Today was an amazing lecture by Dr. David Lee about mitochondria and its role in aging. Dr. Lee started with an overview of what mitochondria is and what it does. You may have heard that the origin of mitochondria is bacteria that was engulfed by the cell early in the course of evolution. There are several things that back this «endosymbioic» theory:
- Mitochondria self-replicates
- It has two membranes
- It has its own independent DNA
- The ribosomes are similar to those of bacteria
- The sizes are very alike
- Mitochondrial DNA shares similar to bacterial structural motifs
- The inner mitochondria membrane has a more bacterial-like lipid composition
Mitochondria vary from 0.5 to 10 micrometers in size. Their outer membrane is freely permeable, it let’s in and out proteins less than 5000 daltons. The inner membrane, however is tightly regulated, nothing gets in or out without the special transport. Inner membrane forms cristae that curve inside to maximize the surface for energy production.
Interestingly, there are no mitochondria in erythrocytes, however liver and muscle cells can have thousands. Mitochondria are very dynamic. They fuse and divide rapidly, however it is not known why.
Mitochondria move around to where energy is needed whithin a cell. They are transferred by kinesin-1 and dynein along the microtubules. Mitochondria are abundant close to the endoplasmatic reticulum.
Mitochondria are strictly inherited from the mother. One of the most interesting questions in biology is how the oocyte erases age-related changes from the old mitochondria during the formation of the eggs in the embryo. This rejuvenation process may hold the key to better understanding how aging can be tackled.
A mitochondrion has its one genome, which is formed by two concentric cirles – the heavy and light strains. There are 37 genes: 13 proteins, 2 ribosomal RNAs, 22 transport RNAs. 90% of the DNA is coding, with no introns and only one non-coding region, called D-loop. The genes are polycistronic, which means that one RNA molecule after transcription has several genes that are translated. All 13 proteins are from the electron transport chain, which is the energy production “factory”.
Quite amazingly, the ancestry bacteria had ~400 genes that were transferred to the nucleus, and only 13 stayed. Nobody know why these 13 and why keep its own machinery in the first place, when about 1,100 proteins come from the nucleus into the mitochondria. Moreover, pretty much all of the 13 mitochondria genes are present in the nuclear genome. They are called NUMT – nuclear mitochondria DNA. They are different than the original sequences – fragmented and scattered.
Mitochondria even have their own genetic code, which is different to what the nucleus uses. For example, AGA and AGG sequences of nucleotides in regular DNA “mean” arginine, but in the mitochondria, they “mean” stop-codone. Also, mitochondria has quite complicated transcriptome, there are small regulatory RNAs that act like siRNAs, for example, miR-1 was recently found, a nuclear RNA that regulates transcription in the mitochondria.
Mutation rate in the mitochondria is 10^4 times higher than in the nucleus and are estimated to be 6*10^-8 base pairs per year. There is a lot of debate going on about how to measure mitochondrial mutations. The methodology is much less worked through, compared to the nucleus, which makes the problem much more interesting.
The main question is whether the mitochondrial mutations come from replication infidelity, or from unrepaired damages (from ROS, for example). It can also be both, or something else, as it often happens in reality. However, this question is uite important in regard to aging, because the oxidative damage theory was one of the major ones for a while. However, now the data is accumulating that points that it may not be the dominant reason for why we age. For example, there are not so many G to T transversions that result from oxidative damage to the DNA, compared to deletions. There are also several DNA repair mechanisms: base excision repair, single-strand break repair and mismatch repair.
Then we talked about the bioenergetics – process of energy production by the mitochondria. It is called oxidative phosphorilation. Basically, the mitochondria create a difference in electrical charge between its intermembrane space and the matrix, which is inside the organelle. This difference in potential is used by complex 5 to convert ADP to ATP, cells most used fuel. More than 90% of cell’s ATP is produced in the mitochondria. They use NADH and FADH2 as proton sources. These molecules are produced inside the mitochondria in the course of nutrient processing. The nutrients are carbs, fatty acids and amino acids. Basically, mitochondria burn everything and convert to energy. I would also like to add that mitochondria are also involved in anabolic processes, meaning creating stuff – amino acids, lipids and nucleotides. Mitochondria are essenntial for proliferation.
What else do mitochondria do?
Well, they are responsible for Ca2+ ion concentration maintenance. They act like a buffer and regulate Ca2+ concentration in the cell. Normally, Ca2+ is abundant in the endoplasmatic reticulum, but it can be released in the cytoplasm, and it can go through the mitochondria. There is a uniporter that gets the ions inside the inner membrane. They are popped out by another channel, because the mitochondria have to maintain a difference in the potential.
Mitochondria regulate apoptosis. Upon breakage or leakage they release parts in the cytoplams that can be recognized as foreign material and the cell can trigger an inflammation cascade. So damaged mitochondria are very bad. There are MAVs – mitochondria anti-viral proteins that act when there’s an infection.
There is no concensus in the scientific community regarding mitochondrial DNA methylation patterns. Apparently, they are very diverse.
Mitochondria also produce heme for hemoglobin used by erythrocytes to carry oxygen.
Age-related changes in the mitochondria:
- More mtDNA mutations
- Declined respiration (ATP production)
- Increases ROS production
- Decline in fatty acid metabolism
It is not clear right now if mitochondrial DNA mutations are the source or concequence of aging.
To conclude, I’d like to say that mitochondria are an extremely interesting object for research, because their changes have a strong relationship with aging, however the details of the relationship are yet to be deciphered.