Structural Biochemistry/DNA and Aging

Introduction

The causes of aging and ways to prolong life have always been an interest to many people. Through trials and errors, there had been many theories put forth and denied or accepted by people regarding the phenomenon of aging. Nowadays, there is a general agreement that aging is in fact a multi-factorial process that is not created by some genetic program but is influenced by certain genes.

There are now theories that specific mutations could prolong the life span drastically. For example, the experiment of reduced insulin signaling prolongs the life span of worms, flies and mice. The reduced insulin signaling suggests that it could be a conserved longevity pathway that came about evolutionarily.

For human beings, it is found that the mitochondrial dysfunction heavily impacts the multi-factorial aging process. Aging is a result of the increased levels of somatic mtDNA mutations because those mutations undergo clonal expansion. The expansion then forces mosaic respiratory chain deficiency in various tissues like the heart, brain, skeletal muscles,, and gut, thus showing that somatic mtDNA mutations and mosaic respiratory chain dysfunction are somehow implicated in the multi-factorial aging process. It has been shown experimentally that the increased levels of somatic mtDNA mutations could cause premature aging.

mtDNA

mtDNA, short for mitochondrial DNA, is strongly associated with human aging because of the damages it acquire over time as well as the results of clonal expansion and mosaic respiratory chain deficiency. The two strands of mtDNA are categorized by their different base compositions as the heavy strand and the light strand.

mtDNA’s replication, transcription, and translation processes are encoded by nuclear genes and then imported into the mitochondria where the mitochondria’s own ribosomes take charge. It is important to note that the replication, transcription, and translation processes of the mtDNA is very different from the same processes of DNA: in fact, the processes take place within the same mitochondrial matrix without separation. Hence, there is coupling involved when transcription and translation takes place.

mtDNA Transcription

Transcription of the mtDNA is extremely necessary for the gene expression of mtDNA. It also produces the RNA primers needed to begin the initiation of the mtDNA replication at the origin of the heavy strand (as indicated in the next section: mtDNA Replication). For mtDNA transcription to occur, there are three major factors that are sufficient and necessary:

1. Mitochondrial RNA polymerase, known as POLRMT.

2. Mitochondrial transcription factor B2, known as TFB2M, is a paralog of TFB2m, meaning that they are homologs that are in the same species but have different functions. However, TFB2M holds no role in mtDNA transcription but is essential for the integrity of the subunit in the mitochondrial ribosome.

3. Mitochondrial transcription factor A, known as TFAM, is a protein that is extremely necessary for transcription initiation as without it, there is no transcription process taking place. It is also responsible for packaging mtDNA.

mtDNA Replication

There are two models that depict mtDNA replication. The first model that described mtDNA replication for mammals is called the asymmetric replication model because it is based on the studies done by the electron microscopy, biochemical characterizations, and pulse-chase labeling experiments that involved replication intermediates and nucleic acids respectively. The importance of this model lies in the fact that it is dependent on an RNA primer formed by transcription as well as the initiation of the leading-strand replication occurs at the origin of the heavy strand. When the initiation of the leading-strand is two-thirds complete around the mtDNA circle, the initiation of the lagging-strand replication happens as the origin of the light strand is activated.

Another model that recently came about argues that the mtDNA replication occurs with the coupling of the leading-strand and lagging-strand synthesis. It also stressed that the ribonucleotide on the lagging strand plays an important role. Although there are two models that are still debated by scientists nowadays, it is important to note that both models predict an involvement of a limited number of enzymes.

References

Larsson, Nils-Goran. “Somatic Mitochondrial DNA Mutations in Mammalian Aging.” 2010. Annual Review of Biochemistry.