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Mitochondrial DNA levels may underlie human diseases

A new study, published in eLife, has identified mitochondrial DNA levels as a potential biomarker of diseases such as cancer and dementia.

The powerhouse of the cell

Almost every cell in your body contains a mitochondrion. Often called the powerhouses of the cell, mitochondria generate the majority of the energy used by our cells. Therefore, all essential cellular processes require mitochondria. In addition, previous studies have linked mitochondrial dysfunction to multiple diseases, including diabetes and dementia.

Mitochondrial DNA copy number (mtDNA-CN) is a measure of the number of mitochondrial genomes per cell. It represents the ratio of mtDNA to nuclear DNA and can be measured directly from peripheral blood. Previous studies have associated mtDNA-CN levels with many human diseases, including cancer. However, the precise link between blood mtDNA-CN, mitochondrial biology and disease is still unclear. To investigate it further, the team behind the current study carried out both genome-wide association studies (GWAS) and exome-wide association studies (ExWAS). 

Measuring mitochondrial DNA

The researchers developed a novel method named AutoMitoC, which can estimate mtDNA-CN levels from genomic data. The team applied AutoMitoC to 395,781 individuals in the UK Biobank in order to estimate the mtDNA-CN levels of each person.

Next, the scientists performed a GWAS to identify any genetic variants associated with mtDNA-CN levels. The researchers identified 71 loci in total that play a role in determining mtDNA-CN levels. One of these loci was the gene SAMHD1, which is involved in the innate immune response. Individuals that carried a SAMHD1 mutation had much higher mtDNA-CN levels than normal.  

Association with cancer

The team then looked for any associations between mutations in SAMHD1 and disease. Interestingly, they found that individuals with these mutations had a two-fold increased risk of breast cancer.

This finding was incredibly fascinating. Previous studies have suggested that high mtDNA-CN levels have a protective effect and signify healthy mitochondrial function. However, the results of this study found that SAMHD1 mutations are associated with both high mtDNA-CN levels and cancer, contradicting the previous studies. Therefore, the researchers stated that they hope to investigate this further in the future.

Association with dementia

Given that mitochondrial dysfunction has been previously linked to dementia, the team decided to investigate dementia and mtDNA-CN levels. They found that genetic variants linked to low mtDNA-CN levels were associated with increased dementia risk. This is believed to be the first evidence implicating low mtDNA-CN as a causative risk factor for dementia.

These results also revealed blood-based mtDNA-CN as a potential biomarker for dementia. In the future, further work will have to be done to investigate which specific mitochondrial processes are being affected by low mtDNA-CN, and therefore underlie dementia.

Future work

In conclusion, these findings show that mtDNA-CN levels are an important and complex biomarker. There are currently no treatments available for patients suffering from mtDNA depletion disorders. Hopefully, the variants and associations identified in this study will help further develop our understanding of mitochondrial DNA, mitochondrial diseases and be used as targets in future therapies.

Picture credit: SkieTheAce on pixabay

More on these topics

GWAS / Mitochondria / Mitochondrial disease