The Electron Transport Chain, DNA and aging - does evolution intentionally expose the Electron Transfer Process to mitochondrial DNA damage?
The Electron Transport Chain has five complexes. These are comprised of a number of subunits. What I find particularly interesting is that some of the proteins are generated via nuclear DNA and some of the proteins are generated via mitochondrial DNA.
Most of the ROS (that damages mtDNA) is generated by Complexes 1 and 3. Complex 1 has 45 subunits in humans, but in fact only 7 of those (ND1, ND2, ND3, ND4, ND4L, ND5, ND6) are encoded by the mitochondrial genome. Complex 3, however, has 11 subunits only 1 of which is in mtDNA (MT-CYB)
Complex 2 is entirely coded by the nucleus, Complex 4 has 3 (MT-CO1, MT-CO2, and MT-CO3) out of 13 units coded in mtDNA. ATP Synthase also called Complex 5 has 16 units two of which are encoded in the mitochondria.
Hence it is clear that complex 1 is perhaps the key complex for mtDNA mutation linked aging and not surprising that this is the complex inhibited in Oocytes.
There is an argument that for hydrophobic subunits the energy cost of transferring them to the mitochondria is such that it is worth having them in the mitochondria, but that also makes them vulnerable to a much greater level of mitochondrial DNA damage. In Complex I, however, NDUFA1 to NDUFA13, NDUFB1 to NDUFB11, NDUFC1 and NDUFC2. (31 in total) which are not involved in electron transfer are nuclear encoded. In Complex II everything is encoded in the nucleus. In Complex III UQCR10, UQCRH and UQCRB are hydrophobic, but in the nucleus. COX6A, COX6B, COX7A, COX7B and COX8A are nuclear encoded and hydrophobic in complex IV.
A logical and interesting conclusion of this is that actually keeping the subunits in the nucleus is better notwithstanding the energy and time requirements unless the cell wishes to expose them to mitochondrial damage.
Edit 2/4/25
Developmental mitochondrial complex I activity determines lifespan is a paper which goes towards confirming the above.
Most of the ROS (that damages mtDNA) is generated by Complexes 1 and 3. Complex 1 has 45 subunits in humans, but in fact only 7 of those (ND1, ND2, ND3, ND4, ND4L, ND5, ND6) are encoded by the mitochondrial genome. Complex 3, however, has 11 subunits only 1 of which is in mtDNA (MT-CYB)
Complex 2 is entirely coded by the nucleus, Complex 4 has 3 (MT-CO1, MT-CO2, and MT-CO3) out of 13 units coded in mtDNA. ATP Synthase also called Complex 5 has 16 units two of which are encoded in the mitochondria.
Hence it is clear that complex 1 is perhaps the key complex for mtDNA mutation linked aging and not surprising that this is the complex inhibited in Oocytes.
There is an argument that for hydrophobic subunits the energy cost of transferring them to the mitochondria is such that it is worth having them in the mitochondria, but that also makes them vulnerable to a much greater level of mitochondrial DNA damage. In Complex I, however, NDUFA1 to NDUFA13, NDUFB1 to NDUFB11, NDUFC1 and NDUFC2. (31 in total) which are not involved in electron transfer are nuclear encoded. In Complex II everything is encoded in the nucleus. In Complex III UQCR10, UQCRH and UQCRB are hydrophobic, but in the nucleus. COX6A, COX6B, COX7A, COX7B and COX8A are nuclear encoded and hydrophobic in complex IV.
A logical and interesting conclusion of this is that actually keeping the subunits in the nucleus is better notwithstanding the energy and time requirements unless the cell wishes to expose them to mitochondrial damage.
Edit 2/4/25
Developmental mitochondrial complex I activity determines lifespan is a paper which goes towards confirming the above.
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