2023). Mitochondrial evolution: Gene shuffling, endosymbiosis, and signaling. Science Advances, 9(32). doi:10.1126/sciadv.adj4493.
Stefano, G.B., Pascal Büttiker, Weissenberger, S., Esch, T., Anders, M., Jiri Raboch, Kream, R.M. and Ptacek, R. (2023). Independent and sensory human mitochondrial functions reflecting symbiotic evolution. Frontiers in Cellular and Infection Microbiology, 13. doi:10.3389/fcimb.2023.1130197.
Wen, H., Deng, H., Li, B., Chen, J., Zhu, J., Zhang, X., Yoshida, S. and Zhou, Y. (2025). Mitochondrial diseases: from molecular mechanisms to therapeutic advances. Signal Transduction and Targeted Therapy, [online] 10(1). doi:10.1038/s41392-024-02044-3.
This article was prepared by Low Yi Xian (Tunku Abdul Rahman University).
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