As we age, we lose bits of our genome in tissues such as the skeletal muscle and the brain. These losses, called deletion mutations, gradually erode the function of a cell component called the mitochondrion.
Muscle cells lacking a sufficient number of functional mitochondria to support their contractile function die and this causes a loss of muscle mass.
Gaining a better understanding of the process that causes deletion mutations might help us to prevent or at least delay it.
The overwhelmingly large fraction of our genome (DNA) resides in the cell’s nucleus. The rest, a mere five-millionth of the nuclear genome, is located in the mitochondrion. The age-related deletion mutations accumulate in the mitochondrial genome (mtDNA).
On November 27, researchers from the University of California Los Angeles and the University of Alberta, Canada, reported in the journal Genome Research that — together with the deletions — many mitochondrial genes also became aberrantly expressed. Both deletion mutations and aberrant expression of mtDNA correlated with biological aging in humans and in rodents.
So although mtDNA represents only a small fraction of our genome, its deletion mutations appear to be a major trigger of the decrepitude that comes with old age.
What are mitochondria?
Mitochondria are the powerhouses of the cell. They are where most synthesis of the compound adenosine triphosphate (ATP) happens. ATP is the energy source for all functions of a cell.
mtDNA encodes only a small subset of proteins required for mitochondrial function. Many more mitochondrial proteins are encoded by the nuclear genome, and enter the mitochondria after they are made in the part of the cell lying outside the mitochondrion and the nucleus (i.e. the cytoplasm).
Mitochondria are the descendants of free-living bacteria that our early single-celled ancestors then absorbed. Since then, many of the bacteria’s genes have been transferred to the nuclear genome, leaving behind only a minor rump in the mtDNA. Today, mitochondria can’t survive independently of their host cell.
Individuals inherit their mitochondria only via the mother’s egg. As far as mitochondria are concerned, males are a dead-end, as they are not passed on by sperm cells to the baby. Each one of us shares mtDNA with only a subset of our maternal relatives, for example with the children of our mother’s sister but not with those of our mother’s brother.
By contrast, the nuclear genome comprises two copies of each of our 23 chromosomes, numbered 1 to 23. One chromosome of each pair came to us via our mother’s egg and the other via our father’s sperm. In turn we transmit only one chromosome of each pair to the sperm or eggs made by us. The fusion of a sperm and an egg creates a zygote, a cell with two copies of each chromosome. This cell then divides to generate all the other cells in the baby’s body.
In other words, nuclear and mitochondrial genomes have different ancestries.
DNA, mRNA, and the gene
Each chromosome contains a single long DNA molecule. The molecule has two strands. Each strand is a sequence of four compounds, called bases, and the strands are held together by bonds between pairs of these compounds. These pairings are collectively called base-pairs.
The 23 chromosomes together have 3.2 billion base-pairs. This nuclear genome encodes about 20,000 genes that contain instructions to make proteins, plus another 15,000-20,000 genes that don’t encode for proteins. In contrast, our mtDNA is a mere 16,569 base-pairs long, and has a circular shape. It encodes 13 protein-coding genes and 24 non-coding genes. Most cells, however, contain multiple mitochondria and each mitochondrion contains multiple copies of the mtDNA molecule. Hence the mtDNA can make up 1% or so of a cell’s total DNA.
A gene is a segment of a DNA molecule, typically a few thousand base-pairs long. When a gene is expressed, the cell arranges for the sequence of bases on the DNA to be transcribed to a sequence of bases in a new molecule called messenger RNA (mRNA). The mRNA moves from the nucleus into the cytoplasm, where the cell ‘reads’ it to make new proteins.
For want of a nail, a muscle was lost
Any of the many mtDNA molecules can suffer deletion mutations. A deletion mutation is when one to few thousands of base-pairs become deleted from a gene. The mtDNA that bears deletion mutations is thus smaller in size, and as a result these molecules slowly outcompete non-mutated mtDNA when the cell makes copies of them during reproduction, and ultimately displace them from the mitochondria.
When the number of completely intact mtDNA molecules becomes too low to help the cell make mitochondrial proteins, the mitochondrion stops producing ATP. If the number of functioning mitochondria, i.e. those producing ATP, also becomes too low, the muscle cell is unable to properly contract and dies. This underlies the loss of muscle mass.
Deletion mutations also bring sequences of two different mtDNA genes into contact with each other to create novel chimeric genes. When these genes are expressed, the effects can interfere with the normal mRNA the cell has made from residual intact mtDNA. Thus, deletion mutations can affect the expression of normal mtDNA and thus also indirectly speed up mitochondrial loss.
The researchers compared mRNA of skeletal muscle biopsies from individuals younger than 30 years with those older than 65 years. They found that the older individuals showed a two-fold increase in chimeric mitochondrial mRNA. The chimeric mtRNAs were indeed products of the mtDNA deletion events.
Given that mtDNA deletion mutations and chimeric mRNA are useful predictors of biological age, they can help researchers develop new ways to delay age-related decline in mtDNA quality. Aside from when teenagers enter a liquor store, no one wants their biological age to outpace their chronological age.
D.P. Kasbekar is a retired scientist.
Published – December 25, 2024 05:30 am IST
