A recent study has suggested that A.Ceratii, a parasite that feeds on small life forms, including the ones that form algal blooms, contains mitochondria that have no mitochondrial DNA, and at least some of this DNA is found in the parasite’s own genetic code. However, a few genes found in humans are missing and replaced with alternatives [1].

What are mitochondria?

Mitochondria, commonly referred to as the “powerhouses of the cell”, are essentially tiny chemical factories in our cells that turn fats and sugars into adenosine triphosphate (ATP), a form of chemical energy. One reason we need to breathe oxygen to live is to keep our mitochondria running.

Mitochondria produce free radicals as a byproduct of energy production, and damaged mitochondria secrete even more free radicals [2]. Free radicals bounce around the interior of the cell and can damage the mitochondrial DNA if they strike it. This can cause more widespread damage, leading to inflammation, cancer, cellular senescence, and other harmful effects [3].

Mitochondria are thought to have originally been individual organisms. According to the widely accepted endosymbiosis theory [4], early mitochondria were consumed by an ancestor of most complex life, including plants and animals, a long time ago. These useful mitochondria were not consumed by our cellular ancestors, and they were allowed to replicate as their host cells divided. Over time, their genetic code has moved to the nucleus, which contains the host cell’s DNA, in order to reduce the risk of damage; however, in humans, there is still an important exception of 13 genes that are vital for energy production.







What is special about this parasite?

Normally, the main vital function of mitochondria has five important structures that are coded for inside the mitochondrial genome: complexes 1, 2, 3, 4, and 5. In this parasite, however, complexes 2, 4, and 5 have been seen working without mitochondrial DNA, while complexes 1 and 3 have been replaced by other proteins with a similar function.

So far, no other lifeform has been seen with working mitochondria (containing each of these complexes or a similar protein) that do not possess mitochondrial DNA, making this parasite unique.

Why is this important?

This is the only natural example of mitochondria that have successfully had all of their vital DNA removed while remaining functional; mimicking this is the goal of MitoSENS, a SENS Research Foundation project that has been crowdfunded on Lifespan.io [5]. Moving our mitochondrial DNA to our nuclei is a proposed way to defeat mitochondrial dysfunction, which is one of the hallmarks of aging.







Complex 4 has been considered a significantly difficult complex to transfer through this method. However, since it and Complex 2 have been already transferred in this parasite, its genetic material may be useful for the development of a future gene therapy. MitoSENS has achieved the transference of Complex 5, which leaves only complexes 1 and 3 without any instances of being expressed without mitochondrial DNA in nature.

In a webinar with scientists from the SENS Research Foundation, it was revealed that at least one subunit-coding gene of complex 1 has been successfully transferred to the host cell genome in an as-of-yet unpublished paper, suggesting an optimistic outlook for the possibility of transferring more of these genes.

A word from Dr. Aubrey de Grey

The founder of the SENS Research Foundation, Dr. Aubrey de Grey, who invented the concept of mitoSENS, provided LEAF with the following comments about the discovery:

This is a remarkable discovery, which completes a series of findings of this nature, the previous of which was the identification a few years ago of another protist that had found a way to dispense with Complex III. Unlike that case (and the much longer-known case of Complex I in yeast), this example may have relevance to our goal of creating backup copies of the human mitochondrial DNA in the nucleus, because here the enzyme (Complex IV) has not been lost – the genes encoding its most hard-to-import subunits have, it seems, genuinely been transferred to the nuclear DNA in a functional form. Let’s hope that further study of this species uncovers more about how import is achieved.

Conclusion







Overall, this discovery should hopefully make it easier to develop a therapy to treat this aging process.

Of the five vital complexes coded for by mitochondrial DNA, the movement of complex 4 to the host cell nucleus opens the possibility of the genetic material of this parasite being useful for the development of future medicines. The fact that this is even possible is encouraging for the development of mitoSENS, leaving only two of the five vital proteins – Complex 1 and Complex 3 – without any natural example of genetic transfer.

However, Complex 1 contains a large number of subunits still found in the mitochondria – 7 of the 13 subunits – so while this is an important step, there is still a long way to go before mitoSENS could become a reality.

Literature







[1] John, U., Lu, Y., Wohlrab, S., Groth, M., Janouškovec, J., & Kohli, G. et al. (2019). An aerobic eukaryotic parasite with functional mitochondria that likely lacks a mitochondrial genome. Science Advances, 5(4), eaav1110. doi: 10.1126/sciadv.aav1110

[2] Guo, C., Sun, L., Chen, X., & Zhang, D. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regeneration Research, 8(21), 2003.

[3] Reuter, S., Gupta, S. C., Chaturvedi, M. M., & Aggarwal, B. B. (2010). Oxidative stress, inflammation, and cancer: how are they linked?. Free Radical Biology and Medicine, 49(11), 1603-1616.

[4] Archibald, J. M. (2015). Endosymbiosis and eukaryotic cell evolution. Current Biology, 25(19), R911-R921.

[5] Boominathan, A., Vanhoozer, S., Basisty, N., Powers, K., Crampton, A. L., Wang, X., … & O’Connor, M. S. (2016). Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic acids research, 44(19), 9342-9357.





