‘Unique-parental’ inheritance of mitochondria
INTRODUCTION
Mitochondria, also known as the ‘powerhouse of the cell’, are cellular machines that provide our bodies with the energy we require to perform various activities ranging from going on adventurous hikes to typing articles about mitochondrial inheritance. Apart from their ability to produce the fuel we need to perform everyday tasks, they also house their own unique DNA. The discovery of the presence of DNA outside the nucleus of a cell was first made in 1963 by a couple, Margit and Sylvan Nass at the Stockholm University, after spending hours observing cells under an electron microscope.
The mitochondrial DNA (mtDNA) accounts for only 37 of the total 20,000 to 25,000 genes that are expressed in our cells. However, what makes the mtDNA so special is that in almost all of us, it is solely inherited from our mothers. This uni-parental inheritance pattern makes mitochondria useful markers for genetic testing companies like 23andme and Ancestry® to study several generations worth of an individual’s maternal lineage — wherein the “mitochondrial eve” (a specific woman from whom a population of humans inherited their mtDNA) of an individual can be traced.
Many unicellular and most multi-cellular organisms inherit mitochondria maternally. The mechanisms by which organisms achieve this vary. For example, in humans, most of the paternal mitochondria reside at the base of the sperm tail and upon fertilization, the sperm loses its tail thereby losing most of the paternal mtDNA. If paternal mitochondria enter the egg during fertilization, they are eliminated with the help of specific ‘mitochondrial destroying’ enzymes. The ones that manage to evade these enzymes would end up being extremely diluted inside the egg because the egg contains close to 200,000 mtDNA molecules while the sperm contains an average of just 5.
However, paternal and bi-parental mitochondrial inheritance is not completely absent in nature. Paternal mitochondrial inheritance has been observed in a few multi-cellular organisms (bivalve mollusks, honeybees, fruit flies and periodical cicadas) as well as in some mammals under specialized lab conditions. For example, lab-grown mice, sheep, and cloned cattle have shown to take in paternal mitochondria during in-vitro fertilization experiments. Bi-parental inheritance is also observed in some mushrooms and yeasts like Saccharomyces cerevisiae. In a recent human study, it was discovered that 17 individuals from three unrelated families inherited mtDNA from both parents. Why maternal mitochondrial inheritance occurs more frequently than paternal or bi-parental mitochondrial inheritance is still an open question. Some scientists speculate that uni-parental mitochondrial inheritance could have evolved as a survival strategy to prevent the propagation of selfish mitochondria that would arise from a mixed population.
Interestingly, a recent study from the Indian Institute of Science, published in the Journal of Cell Biology, discovered a unique inheritance pattern in Schizosaccharomyces pombe, also known as “fission yeast”, which is a species of yeast used in traditional brewing. At the end of sexual reproduction, two of the four progeny inherit mitochondria from one parent while the remaining two progeny inherit mitochondria from the other parent. This inheritance pattern is unlike the conventional uni or bi-parental inheritance because not all the resulting progeny inherit mitochondria from a single parent, but at the same time, none of the progeny inherit mitochondria from both parents. The authors discovered that this ‘unique-parental’ mitochondrial inheritance occurs because of a specialized mitochondrial associated protein named, Mcp5.
KEY POINTS FROM THE PAPER
1. When fission yeast cells undergo sexual reproduction i.e when h+ and h- (opposite mating types) cells come together and fuse, their respective nuclei unite, causing their nuclear material to mix and thereby producing offspring of varying genetic material similar to the variation observed in human siblings.
2. Interestingly, during the entire process of sexual reproduction, the mitochondria of the h+ and h- cells remain separated and thereby don’t mix as the nuclear material does.
3. A cell membrane-bound protein named, ‘Mcp5’ is known to aid nuclear movement (shown in the 1st video) during sexual reproduction through its attachment to a force-generating protein named ‘dynein’. Here the authors show that interestingly, Mcp5 additionally functions as an anchor for mitochondria by physically attaching to it.
4. This attachment of Mcp5 to the mitochondria prevents mitochondria from mixing during sexual reproduction because in the absence of Mcp5 (even in a single cell), the mitochondria from the two cells eventually mix.
5. The membrane-bound Mcp5 is known to bind to dynein through its coiled-coil domain — which is the region of the protein facing the inside of the cell. Removal of this domain leads to mitochondrial mixing.
This finding indicates the existence of heterogeneous populations of Mcp5 — one that attaches to the mitochondria and the other to dynein. Thus, upon deletion of dynein from the cell, increased mitochondrial segregation is observed. This is likely due to the presence of more Mcp5 participating in mitochondrial attachment.
6. Since the mitochondria of the two cells do not mix, their respective mtDNA do not mix either. Cells without mtDNA tend to grow incredibly slow compared to the ones that have mtDNA. Therefore when a cell with mtDNA mates with one without mtDNA, they end up producing progeny in which two of the offspring that inherited mitochondria from the parent without mtDNA grow much slower than the remaining two offspring.
CONCLUSION
Mitochondria, for the most part, are maternally inherited with a few exceptions which either exhibit paternal or bi-parental mitochondrial inheritance. Conversely, in fission yeast, 50% of the offspring from sexual reproduction inherit mitochondria from one parent while the remaining inherit mitochondria from the other parent. This ‘unique-parental’ mitochondrial inheritance is aided by the membrane-bound protein, Mcp5 whose only known function previous to this finding, was to bind to dynein and enable the mixing of nuclear DNA.
What remains to be answered is the consequence of mitochondrial mixing in the absence of Mcp5 and will this pave the way to understand why uni-parental inheritance evolved in the first place?
REFERENCES
1) Chacko, L. A., Mehta, K., & Ananthanarayanan, V. (2019). Cortical tethering of mitochondria by the anchor protein Mcp5 enables uniparental inheritance. The Journal of Cell Biology, jcb.201901108.
2) Ken Sato, Miyuki Sato, Multiple ways to prevent transmission of paternal mitochondrial DNA for maternal inheritance in animals, The Journal of Biochemistry, Volume 162, Issue 4, October 2017, Pages 247–253, https://doi.org/10.1093/jb/mvx052
3) Luo, S., Valencia, C. A., Zhang, J., Lee, N.-C., Slone, J., Gui, B., et al. (2018). Biparental Inheritance of Mitochondrial DNA in Humans. Proc Natl Acad Sci USA, 115(51), 13039–13044. http://doi.org/10.1073/pnas.1810946115
